Difference between revisions of "2009 Group 4 Project"

From CellBiology
(Structure)
(Group Reflection)
 
(28 intermediate revisions by 2 users not shown)
Line 7: Line 7:
  
 
===Introduction===
 
===Introduction===
''''Tropmyosin-related kinase receptors''' (also known as ''Trk'' or colloqiually as ''"Terk"'' receptors), are a specific family of Tyrosine kinase receptors originating from the Trk [[#Glossary|oncogene]]. Trk's are present and expressed at low levels, throughout mammalian tissue types and bear particular signifcance in embryological development, maintainence as well as growth of neuronal cell types. <ref name=ejp>EJ, Reichardt LF. “Trk receptors: roles in neuronal signal transduction”. Annu Rev Biochem. 2003;72:609-42</ref><ref name=manny>Manning.G,. Whyte DB, Martinez R, Hunter T, Sudarsanam S. “The protein kinase complement of the human genome”. Science. 2002;298(5600):1912-34. </ref>During embryonic development, expression is significantly higher than in mature mammals as it is in neuronal expression<ref name=HU>Huang EJ, Reichardt LF: Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001, 24. Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/17196523]</ref>. Thus, Trks appear to be a major component of a highly intricate system of receptor complexes that mediate neurotropin and growth factor control of selective cell death or differentiation<Ref name=SO> Sofroniew MV, Howe CL, Mobley WC: Nerve growth factor signaling neuroprotection and neural repair. Annu Rev Neurosci 2001, 24: Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/11520933] </ref>. There are three particular sub-types of receptor within the Trk loci - Trk A, Trk B and Trk C - each of which is characterised by specific differences in structure and discrimination for different Neurotrophin ligands, and thus, distinct functions.<ref name=ejp/>
+
''''Tropmyosin-related kinase receptors''' (also known as ''Trk'' or colloqiually as ''"Terk"'' receptors), are a specific family of Tyrosine kinase receptors originating from the Trk [[#Glossary|oncogene]]. Trk's are present and expressed at low levels, throughout mammalian tissue types and bear particular signifcance in embryological development, maintainence as well as growth of neuronal cell types<ref name=ejp>EJ, Reichardt LF. “Trk receptors: roles in neuronal signal transduction”. Annu Rev Biochem. 2003;72:609-42</ref><ref name=manny>Manning.G,. Whyte DB, Martinez R, Hunter T, Sudarsanam S. “The protein kinase complement of the human genome”. Science. 2002;298(5600):1912-34. </ref>. During embryonic development, expression is significantly higher than in mature mammals as it is in neuronal expression<ref name=HU>Huang EJ, Reichardt LF: Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001, 24. Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/17196523]</ref>. Thus, Trks appear to be a major component of a highly intricate system of receptor complexes that mediate neurotropin and growth factor control of selective cell death or differentiation<Ref name=SO> Sofroniew MV, Howe CL, Mobley WC: Nerve growth factor signaling neuroprotection and neural repair. Annu Rev Neurosci 2001, 24: Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/11520933] </ref>. There are three particular sub-types of receptor within the Trk loci - Trk A, Trk B and Trk C - each of which is characterised by specific differences in structure and discrimination for different Neurotrophin ligands, and thus, distinct functions.<ref name=ejp/>
  
  
 
'''What are neurotrophins?'''
 
'''What are neurotrophins?'''
Neurotrophins are signalling proteins (growth factors) which are expressed mostly during embryological development to regulate neuronal tissue development<Ref name=SO> Sofroniew MV, Howe CL, Mobley WC: Nerve growth factor signaling neuroprotection and neural repair. Annu Rev Neurosci 2001, 24: Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/11520933] </ref>. There are four typical neurotropic factors – Nerve Growth Factor ([[#Glossary|NGF]]), Brain-derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin-4 (NT-4). These factors are believed to regulate selective tissue death via the Trk receptors and the low-affinity neurotrophin receptor p75NTR<Ref name=SO> Sofroniew MV, Howe CL, Mobley WC: Nerve growth factor signaling neuroprotection and neural repair. Annu Rev Neurosci 2001, 24: Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/11520933] </ref>. The Selectivty of NTs for various receptors is indicated in figure 1.
+
Neurotrophins are signalling proteins (growth factors) which are expressed mostly during embryological development to regulate neuronal tissue development<Ref name=SO> Sofroniew MV, Howe CL, Mobley WC: Nerve growth factor signaling neuroprotection and neural repair. Annu Rev Neurosci 2001, 24: Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/11520933] </ref>. There are four typical neurotropic factors – Nerve Growth Factor ([[#Glossary|NGF]]), Brain-derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin-4 (NT-4). These factors are believed to regulate selective tissue death via Trk receptors and the low-affinity neurotrophin receptor p75NTR<Ref name=SO> Sofroniew MV, Howe CL, Mobley WC: Nerve growth factor signaling neuroprotection and neural repair. Annu Rev Neurosci 2001, 24: Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/11520933] </ref>. The Selectivty of NTs for various receptors is indicated in figure 1.
  
 
[[Image: ZSpecificity.jpg|thumb|300px|'''Figure 1''': Specificity of Trk receptors for neurotrophin ligands: [[#Glossary|NGF]] binds significantly with TrkA. [[#Glossary|BDNF]] & NT-4 bind most significantly with TrkB. NT-3 binds most signifcatly with TrkC, however, NT-3 also elicits low-affinity binding with Trk's B and A. ]]
 
[[Image: ZSpecificity.jpg|thumb|300px|'''Figure 1''': Specificity of Trk receptors for neurotrophin ligands: [[#Glossary|NGF]] binds significantly with TrkA. [[#Glossary|BDNF]] & NT-4 bind most significantly with TrkB. NT-3 binds most signifcatly with TrkC, however, NT-3 also elicits low-affinity binding with Trk's B and A. ]]
Line 19: Line 19:
 
*Trk receptors are composed of an extracellular segment that binds polypeptide ligands, transmembrane helix, and cytoplasmic segment where the tyrosine kinase catalytic activity takes place.<ref name=ej>EJ, Reichardt LF. “Trk receptors: roles in neuronal signal transduction”. Annu Rev Biochem. 2003;72:609-42. Retrieved 2 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/12676795?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.SmartSearch&log$=citationsensor/Huang Pubmed]</ref>  
 
*Trk receptors are composed of an extracellular segment that binds polypeptide ligands, transmembrane helix, and cytoplasmic segment where the tyrosine kinase catalytic activity takes place.<ref name=ej>EJ, Reichardt LF. “Trk receptors: roles in neuronal signal transduction”. Annu Rev Biochem. 2003;72:609-42. Retrieved 2 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/12676795?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.SmartSearch&log$=citationsensor/Huang Pubmed]</ref>  
  
*TrK receptors act as dimeric transmembrane proteins. Distally, three cysteine-rich motiffs and two Leucine rich regions form a conserved [[#Glossary|NGF]] binding region which is common to all TrK's near the amino terminus.<ref name=ej>EJ, Reichardt LF. “Trk receptors: roles in neuronal signal transduction”. Annu Rev Biochem. 2003;72:609-42. Retrieved 2 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/12676795?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.SmartSearch&log$=citationsensor/Huang Pubmed]</ref>  
+
*TrK receptors act as dimeric transmembrane proteins. Distally, three cysteine-rich motiffs and two Leucine-rich regions form a conserved [[#Glossary|NGF]] binding region which are common to all TrK's near the amino terminus (Figure 2).<ref name=ej>EJ, Reichardt LF. “Trk receptors: roles in neuronal signal transduction”. Annu Rev Biochem. 2003;72:609-42. Retrieved 2 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/12676795?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.SmartSearch&log$=citationsensor/Huang Pubmed]</ref>  
  
 
*Additionally, the common binding region is flanked by a pair of extracellular immunoglobulin-like domains located proximally to the cell membrane<Ref name=RU> R. Urfer, P. Tsoulfas, L. O'Connell, J.A. Hongo, W. Zhao and L.G. Presta , High resolution mapping of the binding site of TrkA for nerve growth factor and TrkC for neurotrophin-3 on the second immunoglobulin-like domain of the Trk receptors. J Biol Chem 273 (1998), pp. 5829–5840 [http://www.ncbi.nlm.nih.gov/pubmed/9488719]</ref>. The juxtamembrane complex contains a variable amino-acid sequence, which determines ligand bindng affinity and specificity. The localization of these peptides appears to be non-specific in tertiary NGF-TrKA complex structures, however their conformation within this complex indicate direct participation in complex binding<Ref name=RU> R. Urfer, P. Tsoulfas, L. O'Connell, J.A. Hongo, W. Zhao and L.G. Presta , High resolution mapping of the binding site of TrkA for nerve growth factor and TrkC for neurotrophin-3 on the second immunoglobulin-like domain of the Trk receptors. J Biol Chem 273 (1998), pp. 5829–5840 [http://www.ncbi.nlm.nih.gov/pubmed/9488719]</ref>.
 
*Additionally, the common binding region is flanked by a pair of extracellular immunoglobulin-like domains located proximally to the cell membrane<Ref name=RU> R. Urfer, P. Tsoulfas, L. O'Connell, J.A. Hongo, W. Zhao and L.G. Presta , High resolution mapping of the binding site of TrkA for nerve growth factor and TrkC for neurotrophin-3 on the second immunoglobulin-like domain of the Trk receptors. J Biol Chem 273 (1998), pp. 5829–5840 [http://www.ncbi.nlm.nih.gov/pubmed/9488719]</ref>. The juxtamembrane complex contains a variable amino-acid sequence, which determines ligand bindng affinity and specificity. The localization of these peptides appears to be non-specific in tertiary NGF-TrKA complex structures, however their conformation within this complex indicate direct participation in complex binding<Ref name=RU> R. Urfer, P. Tsoulfas, L. O'Connell, J.A. Hongo, W. Zhao and L.G. Presta , High resolution mapping of the binding site of TrkA for nerve growth factor and TrkC for neurotrophin-3 on the second immunoglobulin-like domain of the Trk receptors. J Biol Chem 273 (1998), pp. 5829–5840 [http://www.ncbi.nlm.nih.gov/pubmed/9488719]</ref>.
  
*Further [[#Glossary|NGF]] binding site affinity is generated through collaboration with the p75 protein/neurotrophin receptor ([[p75NTR]])<ref name=Barker>Barker PA. High affinity not in the vicinity? Neuron. 2007 Jan 4;53(1):1-4. Review retrieved from [http://www.ncbi.nlm.nih.gov/pubmed/17196523] </ref>. Furthermore, [[p75NTR]] regulates NT-3-TrkA and NT-4/5-TrkB mediated receptor activation by increasing signal transduction sensitivity of these neurotropins for receptor activation. This is acheived through allosteric distortion of Trk binding regions<ref name=Barker>Barker PA. High affinity not in the vicinity? Neuron. 2007 Jan 4;53(1):1-4. Review retrieved from [http://www.ncbi.nlm.nih.gov/pubmed/17196523] </ref>.
+
*Further [[#Glossary|NGF]] binding site affinity is generated through collaboration with the p75 protein/neurotrophin receptor ([[p75NTR]])<ref name=Barker>Barker PA. High affinity not in the vicinity? Neuron. 2007 Jan 4;53(1):1-4. Review retrieved from [http://www.ncbi.nlm.nih.gov/pubmed/17196523] </ref>. Furthermore, [[p75NTR]] regulates NT-3-TrkA and NT-4/5-TrkB mediated receptor activation by increasing signal transduction sensitivity of these neurotropins for receptor activation. This is achieved through allosteric distortion of Trk binding regions<ref name=Barker>Barker PA. High affinity not in the vicinity? Neuron. 2007 Jan 4;53(1):1-4. Review retrieved from [http://www.ncbi.nlm.nih.gov/pubmed/17196523] </ref>.
  
*intracellularly, Trk shares many of the highy conserved motifs of other tyrosine kinases with some distinct variations. There are 10 conserved tyrosines in the intracellular domain, three of which, are known to contribute to the autoregulatory loop within the kinase region<Ref name= TP> T. Pawson and P. Nash , Protein–protein interactions define specificity in signal transduction. Genes Dev 14 (2000), pp. 1027–1047. [http://www.ncbi.nlm.nih.gov/pubmed/10809663]</ref>. Overall, 8 of the 10 tyrosines contribute to the kinase region, either by regulating kinase activity directly or by inducing adaptor protein binding including those of the [[#Glossary|Ras]] and phosphatidylinositol pathways<Ref name= TP> T. Pawson and P. Nash , Protein–protein interactions define specificity in signal transduction. Genes Dev 14 (2000), pp. 1027–1047. [http://www.ncbi.nlm.nih.gov/pubmed/10809663]</ref>. The two remaining tyrosine residues contribute to second-messenger events coupled by Shc and PLC-γ1 protein and are located outside the kinase domain<Ref name= TP> T. Pawson and P. Nash , Protein–protein interactions define specificity in signal transduction. Genes Dev 14 (2000), pp. 1027–1047. [http://www.ncbi.nlm.nih.gov/pubmed/10809663]</ref>.
+
*Intracellularly, Trk shares many of the highly conserved motifs of other tyrosine kinases with some distinct variations. There are 10 conserved tyrosines in the intracellular domain, three of which, are known to contribute to the autoregulatory loop within the kinase region (Figure 2)<Ref name= TP> T. Pawson and P. Nash , Protein–protein interactions define specificity in signal transduction. Genes Dev 14 (2000), pp. 1027–1047. [http://www.ncbi.nlm.nih.gov/pubmed/10809663]</ref>. Overall, 8 of the 10 tyrosines contribute to the kinase region, either by regulating kinase activity directly or by inducing adaptor protein binding including those of the [[#Glossary|Ras]] and phosphatidylinositol pathways<Ref name= TP> T. Pawson and P. Nash , Protein–protein interactions define specificity in signal transduction. Genes Dev 14 (2000), pp. 1027–1047. [http://www.ncbi.nlm.nih.gov/pubmed/10809663]</ref>. The two remaining tyrosine residues contribute to second-messenger events coupled by Shc and PLC-γ1 protein and are located outside the kinase domain<Ref name= TP> T. Pawson and P. Nash , Protein–protein interactions define specificity in signal transduction. Genes Dev 14 (2000), pp. 1027–1047. [http://www.ncbi.nlm.nih.gov/pubmed/10809663]</ref>.
  
 
===Function===
 
===Function===
 
[[Image: ZTrk stucture.jpg|thumb|300px|'''Figure 2''': Common structural features of Trk receptors: a Trk in dimer complex with various conserved regions and residues. Each Trk (A, B or C) is composed of a number of highly conserved elements. Variability mainly occurs in the ligand binding regions. Variations in binding site affinity can affect phosphorylative domain regions and adaptor protein association differently, thus stimulating different signalling events.]]
 
[[Image: ZTrk stucture.jpg|thumb|300px|'''Figure 2''': Common structural features of Trk receptors: a Trk in dimer complex with various conserved regions and residues. Each Trk (A, B or C) is composed of a number of highly conserved elements. Variability mainly occurs in the ligand binding regions. Variations in binding site affinity can affect phosphorylative domain regions and adaptor protein association differently, thus stimulating different signalling events.]]
  
Trk receptors achieve their function primarily via neuroptrophin signaling. Their role is to bind with neuroptrophin which are a family of closely related proteins taking roles in the regulation of survival of the neurons. There are three types of trk receptors, namely trkA, trkB and trkC. These receptors have different binding affinity to certain types of neurotrophins. Hence, the signalling by these distinct receptors will result in various cellular functions.Trk receptors regulate cell survival, proliferation, axon and dendrite growth and the expression and activity of ion channels and neurotransmitter receptors.<ref name=py>Pyle AD, Lock LF, Donovan PJ. Neurotrophins mediate human embryonic stem cell survival. Nat Biotechnology 1996;24:344–50. Retrieved 13 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/16444268 Pubmed]</ref> TrK also regulate synaptic strength and plasticity in adult nervous system. As a family of tyrosine kinase receptors, TrK receptors are activated and regulated in a similar fashion. TrK receptor signaling is involved in G proteins activation and pathways regulated by MAP kinase, PI3K and PLC.<ref name=me>Melamed et al., A Novel Lymphocyte Singnaling Defect: trk A Mutation in the Syndrome of Congenital Insensitivity to Pain and Anhidrosis (CIPA). Journal of Clinical Immunology, 2004;24:(4)441-448. Retrieved on 13 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/15163901 Pubmed]</ref>
+
Trk receptors achieve their function primarily via neuroptrophin signaling. Their role is to bind with neuroptrophin which are a family of closely related proteins taking roles in the regulation of survival of the neurons. There are three types of trk receptors, namely trkA, trkB and trkC. These receptors have different binding affinity to certain types of neurotrophins (Figure 1). Hence, the signalling by these distinct receptors will result in various cellular functions. Trk receptors regulate cell survival, proliferation, axon and dendrite growth, the expression and activity of ion channels and neurotransmitter receptors<ref name=py>Pyle AD, Lock LF, Donovan PJ. Neurotrophins mediate human embryonic stem cell survival. Nat Biotechnology 1996;24:344–50. Retrieved 13 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/16444268 Pubmed]</ref>. TrK also regulate synaptic strength and plasticity in adult nervous system. As a family of tyrosine kinase receptors, TrK receptors are activated and regulated in a similar fashion. TrK receptor signaling are mainly regulated by MAP kinase, PI3K and PLC pathways.<ref name=me>Melamed et al., A Novel Lymphocyte Singnaling Defect: trk A Mutation in the Syndrome of Congenital Insensitivity to Pain and Anhidrosis (CIPA). Journal of Clinical Immunology, 2004;24:(4)441-448. Retrieved on 13 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/15163901 Pubmed]</ref>
  
  
 
*'''Trk A'''
 
*'''Trk A'''
  
Trk A also known as Neurotrophic tyrosine kinase, receptor, type 1 is a high affinity receptor for nerve growth factor ([[#Glossary|NGF]]). Binding of [[#Glossary|NGF]] to TrK A leads to the recruitment of proteins that interact with specific phosphotyrosine residues in the cytoplasmic domains of Trk receptor A. Such interactions activate signaling pathways, such as the [[#Glossary|Ras]], PI3K, and PLC pathways and result in activation of gene expression, neuronal growth and proliferation.<ref name=py>Pyle AD, Lock LF, Donovan PJ. Neurotrophins mediate human embryonic stem cell survival. Nat Biotechnology 1996;24:344–50. Retrieved 13 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/16444268 Pubmed]</ref><ref name=me>MELAMED  et al., A Novel Lymphocyte Singnaling Defect: trk A Mutation in the Syndrome of Congenital Insensitivity to Pain and Anhidrosis (CIPA). Journal of Clinical Immunology, 2004;24:(4)441-448. Retrieved on 13 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/15163901 Pubmed]</ref>
+
Trk A also known as Neurotrophic tyrosine-kinase receptor (type 1), is a high affinity receptor for nerve growth factor ([[#Glossary|NGF]]). Binding of [[#Glossary|NGF]] to TrK A leads to the recruitment of proteins that interact with specific phosphotyrosine residues in the cytoplasmic domains of Trk receptor A. Such interactions activate signaling pathways, such as the [[#Glossary|Ras]], PI3K, and PLC pathways and result in activation of gene expression, neuronal growth and proliferation<ref name=py>Pyle AD, Lock LF, Donovan PJ. Neurotrophins mediate human embryonic stem cell survival. Nat Biotechnology 1996;24:344–50. Retrieved 13 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/16444268 Pubmed]</ref><ref name=me>MELAMED  et al., A Novel Lymphocyte Singnaling Defect: trk A Mutation in the Syndrome of Congenital Insensitivity to Pain and Anhidrosis (CIPA). Journal of Clinical Immunology, 2004;24:(4)441-448. Retrieved on 13 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/15163901 Pubmed]</ref>
  
  
 
*'''Trk B'''
 
*'''Trk B'''
  
Trk B also known as Neurotrophic tyrosine kinase, receptor, type 2 is a high affinity receptor for brain derived growth factor ([[#Glossary|BDNF]]) and neurotrophin-4 (NT4). Trk B are consisted of 3 isoforms in human central nervous system. The isoform (TK+) is a typical tyrosine kinase receptor, and transduce the [[#Glossary|BDNF]] signal via the common signaling pathways such as Ras-ERK, PI3K, and PLCγ. The other two isoforms, TKT1 and TKT2 are distinct from the typical kinase receptors as the C-terminal sequences are T1 and T2 specific.<ref name=py>Pyle AD, Lock LF, Donovan PJ. Neurotrophins mediate human embryonic stem cell survival. Nat Biotechnology 1996;24:344–50. Retrieved 13 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/16444268 Pubmed]</ref><ref name=me>MELAMED  et al., A Novel Lymphocyte Singnaling Defect: trk A Mutation in the Syndrome of Congenital Insensitivity to Pain and Anhidrosis (CIPA). Journal of Clinical Immunology, 2004;24:(4)441-448. Retrieved on 13 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/15163901 Pubmed]</ref>
+
Trk B also known as Neurotrophic tyrosine-kinase receptor (type 2), is a high affinity receptor for brain derived growth factor ([[#Glossary|BDNF]]) and neurotrophin-4 (NT4). Trk Bs are consisted of 3 isoforms in human central nervous system. The isoform (TK+) is a typical tyrosine kinase receptor, which transduces the [[#Glossary|BDNF]] signal via pathways such as Ras-ERK, PI3K and PLCγ. The other two isoforms, TKT1 and TKT2 are distinct from the typical kinase receptors as the C-terminal sequences are T1 and T2 specific.<ref name=py>Pyle AD, Lock LF, Donovan PJ. Neurotrophins mediate human embryonic stem cell survival. Nat Biotechnology 1996;24:344–50. Retrieved 13 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/16444268 Pubmed]</ref><ref name=me>MELAMED  et al., A Novel Lymphocyte Singnaling Defect: trk A Mutation in the Syndrome of Congenital Insensitivity to Pain and Anhidrosis (CIPA). Journal of Clinical Immunology, 2004;24:(4)441-448. Retrieved on 13 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/15163901 Pubmed]</ref>
  
  
 
*'''Trk C'''
 
*'''Trk C'''
  
Trk C also known as Neurotrophic tyrosine kinase, receptor, type 3 is a high affinity receptor for neurotrophin-3 (NT3). Binding of NT3 on Trk C triggers the neuronal growth from neural stem cells in a process known as neurogenesis. NT3 is particularly important in proprioceptive neuron growth.<ref name=me>MELAMED  et al., A Novel Lymphocyte Singnaling Defect: trk A Mutation in the Syndrome of Congenital Insensitivity to Pain and Anhidrosis (CIPA). Journal of Clinical Immunology, 2004;24:(4)441-448. Retrieved on 13 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/15163901 Pubmed]</ref>
+
Trk C also known as Neurotrophic tyrosine-kinase receptor is a high affinity receptor for neurotrophin-3 (NT3). Binding of NT3 on Trk C triggers the neuronal growth from neural stem cells in a process known as neurogenesis. NT3 is particularly important in proprioceptive neuron growth<ref name=me>MELAMED  et al., A Novel Lymphocyte Singnaling Defect: trk A Mutation in the Syndrome of Congenital Insensitivity to Pain and Anhidrosis (CIPA). Journal of Clinical Immunology, 2004;24:(4)441-448. Retrieved on 13 May 2009 from [http://www.ncbi.nlm.nih.gov/pubmed/15163901 Pubmed]</ref>.
  
  
Line 52: Line 52:
 
*''Trk Defective'':  Overall, Trk defective mice demonstrate a significant reduction in survival over a 30 day period<Ref name=SO> Sofroniew MV, Howe CL, Mobley WC: Nerve growth factor signaling neuroprotection and neural repair. Annu Rev Neurosci 2001, 24: Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/11520933] </ref>. Specifically, such knockouts result in impaired olfactory function, as well as poor pain and thermoception responses. This is attributed to a >70% reduction in neuronal cells in the dorsal root, trigeminal and sympathetic ganglia over this period. Multiple other pathological conditions exist but it is unclear as to whether these are attributable to Trk deficiency or secondary to extremely impaired nervous function<Ref name=SO> Sofroniew MV, Howe CL, Mobley WC: Nerve growth factor signaling neuroprotection and neural repair. Annu Rev Neurosci 2001, 24: Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/11520933] </ref>.
 
*''Trk Defective'':  Overall, Trk defective mice demonstrate a significant reduction in survival over a 30 day period<Ref name=SO> Sofroniew MV, Howe CL, Mobley WC: Nerve growth factor signaling neuroprotection and neural repair. Annu Rev Neurosci 2001, 24: Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/11520933] </ref>. Specifically, such knockouts result in impaired olfactory function, as well as poor pain and thermoception responses. This is attributed to a >70% reduction in neuronal cells in the dorsal root, trigeminal and sympathetic ganglia over this period. Multiple other pathological conditions exist but it is unclear as to whether these are attributable to Trk deficiency or secondary to extremely impaired nervous function<Ref name=SO> Sofroniew MV, Howe CL, Mobley WC: Nerve growth factor signaling neuroprotection and neural repair. Annu Rev Neurosci 2001, 24: Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/11520933] </ref>.
  
*''Trk A defective:'' TrkA defective mice lack the ability to perceive painful and thermoceptive stimuli. This is attributed to the malformation of applicable peripheral sensory neurons during embryonic and post-natal development<ref name=HU>Huang EJ, Reichardt LF: Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001, 24. Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/17196523]</ref>.
+
*''Trk A defective:'' Trk A defective mice lack the ability to perceive painful and thermoceptive stimuli. This is attributed to the malformation of applicable peripheral sensory neurons during embryonic and post-natal development<ref name=HU>Huang EJ, Reichardt LF: Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001, 24. Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/17196523]</ref>.
  
*''Trk B Defective:'' inactivation of the Trk B gene product results in significant neurological deficiencies; poor feeding responses, poor touch perception in addition other behavioural abnormalities. Overall, this is perceived to be due to a >80% depletion of catecholaminergic neurons known to relay sensory input from the  gastrointestinal, cardiovascular and pulmonary systems<ref name=HU>Huang EJ, Reichardt LF: Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001, 24. Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/17196523]</ref>.
+
*''Trk B Defective:'' inactivation of the Trk B gene product results in significant neurological deficiencies, poor feeding responses and poor touch perception. Overall, this is perceived to be due to a >80% depletion of catecholaminergic neurons known to relay sensory input from the  gastrointestinal, cardiovascular and pulmonary systems<ref name=HU>Huang EJ, Reichardt LF: Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001, 24. Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/17196523]</ref>.
  
 
*''Trk C Defective'': Defective mice demonstrate unusual postural responses as well as severely impaired proprioception. It is believed that these deficiencies are attributable to an absolute deficiency of Ia muscle afferents that innervate proprioceptive spindle fibres during embryological development<ref name=HU>Huang EJ, Reichardt LF: Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001, 24. Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/17196523]</ref>.
 
*''Trk C Defective'': Defective mice demonstrate unusual postural responses as well as severely impaired proprioception. It is believed that these deficiencies are attributable to an absolute deficiency of Ia muscle afferents that innervate proprioceptive spindle fibres during embryological development<ref name=HU>Huang EJ, Reichardt LF: Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001, 24. Retreived from [http://www.ncbi.nlm.nih.gov/pubmed/17196523]</ref>.
 
  
 
===Dynamic Process===
 
===Dynamic Process===
  
[[Image: ZTrk copy.jpg|thumb|300px| '''Figure 3''': Overview of dynamic processes shared by Trk receptors. Multiple transduction pathways are employed to illicit specific responses regulating survival and differentiation. The end point of signal transduction is often gene regulation and may involve Calcium second messenger events to preciptate expressor/repressor protein dissociation/association from promoter regions.]] [[#Glossary|NGF]] binding to ligation region facilitates dimerisation of Trk Receptor monomers into the signal transductive unit- activating the kinase unit<ref name=Pat>Patapoutian A, and Reichardt LF. Trk receptors: mediators of neurotrophin action. Current Opinion in Neurobiology 2001; 11:272–280;  Retrieved May 20, 2009, from [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS3-436W778-4&_user=37161&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000004218&_version=1&_urlVersion=0&_userid=37161&md5=61e126fa1dabc85ae170386d18189a9c]</ref>. [[#Glossary|Phosphorylation]] of the autoregulatory loop tyrosines of the cytoplasmic domain further activates the kinase. [[#Glossary|Phosphorylation]] of an additional five tyrosines within this region promotes signalling by providing docking sites for adaptor proteins which regulate signalling-cascade couples. Overall, the purpose of this process appears to be to facilitate down-stream [[#Glossary|phosphorylation]] and gene expression regulation(Eg. upregulation of Neuronal Factor Kappa B) via multiple transductive pathways, many of which, are synonymous with tyrosine kinase receptor activity.<ref name=Pat>Patapoutian A, and Reichardt LF. Trk receptors: mediators of neurotrophin action. Current Opinion in Neurobiology 2001; 11:272–280;  Retrieved May 20, 2009, from [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS3-436W778-4&_user=37161&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000004218&_version=1&_urlVersion=0&_userid=37161&md5=61e126fa1dabc85ae170386d18189a9c]</ref> Thus, the [[#Glossary|autophosphorylation]] of intracellular domain tyrosine residues precipitates the association of second-messenger adaptor proteins which may or may not themselves be phosphorylated in order to illicit the desired signalling event.(see dynamics overview image for some examples in addition to those below)
+
[[Image: ZTrk copy.jpg|thumb|300px| '''Figure 3''': Overview of dynamic processes shared by Trk receptors. Multiple transduction pathways are employed to illicit specific responses regulating survival and differentiation. The end point of signal transduction is often gene regulation and may involve Calcium second messenger events to preciptate expressor/repressor protein dissociation/association from promoter regions.]] [[#Glossary|NGF]] binding to ligation region facilitates dimerisation of Trk Receptor monomers into the signal transductive unit- activating the kinase unit<ref name=Pat>Patapoutian A, and Reichardt LF. Trk receptors: mediators of neurotrophin action. Current Opinion in Neurobiology 2001; 11:272–280;  Retrieved May 20, 2009, from [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS3-436W778-4&_user=37161&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000004218&_version=1&_urlVersion=0&_userid=37161&md5=61e126fa1dabc85ae170386d18189a9c]</ref>. [[#Glossary|Phosphorylation]] of the autoregulatory loop tyrosines of the cytoplasmic domain further activates the kinase. [[#Glossary|Phosphorylation]] of an additional five tyrosines within this region promotes signalling by providing docking sites for adaptor proteins which regulate signalling-cascade couples. Overall, the purpose of this process appears to be to facilitate down-stream [[#Glossary|phosphorylation]] and gene expression regulation(Eg. upregulation of Neuronal Factor Kappa B) via multiple transductive pathways, many of which, are synonymous with tyrosine kinase receptor activity.<ref name=Pat>Patapoutian A, and Reichardt LF. Trk receptors: mediators of neurotrophin action. Current Opinion in Neurobiology 2001; 11:272–280;  Retrieved May 20, 2009, from [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS3-436W778-4&_user=37161&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000004218&_version=1&_urlVersion=0&_userid=37161&md5=61e126fa1dabc85ae170386d18189a9c]</ref> Thus, the [[#Glossary|autophosphorylation]] of intracellular domain tyrosine residues precipitates the association of second-messenger adaptor proteins which may or may not themselves be phosphorylated in order to illicit the desired signalling event (Figure 3).
  
  
 
'''co-operation with p75NTR''': Association with p75NTR(also known as the "low affinity neurotropin receptor") appears to be an integral component of regulation of Trk's. This combination of Trk and p75NTR proteins results in the formation of a high-affinity binding site within the Trk binding region, increasing the responsiveness of receptors for thier ligands<ref name=Barker>Barker PA. High affinity not in the vicinity? Neuron. 2007 Jan 4;53(1):1-4. Review retrieved from [http://www.ncbi.nlm.nih.gov/pubmed/17196523] </ref>. Additionally, coordination with p75NTR has been implicated in a reduction in ubiquitination, delay of internalisation of receptors during sensitisation, and overall decreases the apoptotic potential of cell lines <ref>Barker PA. p75NTR is positively promiscuous: novel partners and new insights. Neuron. 2004 May 27;42(4):529-33. Review. Retrieved from [http://www.ncbi.nlm.nih.gov/pubmed/15157416?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum]</ref> .
 
'''co-operation with p75NTR''': Association with p75NTR(also known as the "low affinity neurotropin receptor") appears to be an integral component of regulation of Trk's. This combination of Trk and p75NTR proteins results in the formation of a high-affinity binding site within the Trk binding region, increasing the responsiveness of receptors for thier ligands<ref name=Barker>Barker PA. High affinity not in the vicinity? Neuron. 2007 Jan 4;53(1):1-4. Review retrieved from [http://www.ncbi.nlm.nih.gov/pubmed/17196523] </ref>. Additionally, coordination with p75NTR has been implicated in a reduction in ubiquitination, delay of internalisation of receptors during sensitisation, and overall decreases the apoptotic potential of cell lines <ref>Barker PA. p75NTR is positively promiscuous: novel partners and new insights. Neuron. 2004 May 27;42(4):529-33. Review. Retrieved from [http://www.ncbi.nlm.nih.gov/pubmed/15157416?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum]</ref> .
 
 
  
 
==Mechanism of ''Trk'' Activation via multiple Signalling pathways==
 
==Mechanism of ''Trk'' Activation via multiple Signalling pathways==
  
Tropomyosine receptor kinases (Trk) enhance neuronal cell growth and differentiation of neurites via the activation of various signalling pathways. PKC, PLCy1, [[#Glossary|Ras]]/MAPK and PI3 are the four well known pathways, which exhibit this activity. The latter process involves the activation of transcription factors that will bind onto a specific target gene, thus trigerring neuronal cell division and/ differentiation via production of specific proteins that inhibit [[#Glossary|apoptosis]]. <ref name=ejp>  
+
Tropomyosine receptor kinases (Trk) enhance neuronal cell growth and differentiation of neurites via the activation of various signalling pathways. PKC, PLCy1, [[#Glossary|Ras]]/MAPK and PI3 are the four well known pathways, which exhibit this activity. The latter process involves the activation of transcription factors that will bind onto a specific target gene, thus trigerring neuronal cell division and/ differentiation via production of specific proteins that inhibit [[#Glossary|apoptosis]] (Figure 3). <ref name=ejp>  
  
  
Line 92: Line 89:
 
===PLC-y<sub>1</sub> Pathway===
 
===PLC-y<sub>1</sub> Pathway===
  
Phospholipase C, comes in many forms and plays and important role in the signal transduction for many processes, including, proliferation, differentiation and motility. Its main function is to hydrolyze phosphatidylinositoldi phosphate (PIP2) into diacylglycerol (DAG) and inositoltriphosphate (IP3). <ref name=phdher> PhD, Hershel Raff. Physiology Secrets. Philadelphia: Hanley & Belfus, 2002.</ref>  This occurs by the activation of the membrane bound receptor by a number of growth factors, cytokines and immunoglobins. <ref name=mandk>Mankidy, R., Hastings, J., & Thackeray, J. (2003). Distinct Phospholipase C-#-Dependent Signaling Pathways in the Drosophila Eye and Wing Are Revealed by a New small wing Allele. Genetics Society of America. 164(2): 553–563.</ref>
+
Phospholipase C, comes in many forms and plays an important role in the signal transduction for many processes, including proliferation, differentiation and motility. Its main function is to hydrolyze phosphatidylinositoldi phosphate (PIP2) into diacylglycerol (DAG) and inositoltriphosphate (IP3). <ref name=phdher> PhD, Hershel Raff. Physiology Secrets. Philadelphia: Hanley & Belfus, 2002.</ref>  This occurs by the activation of the membrane bound receptor by a number of growth factors, cytokines and immunoglobins. <ref name=mandk>Mankidy, R., Hastings, J., & Thackeray, J. (2003). Distinct Phospholipase C-#-Dependent Signaling Pathways in the Drosophila Eye and Wing Are Revealed by a New small wing Allele. Genetics Society of America. 164(2): 553–563.</ref>
 
DAG is necessary for the further activation of the PKC and it remains bound to the cell membrane. IP3, a water soluble protein  , in turn is released into the cytoplasm and leads to the release of Ca2+ reserves from the endoplasmic reticulum. This increase of calcium ions activates the classic isoforms of [[Protein Kinase C]].  <ref name=biothe>Bioengineering; Research from University of Tokyo broadens understanding of bioengineering. (2009,May). Medical Devices & Surgical Technology Week,70.</ref>
 
DAG is necessary for the further activation of the PKC and it remains bound to the cell membrane. IP3, a water soluble protein  , in turn is released into the cytoplasm and leads to the release of Ca2+ reserves from the endoplasmic reticulum. This increase of calcium ions activates the classic isoforms of [[Protein Kinase C]].  <ref name=biothe>Bioengineering; Research from University of Tokyo broadens understanding of bioengineering. (2009,May). Medical Devices & Surgical Technology Week,70.</ref>
  
Line 109: Line 106:
  
 
[[Image:Zani1.gif|thumb|10000x10000px|'''Figure 5''': Simplified Animation of PKC pathway. [http://cellbiology.med.unsw.edu.au/cellbiology/images/4/43/Zgifpath.gif Full size animation] ]]
 
[[Image:Zani1.gif|thumb|10000x10000px|'''Figure 5''': Simplified Animation of PKC pathway. [http://cellbiology.med.unsw.edu.au/cellbiology/images/4/43/Zgifpath.gif Full size animation] ]]
 +
 
===PKC Pathway===
 
===PKC Pathway===
  
 
[http://cellbiology.med.unsw.edu.au/cellbiology/index.php?title=User:Z3189925 '''''See also: Protein Kinase C''''']
 
[http://cellbiology.med.unsw.edu.au/cellbiology/index.php?title=User:Z3189925 '''''See also: Protein Kinase C''''']
  
Protein Kinase C (PKC) is a family of  nucleotide-independent, Ca2+-dependent serine kinases. <ref name=na>Takai, Y., Kishimoto, A., Inoue, M., & Nishizuka, Y. (1977). Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum. J. Biol. Chem., 252(21), 7603-7609. [http://www.ncbi.nlm.nih.gov.viviena.library.unsw.edu.au/pubmed/199594?dopt=Abstract] </ref>. At least 11 [[#Glossary|isozymes]] have been identified, <ref name=peter>Acs, P., Wang, Q., Bogi, K., Marquez, A., Lorenzo, P., Biro, T., Szallai, Z., Mushinski, F., & Blue, P. (1997). Both the Catalytic and Regulatory Domains of Protein Kinase C Chimeras Modulate the Proliferative Properties of NIH 3T3 Cells. J Biol Chem., 272(45), 28793-28799. Retrieved May 15, 2009, from [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=9353351&dopt=Abstract Pubmed]</ref> most PKC [[#Glossary|isozymes]] are ubiquitous and multiple members of the family can be coexpressed within the same cell leading to complex pathways. However, the basic signal transduction pathway involves the allosteric activation of PKC by the intracellular messengers diacylglycerol and Calcium ions. The inactive PKC is mainly found in the cytosol. Upon stimulation the PKC proteins translocate to the cell membrane. This translocation is the result of a cascade initiated by the binding of a number of extracellular ligands, such as, growth factors, hormones, and neurotransmitters to a G protein-coupled receptor (GPRC) found on the plasma membrane. This in turn activates a stimulating G protein which in turn activates phospholipase C (PLC). <ref name=Dekker>Dekker, L (2004). Protein Kinase C (Molecular Biology Intelligence Unit). New York: Springer.</ref> A G protein is then activated, which then activates phospholipase C (PLC). The PLC cleaves phosphoinositol-4,5-bisphosphate (PIP2) into 1,2-diacylglycerol (DAG) and inositol-1.,4,5-triphosphate (IP3). <ref name=promega>Signal Transduction Resource. (n.d.). Retrieved May 15, 2009, from [http://www.promega.com/guides/sigtrans_guide/strg_chap03.pdf Promega] </ref> The  IP3, couples to Ca2+ channels found on the endoplasmic reticulum releasing Ca2+ reserves. The increased concentration of calcium ions bind to inactive PKC molecules and then translocates to the plasma membrane. Here is binds to DAG giving rise to the active PKC enzyme. <ref name=na>Takai, Y., Kishimoto, A., Inoue, M., & Nishizuka, Y. (1977). Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum. J. Biol. Chem., 252(21), 7603-7609. [http://www.ncbi.nlm.nih.gov.viviena.library.unsw.edu.au/pubmed/199594?dopt=Abstract] </ref>  
+
Protein Kinase C (PKC) is a family of  nucleotide-independent, Ca2+-dependent serine kinases. <ref name=na>Takai, Y., Kishimoto, A., Inoue, M., & Nishizuka, Y. (1977). Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum. J. Biol. Chem., 252(21), 7603-7609. [http://www.ncbi.nlm.nih.gov.viviena.library.unsw.edu.au/pubmed/199594?dopt=Abstract] </ref>. At least 11 [[#Glossary|isozymes]] have been identified, <ref name=peter>Acs, P., Wang, Q., Bogi, K., Marquez, A., Lorenzo, P., Biro, T., Szallai, Z., Mushinski, F., & Blue, P. (1997). Both the Catalytic and Regulatory Domains of Protein Kinase C Chimeras Modulate the Proliferative Properties of NIH 3T3 Cells. J Biol Chem., 272(45), 28793-28799. Retrieved May 15, 2009, from [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=9353351&dopt=Abstract Pubmed]</ref> most PKC [[#Glossary|isozymes]] are ubiquitous and multiple members of the family can be coexpressed within the same cell leading to complex pathways. However, the basic signal transduction pathway involves the allosteric activation of PKC by the intracellular messengers diacylglycerol and Calcium ions. The inactive PKC is mainly found in the cytosol. Upon stimulation the PKC proteins translocate to the cell membrane. This translocation is the result of a cascade initiated by the binding of a number of extracellular ligands, such as, growth factors, hormones, and neurotransmitters to a G protein-coupled receptor (GPRC) found on the plasma membrane. This in turn activates a stimulating G protein which in turn activates phospholipase C (PLC). <ref name=Dekker>Dekker, L (2004). Protein Kinase C (Molecular Biology Intelligence Unit). New York: Springer.</ref> A G protein is then activated, which then activates phospholipase C (PLC). The PLC cleaves phosphoinositol-4,5-bisphosphate (PIP2) into 1,2-diacylglycerol (DAG) and inositol-1.,4,5-triphosphate (IP3). <ref name=promega>Signal Transduction Resource. (n.d.). Retrieved May 15, 2009, from [http://www.promega.com/guides/sigtrans_guide/strg_chap03.pdf Promega] </ref> The  IP3, couples to Ca2+ channels found on the endoplasmic reticulum releasing Ca2+ reserves. The increased concentration of calcium ions bind to inactive PKC molecules and then translocates to the plasma membrane, giving rise to the active PKC enzyme. <ref name=na>Takai, Y., Kishimoto, A., Inoue, M., & Nishizuka, Y. (1977). Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum. J. Biol. Chem., 252(21), 7603-7609. [http://www.ncbi.nlm.nih.gov.viviena.library.unsw.edu.au/pubmed/199594?dopt=Abstract] </ref>  
 
The PKC family plays a major role in cellular signal transduction. <ref name=Stein>Steinberg, S. (2008). Structural Basis of Protein Kinase C Isoform Function. Physiol. Rev., 88, 1341-1378. Retrieved October 5, 2009, from [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=18923184&dopt=Abstract Pubmed]</ref>Their main roles consist in the regulation of cell proliferation, differentiation, survival
 
The PKC family plays a major role in cellular signal transduction. <ref name=Stein>Steinberg, S. (2008). Structural Basis of Protein Kinase C Isoform Function. Physiol. Rev., 88, 1341-1378. Retrieved October 5, 2009, from [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=18923184&dopt=Abstract Pubmed]</ref>Their main roles consist in the regulation of cell proliferation, differentiation, survival
 
and [[#Glossary|apoptosis]]. <ref name=breit>D Breitkreutz,  L Braiman-Wiksman,  N Daum,  M F Denning,  T Tennenbaum. (2007). Protein kinase C family: On the crossroads of cell signaling in skin and tumor epithelium. Journal of Cancer Research & Clinical Oncology, 133(11), 793-808.  Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=17661083&dopt=Abstract Pubmed]</ref>
 
and [[#Glossary|apoptosis]]. <ref name=breit>D Breitkreutz,  L Braiman-Wiksman,  N Daum,  M F Denning,  T Tennenbaum. (2007). Protein kinase C family: On the crossroads of cell signaling in skin and tumor epithelium. Journal of Cancer Research & Clinical Oncology, 133(11), 793-808.  Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=17661083&dopt=Abstract Pubmed]</ref>
 
 
 
 
 
 
  
 
===Ras-MAPK (mitogen-activated protein kinase) Pathway===
 
===Ras-MAPK (mitogen-activated protein kinase) Pathway===
  
Activation of Ras-MAPK signalling pathway is predominantly essential for promoting neuronal cell growth and differentiation. <ref name=wip>Wiesmüller L, Wittinghofer F.,“Signal Transduction pathways involving [[#Glossary|Ras]]. Mini Review”.Cellular Signalling.1994;6(3) 247-267. </ref>Several pathways derive from Trk receptors for activation of [[#Glossary|Ras]] molecules, which begin by formation of ligand-bound mitogen ([[#Glossary|BDNF]] or [[#Glossary|NGF]]) at an extracellular domain of the trk, causing receptor dimerization. This subsequently will lead to [[#Glossary|phosphorylation]] of the intracellular parts of the receptors, which activates Guanine Exchange factors (GEFs), such as sos, Grb2 and Shc. GEFs trigger the exchange of GDP bound to inactive [[#Glossary|Ras]] to GTP, resulting [[#Glossary|Ras]] to activate. The presence of activated [[#Glossary|Ras]] molecules, stimulate signaling via a major downstream pathway known as MAP kinase (mitogen-activated protein kinase)-although activated [[#Glossary|Ras]], would be also capable of triggering several other downstream pathways such as PLC-y1 and PI3-kinases (Figure..). <ref name=wip/>
+
Activation of Ras-MAPK signalling pathway is predominantly essential for promoting neuronal cell growth and differentiation<ref name=wip>Wiesmüller L, Wittinghofer F.,“Signal Transduction pathways involving [[#Glossary|Ras]]. Mini Review”.Cellular Signalling.1994;6(3) 247-267. </ref>. Several pathways derive from Trk receptors for activation of [[#Glossary|Ras]] molecules, which begin by formation of ligand-bound mitogen ([[#Glossary|BDNF]] or [[#Glossary|NGF]]) at an extracellular domain of the trk, causing receptor dimerization. This subsequently will lead to [[#Glossary|phosphorylation]] of the intracellular parts of the receptors, which activates Guanine Exchange factors (GEFs), such as sos, Grb2 and Shc. GEFs trigger the exchange of GDP bound to inactive [[#Glossary|Ras]] to GTP, resulting [[#Glossary|Ras]] to activate. The presence of activated [[#Glossary|Ras]] molecules, stimulate signaling via a major downstream pathway known as MAP kinase (mitogen-activated protein kinase)-although activated [[#Glossary|Ras]], would be also capable of triggering several other downstream pathways such as PLC-y1 and PI3-kinases (Figure 4 & 6). <ref name=wip/>
  
Mitogen-activated protein kinase (MAPK) pathway involves a series of signalling cascade. Raf is the first component of MAPK, activated by Ras-GTP on the plasma membrane. <ref name=wip/> Raf then phosphorylates MEK1/2, which in turn activates the ERK1/2 by [[#Glossary|phosphorylation]]. ERK1/2 kinase would further phosphorylate a variety of downstream targets. These pathways may include [[#Glossary|phosphorylation]] of MAP 2-kinase by MAP 3-kinase on its serine and threonine amino-acid residues. Further [[#Glossary|phosphorylation]] of MAP- kinase by MAP 2-kinase on its serine and tyrosine amino-acid residues subsequently yields activated MAP-kinase. This results in activation of transcription factors that will lead to changes in gene expression. <ref name=wip/> <ref name=hap>Harvey, J., and Ashford, M.L.J. “Leptin in the CNS: much more than a satiety signal”. Neuropharmacology. 2003;44, 845-854. </ref>. ([http://www.youtube.com/watch?v=bYioSvT33cA Click here for well illustration of MAP-kinase pathway on You-tube])Nonetheless, aberrant Ras-MAPK signaling has been identified to be a possible factor responsible for the uncontrolled proliferation and malignancy. ''Also see:[[#Current Research|Cancer Biotherapy]]'' .<ref name=hap/>  
+
Mitogen-activated protein kinase (MAPK) pathway involves a series of signalling cascade. Raf is the first component of MAPK, activated by Ras-GTP on the plasma membrane. <ref name=wip/> Raf then phosphorylates MEK1/2, which in turn activates the ERK1/2 by [[#Glossary|phosphorylation]]. ERK1/2 kinase would further phosphorylate a variety of downstream targets. These pathways may include [[#Glossary|phosphorylation]] of MAP 2-kinase by MAP 3-kinase on its serine and threonine amino-acid residues. Further [[#Glossary|phosphorylation]] of MAP- kinase by MAP 2-kinase on its serine and tyrosine amino-acid residues subsequently yields activated MAP-kinase. This results in activation of transcription factors that will lead to changes in gene expression<ref name=wip/> <ref name=hap>Harvey, J., and Ashford, M.L.J. “Leptin in the CNS: much more than a satiety signal”. Neuropharmacology. 2003;44, 845-854. </ref>. ([http://www.youtube.com/watch?v=bYioSvT33cA Click here for well illustration of MAP-kinase pathway on You-tube]). Nonetheless, aberrant Ras-MAPK signaling has been identified to be a possible factor responsible for the uncontrolled proliferation and malignancy. ''Also see:[[#Current Research|Cancer Biotherapy]]'' .<ref name=hap/>  
  
  
Line 139: Line 131:
 
[http://cellbiology.med.unsw.edu.au/cellbiology/index.php?title=3189168 '''''See also: Phosphatidylinositol 3-kinase''''']
 
[http://cellbiology.med.unsw.edu.au/cellbiology/index.php?title=3189168 '''''See also: Phosphatidylinositol 3-kinase''''']
  
The role of PI3K is essential in promoting survival of neuronal cells.<ref name=kr> Krasilnikov MA. Phoshatidylinositol-3 kinase dependent pathways: the role in control of cell growth, survival, and malignant transformation. Biochemistry. Review 2000;65(1):59-67. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/10702641 Pubmed] </ref> PI3K directly activates Ras-dependent pathway through which Trk signaling promotes survival in many, but not all, neurons. Ras-dependent activation of PI3K is the most important pathway through which neurotrophins promote cell survival. In some cells, however, PI3K can also be activated through three adaptor proteins, Shc, Grb-2 and Gab-1. PI3K has an array of main effectors which include the mitogen-transducing signal proteins such as protein kinase C, phosphoinositide-dependent kinases and mitogen activated protein kinases. They are activated either via their interaction with lipid products of PI3K or through PI3K-dependent [[#Glossary|phosphorylation]] of proteins.<ref>Kapeller R, and Cantley LC. Phosphatidylinositol 3-kinase. Bioessays. 1994;16(8):565-576. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/8086005]</ref> PI3K is activated by number of growth factor receptors with intrinsic and tyrosine kinase activity. BAD is an important protein in controlling cell survival and is a Bcl-2 family member which promotes [[#Glossary|apoptosis]] by binding to Bcl-xL. When BAD are phosphorylated by Akt or MAPKs, it involves in the regulation of signal transduction in neuronal cells <ref> Stephens LR, Jackson TR, and Hawkins PT. Agonist-stimulated synthesis of phosphatidylinosital(3,4,5)-triphosphate: a new intracellular signaling system? Biochim Biophys Acta 1993;1179(1):27-75. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/8399352 Pubmed]</ref> On the other hand, PI3K/Akt signal transduction cascade is predominantly important in the formation of neuronal tumours. This cascade promotes the growth and proliferation of cancer cells and its components represent attractive targets for the design of anticancer agents. mTOR which is a serine/threonine kinase acts on the downstream activation of PI3K for the mediation of prosurvival activity. This will inhibit [[#Glossary|apoptosis]], resulting in the formation of cancer cells.<ref name=kr> Krasilnikov MA. Phoshatidylinositol-3 kinase dependent pathways: the role in control of cell growth, survival, and malignant transformation. Biochemistry. Review 2000;65(1):59-67. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/10702641 Pubmed] </ref><ref>Kapeller R, and Cantley LC. Phosphatidylinositol 3-kinase. Bioessays. 1994;16(8):565-576. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/8086005]</ref>
+
The role of PI3K is essential in promoting survival of neuronal cells.<ref name=kr> Krasilnikov MA. Phoshatidylinositol-3 kinase dependent pathways: the role in control of cell growth, survival, and malignant transformation. Biochemistry. Review 2000;65(1):59-67. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/10702641 Pubmed] </ref> PI3K directly activates Ras-dependent pathway through which Trk signaling promotes survival in many, but not all, neurons. In some cells PI3K can be activated through three adaptor proteins, Shc, Grb-2 and Gab-1. PI3K has an array of main effectors, which include the mitogen-transducing signal proteins such as protein kinase C, phosphoinositide-dependent kinases and mitogen activated protein kinases. They are either activated via interaction with lipid products of PI3K or through PI3K-dependent [[#Glossary|phosphorylation]] of proteins.<ref>Kapeller R, and Cantley LC. Phosphatidylinositol 3-kinase. Bioessays. 1994;16(8):565-576. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/8086005]</ref> PI3K is activated by number of growth factor receptors with intrinsic and tyrosine kinase activity. BAD is an important protein in controlling cell survival and is a Bcl-2 family member which promotes [[#Glossary|apoptosis]] by binding to Bcl-xL. When BAD are phosphorylated by Akt or MAPKs, it involves in the regulation of signal transduction in neuronal cells <ref> Stephens LR, Jackson TR, and Hawkins PT. Agonist-stimulated synthesis of phosphatidylinosital(3,4,5)-triphosphate: a new intracellular signaling system? Biochim Biophys Acta 1993;1179(1):27-75. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/8399352 Pubmed]</ref> On the other hand, PI3K/Akt signal transduction cascade is predominantly important in the formation of neuronal tumours. This cascade promotes the growth and proliferation of cancer cells and its components represent attractive targets for the design of anticancer agents. mTOR which is a serine/threonine kinase acts on the downstream activation of PI3K for the mediation of prosurvival activity. This will inhibit [[#Glossary|apoptosis]], resulting in the formation of cancer cells.<ref name=kr> Krasilnikov MA. Phoshatidylinositol-3 kinase dependent pathways: the role in control of cell growth, survival, and malignant transformation. Biochemistry. Review 2000;65(1):59-67. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/10702641 Pubmed] </ref><ref>Kapeller R, and Cantley LC. Phosphatidylinositol 3-kinase. Bioessays. 1994;16(8):565-576. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/8086005]</ref>
  
 
==Current Research==
 
==Current Research==
  
 
===Cancer biotherapy via targeting ‘Ras / Ras-MAP-kinase’ signalling pathway===
 
===Cancer biotherapy via targeting ‘Ras / Ras-MAP-kinase’ signalling pathway===
Recent studies have hypothesized that receptors responsible for Ras activation would be effective target for treating human cancers. <ref name=wip/>Based on this hypothesis, since 1995, therapies utilizing the inhibition of Ras activation have aroused a major interest. Farnesylation is a process by which small G-proteins like Ras are activated and adhered to the cell membrane. In a recent paper <ref name=kohl>Kohl,N.E., Omer C.A., Conner MW., Anthony NJ, Davide JP, deSolms SJ, Giuliani EA, Gomez RP., Graham SL., Hamilton K., “Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice”. Nat Med (1995).1(8): 792-7. </ref>, [[#Glossary|farnesyl transferase inhibitors]] were used in order to block the farnesylation of Ras proteins. The results revealed promising hopes in animal models but unfortunately have not been effective in human cancer treatment.<ref name=kohl/> The major downstream target of Ras-MAP-Kinase (MAPK) has also been taken as a subject for drug design. Sebolt and his colleagues showed that MAPK-inhibitors are effective in cancer therapy using mouse models <ref name=sebol> Sebolt,J.S,. Dudley D.T,. Herrera.R, Van Becelaere.K, Wiland A, Gowan RC, Tecle H, Barrett SD, Bridges A, Przybranowski.S,. Leopold WR. Saltiel A.R,. “Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo”. Nat Med. (1999).5(7): 810-6.</ref> . It has been also suggested that Inhibition of the Ras-MAPK signaling pathway can serve as a potential therapy for NF1 in humans. <ref name=sep> Sebti S.M., Hamilton A.D,. “Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: lessons from mechanism and bench-to-bedside translational studies”. Oncogene.(2000).19(56): 6584-93.</ref>
+
Recent studies have hypothesized that receptors responsible for Ras activation would be effective target for treating human cancers<ref name=wip/>. Based on this hypothesis, since 1995, therapies utilizing the inhibition of Ras activation have aroused a major interest. Farnesylation is a process by which small G-proteins like Ras are activated and adhered to the cell membrane. In a recent paper <ref name=kohl>Kohl,N.E., Omer C.A., Conner MW., Anthony NJ, Davide JP, deSolms SJ, Giuliani EA, Gomez RP., Graham SL., Hamilton K., “Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice”. Nat Med (1995).1(8): 792-7. </ref>, [[#Glossary|farnesyl transferase inhibitors]] were used in order to block the farnesylation of Ras proteins. The results revealed promising hopes in animal models but unfortunately have not been effective in human cancer treatment<ref name=kohl/>. The major downstream target of Ras-MAP-Kinase (MAPK) has also been taken as a subject for drug design. Sebolt and his colleagues showed that MAPK-inhibitors are effective in cancer therapy using mouse models <ref name=sebol> Sebolt,J.S,. Dudley D.T,. Herrera.R, Van Becelaere.K, Wiland A, Gowan RC, Tecle H, Barrett SD, Bridges A, Przybranowski.S,. Leopold WR. Saltiel A.R,. “Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo”. Nat Med. (1999).5(7): 810-6.</ref> . It has been also suggested that Inhibition of the Ras-MAPK signaling pathway can serve as a potential therapy for NF1 in humans. <ref name=sep> Sebti S.M., Hamilton A.D,. “Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: lessons from mechanism and bench-to-bedside translational studies”. Oncogene.(2000).19(56): 6584-93.</ref>
  
 
===''Trk'' receptors can behave as signalling endosomes===
 
===''Trk'' receptors can behave as signalling endosomes===
Line 152: Line 144:
 
===The interplay between miRNA and ''Trk''s (''tropomyosin-related kinases'')===
 
===The interplay between miRNA and ''Trk''s (''tropomyosin-related kinases'')===
  
MicroRNAs are tissue specific, small non-coding RNAs, which are involved in post-trancriptional-silencing mechanism ([http://cellbiology.med.unsw.edu.au/cellbiology/index.php?title=3191358'''''See also: miRNA Science Overview''''']). In non-mammals, miRNAs have been discovered to be involved in developmental process of the nervous system. For instance, in Caenorhabditis elegans, miR-273 participate in a regulatory mechanism in which ensures for the morphgenesis and differentiation of receptor neurons. <ref name=smip>Smirnova L, Gräfe A, Seiler A, Schumacher S, Nitsch R, Wulczyn FG. “Regulation of miRNA expression during neural cell specification”. Eur J Neurosci. 2005;21(6):1469-77</ref>
+
MicroRNAs are tissue specific, small non-coding RNAs, which are involved in post-trancriptional-silencing mechanism ([http://cellbiology.med.unsw.edu.au/cellbiology/index.php?title=3191358'''''See also: miRNA Science Overview''''']). In non-mammals, miRNAs have been discovered to be involved in developmental process of the nervous system. For instance, in ''Caenorhabditis elegans'', miR-273 participate in a regulatory mechanism in which ensures for the morphgenesis and differentiation of receptor neurons. <ref name=smip>Smirnova L, Gräfe A, Seiler A, Schumacher S, Nitsch R, Wulczyn FG. “Regulation of miRNA expression during neural cell specification”. Eur J Neurosci. 2005;21(6):1469-77</ref>
Likewise, in mammalian brain tissue, recent studies show that certain miRNAs have been identified, in which suggest an important role of these small molecules in modulating Trk receptors and development of nervous system. In addition, functional regulation of these miRNAs is also linked to tumorgenesis of nervous system. For instance, three neuronal miRNAs (9,125a and 125b) are found to be involved in human neuroblastoma cell proliferation by down-modulating TrkC isoform. <ref name=miska>Miska EA, Alvarez-Saavedra E, Townsend M, Yoshii A, Sestan N, Rakic P, Constantine-Paton M, Horvitz HR. “Microarray analysis of microRNA expression in the developing mammalian brain”. Genome Biol. 2004;5(9):R68 </ref>
+
Likewise, in mammalian brain tissue certain miRNAs have been identified, in which suggest an important role of these small molecules in modulating Trk receptors and development of nervous system. In addition, functional regulation of these miRNAs is also linked to tumorgenesis of nervous system. For instance, three neuronal miRNAs (9,125a and 125b) are found to be involved in human neuroblastoma cell proliferation by down-modulating TrkC isoform. <ref name=miska>Miska EA, Alvarez-Saavedra E, Townsend M, Yoshii A, Sestan N, Rakic P, Constantine-Paton M, Horvitz HR. “Microarray analysis of microRNA expression in the developing mammalian brain”. Genome Biol. 2004;5(9):R68 </ref>
  
 
==Glossary==
 
==Glossary==
Line 193: Line 185:
  
  
 +
==External Link/s==
 +
 +
[http://www.youtube.com/watch?v=bYioSvT33cA&feature=channel_page/ MAP Kinase pathway. Cell and Molecular Biology Videos,  sponsored by : Garland Science Broadcaster.]
 +
 +
Website: http://www.garlandscience.com
  
 
==Group Reflection==
 
==Group Reflection==
  
 +
In our teamwork, we not only achieved a great deal of collaboration toward our common goals; the work also reflected each member’s scientific assessment of the topic. Many challenges were faced and overcome over an 11-week period. The first challenge was ambiguity over the distinction between Trk and Tyrosine-kinases. After a few weeks of debate we eventually came to understand these distinctions through an extensive search of the literature using PubMed, and now know that Trk receptors are Tropomyosin-related kinase receptors and not, as is often but erroneously supposed, Tyrosine receptor kinases. Tropomyosine-related kinase (Trk) receptors are in fact classified as a subfamily of Tyrosine-kinase (TK) receptors.
 +
 +
 +
Trk receptors share some functional similarities with Tyrosine-kinase receptors in that once activated by an extracellular ligand, their intracellular domain will be also activated by phosphorylation, which then stimulates a series of signaling cascades to activate its target gene. Unlike Tyrosine-receptor kinases, which are commonly found in various types of cells, Trks are specific to neuronal cells, particularly with respect to neuronal differentiation, growth and establishment of synaptic plasticity. Each trk receptor shows an interest and affinity to a specific neutrophin (growth factor). Based on our research we are now comfortable in relating this differential specificity to the ‘splice-variants’ present in receptor gene alleles. Furthermore, multiple transduction pathways carry specific responses regulating survival and differentiation. The latter process is often gene regulation by association/dissociation of expresser/repressor protein from promoter regions. PKC, PLCy1, Ras/MAPK and PI3 are the main four pathways involved in this activity. Interestingly, recent studies have pinpointed the Ras/MAP kinase pathway as an effective target for cancer biotherapy, and it has proven to be effective in the first experimental mouse model. Although the mechanism by which trk is involved in gene regulation is now largely understood, there are still many unanswered questions associated with it.
 +
 +
 +
Our group found the experience of delegation, with each member contributing only in areas where they felt comfortable doing so, to be extremely useful. We are satisfied that we have adequately communicated our proficiency on this topic to our undergraduate peers at a technical level appropriate for this audience. Overall, this collaborative project was a very rewarding exercise that has instilled us with a renewed appreciation for the value of team-work and communication.
  
----
 
  
== 2009 Group Projects ==
 
--[[User:S8600021|Mark Hill]] 14:02, 19 March 2009 (EST) Please leave these links to all group projects at the bottom of your project page.
 
  
[[2009 Group 1 Project|Group 1 Meiosis]] |
+
{{Template:2009_Group_Projects}}
[[2009 Group 2 Project|Group 2 Cell Death - Apoptosis]] |
 
[[2009 Group 3 Project|Group 3 Cell Division]] |
 
[[2009 Group 4 Project|Group 4 Trk Receptors]] |
 
[[2009 Group 5 Project|Group 5 The Cell Cycle]] |
 
[[2009 Group 6 Project|Group 6 Golgi Apparatus]] |
 
[[2009 Group 7 Project|Group 7 Mitochondria]] |
 
[[2009 Group 8 Project|Group 8 Cell Death - Necrosis]] |
 
[[2009 Group 9 Project|Group 9 Nucleus]] |
 
[[2009 Group 10 Project|Group 10 Cell Shape]]
 

Latest revision as of 14:30, 18 November 2009

'Tropomyosin-related Kinase(Trk): a novel family of cell surface receptor tyrosine-kinase'

Introduction

'Tropmyosin-related kinase receptors (also known as Trk or colloqiually as "Terk" receptors), are a specific family of Tyrosine kinase receptors originating from the Trk oncogene. Trk's are present and expressed at low levels, throughout mammalian tissue types and bear particular signifcance in embryological development, maintainence as well as growth of neuronal cell types[1][2]. During embryonic development, expression is significantly higher than in mature mammals as it is in neuronal expression[3]. Thus, Trks appear to be a major component of a highly intricate system of receptor complexes that mediate neurotropin and growth factor control of selective cell death or differentiation[4]. There are three particular sub-types of receptor within the Trk loci - Trk A, Trk B and Trk C - each of which is characterised by specific differences in structure and discrimination for different Neurotrophin ligands, and thus, distinct functions.[1]


What are neurotrophins? Neurotrophins are signalling proteins (growth factors) which are expressed mostly during embryological development to regulate neuronal tissue development[4]. There are four typical neurotropic factors – Nerve Growth Factor (NGF), Brain-derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin-4 (NT-4). These factors are believed to regulate selective tissue death via Trk receptors and the low-affinity neurotrophin receptor p75NTR[4]. The Selectivty of NTs for various receptors is indicated in figure 1.

Figure 1: Specificity of Trk receptors for neurotrophin ligands: NGF binds significantly with TrkA. BDNF & NT-4 bind most significantly with TrkB. NT-3 binds most signifcatly with TrkC, however, NT-3 also elicits low-affinity binding with Trk's B and A.

Structure

  • Trk receptors are composed of an extracellular segment that binds polypeptide ligands, transmembrane helix, and cytoplasmic segment where the tyrosine kinase catalytic activity takes place.[5]
  • TrK receptors act as dimeric transmembrane proteins. Distally, three cysteine-rich motiffs and two Leucine-rich regions form a conserved NGF binding region which are common to all TrK's near the amino terminus (Figure 2).[5]
  • Additionally, the common binding region is flanked by a pair of extracellular immunoglobulin-like domains located proximally to the cell membrane[6]. The juxtamembrane complex contains a variable amino-acid sequence, which determines ligand bindng affinity and specificity. The localization of these peptides appears to be non-specific in tertiary NGF-TrKA complex structures, however their conformation within this complex indicate direct participation in complex binding[6].
  • Further NGF binding site affinity is generated through collaboration with the p75 protein/neurotrophin receptor (p75NTR)[7]. Furthermore, p75NTR regulates NT-3-TrkA and NT-4/5-TrkB mediated receptor activation by increasing signal transduction sensitivity of these neurotropins for receptor activation. This is achieved through allosteric distortion of Trk binding regions[7].
  • Intracellularly, Trk shares many of the highly conserved motifs of other tyrosine kinases with some distinct variations. There are 10 conserved tyrosines in the intracellular domain, three of which, are known to contribute to the autoregulatory loop within the kinase region (Figure 2)[8]. Overall, 8 of the 10 tyrosines contribute to the kinase region, either by regulating kinase activity directly or by inducing adaptor protein binding including those of the Ras and phosphatidylinositol pathways[8]. The two remaining tyrosine residues contribute to second-messenger events coupled by Shc and PLC-γ1 protein and are located outside the kinase domain[8].

Function

Figure 2: Common structural features of Trk receptors: a Trk in dimer complex with various conserved regions and residues. Each Trk (A, B or C) is composed of a number of highly conserved elements. Variability mainly occurs in the ligand binding regions. Variations in binding site affinity can affect phosphorylative domain regions and adaptor protein association differently, thus stimulating different signalling events.

Trk receptors achieve their function primarily via neuroptrophin signaling. Their role is to bind with neuroptrophin which are a family of closely related proteins taking roles in the regulation of survival of the neurons. There are three types of trk receptors, namely trkA, trkB and trkC. These receptors have different binding affinity to certain types of neurotrophins (Figure 1). Hence, the signalling by these distinct receptors will result in various cellular functions. Trk receptors regulate cell survival, proliferation, axon and dendrite growth, the expression and activity of ion channels and neurotransmitter receptors[9]. TrK also regulate synaptic strength and plasticity in adult nervous system. As a family of tyrosine kinase receptors, TrK receptors are activated and regulated in a similar fashion. TrK receptor signaling are mainly regulated by MAP kinase, PI3K and PLC pathways.[10]


  • Trk A

Trk A also known as Neurotrophic tyrosine-kinase receptor (type 1), is a high affinity receptor for nerve growth factor (NGF). Binding of NGF to TrK A leads to the recruitment of proteins that interact with specific phosphotyrosine residues in the cytoplasmic domains of Trk receptor A. Such interactions activate signaling pathways, such as the Ras, PI3K, and PLC pathways and result in activation of gene expression, neuronal growth and proliferation[9][10]


  • Trk B

Trk B also known as Neurotrophic tyrosine-kinase receptor (type 2), is a high affinity receptor for brain derived growth factor (BDNF) and neurotrophin-4 (NT4). Trk Bs are consisted of 3 isoforms in human central nervous system. The isoform (TK+) is a typical tyrosine kinase receptor, which transduces the BDNF signal via pathways such as Ras-ERK, PI3K and PLCγ. The other two isoforms, TKT1 and TKT2 are distinct from the typical kinase receptors as the C-terminal sequences are T1 and T2 specific.[9][10]


  • Trk C

Trk C also known as Neurotrophic tyrosine-kinase receptor is a high affinity receptor for neurotrophin-3 (NT3). Binding of NT3 on Trk C triggers the neuronal growth from neural stem cells in a process known as neurogenesis. NT3 is particularly important in proprioceptive neuron growth[10].


Demonstration of function in Knock-out mice:Multiple studies of utilizing transgenic mouse models have been employed to highlight the effects of Trk deficiency on embryological development of mice.

  • Trk Defective: Overall, Trk defective mice demonstrate a significant reduction in survival over a 30 day period[4]. Specifically, such knockouts result in impaired olfactory function, as well as poor pain and thermoception responses. This is attributed to a >70% reduction in neuronal cells in the dorsal root, trigeminal and sympathetic ganglia over this period. Multiple other pathological conditions exist but it is unclear as to whether these are attributable to Trk deficiency or secondary to extremely impaired nervous function[4].
  • Trk A defective: Trk A defective mice lack the ability to perceive painful and thermoceptive stimuli. This is attributed to the malformation of applicable peripheral sensory neurons during embryonic and post-natal development[3].
  • Trk B Defective: inactivation of the Trk B gene product results in significant neurological deficiencies, poor feeding responses and poor touch perception. Overall, this is perceived to be due to a >80% depletion of catecholaminergic neurons known to relay sensory input from the gastrointestinal, cardiovascular and pulmonary systems[3].
  • Trk C Defective: Defective mice demonstrate unusual postural responses as well as severely impaired proprioception. It is believed that these deficiencies are attributable to an absolute deficiency of Ia muscle afferents that innervate proprioceptive spindle fibres during embryological development[3].

Dynamic Process

Figure 3: Overview of dynamic processes shared by Trk receptors. Multiple transduction pathways are employed to illicit specific responses regulating survival and differentiation. The end point of signal transduction is often gene regulation and may involve Calcium second messenger events to preciptate expressor/repressor protein dissociation/association from promoter regions.

NGF binding to ligation region facilitates dimerisation of Trk Receptor monomers into the signal transductive unit- activating the kinase unit[11]. Phosphorylation of the autoregulatory loop tyrosines of the cytoplasmic domain further activates the kinase. Phosphorylation of an additional five tyrosines within this region promotes signalling by providing docking sites for adaptor proteins which regulate signalling-cascade couples. Overall, the purpose of this process appears to be to facilitate down-stream phosphorylation and gene expression regulation(Eg. upregulation of Neuronal Factor Kappa B) via multiple transductive pathways, many of which, are synonymous with tyrosine kinase receptor activity.[11] Thus, the autophosphorylation of intracellular domain tyrosine residues precipitates the association of second-messenger adaptor proteins which may or may not themselves be phosphorylated in order to illicit the desired signalling event (Figure 3).


co-operation with p75NTR: Association with p75NTR(also known as the "low affinity neurotropin receptor") appears to be an integral component of regulation of Trk's. This combination of Trk and p75NTR proteins results in the formation of a high-affinity binding site within the Trk binding region, increasing the responsiveness of receptors for thier ligands[7]. Additionally, coordination with p75NTR has been implicated in a reduction in ubiquitination, delay of internalisation of receptors during sensitisation, and overall decreases the apoptotic potential of cell lines [12] .

Mechanism of Trk Activation via multiple Signalling pathways

Tropomyosine receptor kinases (Trk) enhance neuronal cell growth and differentiation of neurites via the activation of various signalling pathways. PKC, PLCy1, Ras/MAPK and PI3 are the four well known pathways, which exhibit this activity. The latter process involves the activation of transcription factors that will bind onto a specific target gene, thus trigerring neuronal cell division and/ differentiation via production of specific proteins that inhibit apoptosis (Figure 3). Cite error: Closing </ref> missing for <ref> tag This occurs by the activation of the membrane bound receptor by a number of growth factors, cytokines and immunoglobins. [13] DAG is necessary for the further activation of the PKC and it remains bound to the cell membrane. IP3, a water soluble protein , in turn is released into the cytoplasm and leads to the release of Ca2+ reserves from the endoplasmic reticulum. This increase of calcium ions activates the classic isoforms of Protein Kinase C. [14]



Figure 4:Simplified PLC γ1 Pathway. Full sized animation

PLC-y1 Pathway

Phospholipase C, comes in many forms and plays an important role in the signal transduction for many processes, including proliferation, differentiation and motility. Its main function is to hydrolyze phosphatidylinositoldi phosphate (PIP2) into diacylglycerol (DAG) and inositoltriphosphate (IP3). [15] This occurs by the activation of the membrane bound receptor by a number of growth factors, cytokines and immunoglobins. [16] DAG is necessary for the further activation of the PKC and it remains bound to the cell membrane. IP3, a water soluble protein , in turn is released into the cytoplasm and leads to the release of Ca2+ reserves from the endoplasmic reticulum. This increase of calcium ions activates the classic isoforms of Protein Kinase C. [17]








Figure 5: Simplified Animation of PKC pathway. Full size animation

PKC Pathway

See also: Protein Kinase C

Protein Kinase C (PKC) is a family of nucleotide-independent, Ca2+-dependent serine kinases. [18]. At least 11 isozymes have been identified, [19] most PKC isozymes are ubiquitous and multiple members of the family can be coexpressed within the same cell leading to complex pathways. However, the basic signal transduction pathway involves the allosteric activation of PKC by the intracellular messengers diacylglycerol and Calcium ions. The inactive PKC is mainly found in the cytosol. Upon stimulation the PKC proteins translocate to the cell membrane. This translocation is the result of a cascade initiated by the binding of a number of extracellular ligands, such as, growth factors, hormones, and neurotransmitters to a G protein-coupled receptor (GPRC) found on the plasma membrane. This in turn activates a stimulating G protein which in turn activates phospholipase C (PLC). [20] A G protein is then activated, which then activates phospholipase C (PLC). The PLC cleaves phosphoinositol-4,5-bisphosphate (PIP2) into 1,2-diacylglycerol (DAG) and inositol-1.,4,5-triphosphate (IP3). [21] The IP3, couples to Ca2+ channels found on the endoplasmic reticulum releasing Ca2+ reserves. The increased concentration of calcium ions bind to inactive PKC molecules and then translocates to the plasma membrane, giving rise to the active PKC enzyme. [18] The PKC family plays a major role in cellular signal transduction. [22]Their main roles consist in the regulation of cell proliferation, differentiation, survival and apoptosis. [23]

Ras-MAPK (mitogen-activated protein kinase) Pathway

Activation of Ras-MAPK signalling pathway is predominantly essential for promoting neuronal cell growth and differentiation[24]. Several pathways derive from Trk receptors for activation of Ras molecules, which begin by formation of ligand-bound mitogen (BDNF or NGF) at an extracellular domain of the trk, causing receptor dimerization. This subsequently will lead to phosphorylation of the intracellular parts of the receptors, which activates Guanine Exchange factors (GEFs), such as sos, Grb2 and Shc. GEFs trigger the exchange of GDP bound to inactive Ras to GTP, resulting Ras to activate. The presence of activated Ras molecules, stimulate signaling via a major downstream pathway known as MAP kinase (mitogen-activated protein kinase)-although activated Ras, would be also capable of triggering several other downstream pathways such as PLC-y1 and PI3-kinases (Figure 4 & 6). [24]

Mitogen-activated protein kinase (MAPK) pathway involves a series of signalling cascade. Raf is the first component of MAPK, activated by Ras-GTP on the plasma membrane. [24] Raf then phosphorylates MEK1/2, which in turn activates the ERK1/2 by phosphorylation. ERK1/2 kinase would further phosphorylate a variety of downstream targets. These pathways may include phosphorylation of MAP 2-kinase by MAP 3-kinase on its serine and threonine amino-acid residues. Further phosphorylation of MAP- kinase by MAP 2-kinase on its serine and tyrosine amino-acid residues subsequently yields activated MAP-kinase. This results in activation of transcription factors that will lead to changes in gene expression[24] [25]. (Click here for well illustration of MAP-kinase pathway on You-tube). Nonetheless, aberrant Ras-MAPK signaling has been identified to be a possible factor responsible for the uncontrolled proliferation and malignancy. Also see:Cancer Biotherapy .[25]



Figure 6: The image depicts the role of PI3K/Akt signal transduction cascade along with the downstream activation in the formation of cancer cells.

PI3K (Phosphatidylinositol 3-kinase) Pathway

See also: Phosphatidylinositol 3-kinase

The role of PI3K is essential in promoting survival of neuronal cells.[26] PI3K directly activates Ras-dependent pathway through which Trk signaling promotes survival in many, but not all, neurons. In some cells PI3K can be activated through three adaptor proteins, Shc, Grb-2 and Gab-1. PI3K has an array of main effectors, which include the mitogen-transducing signal proteins such as protein kinase C, phosphoinositide-dependent kinases and mitogen activated protein kinases. They are either activated via interaction with lipid products of PI3K or through PI3K-dependent phosphorylation of proteins.[27] PI3K is activated by number of growth factor receptors with intrinsic and tyrosine kinase activity. BAD is an important protein in controlling cell survival and is a Bcl-2 family member which promotes apoptosis by binding to Bcl-xL. When BAD are phosphorylated by Akt or MAPKs, it involves in the regulation of signal transduction in neuronal cells [28] On the other hand, PI3K/Akt signal transduction cascade is predominantly important in the formation of neuronal tumours. This cascade promotes the growth and proliferation of cancer cells and its components represent attractive targets for the design of anticancer agents. mTOR which is a serine/threonine kinase acts on the downstream activation of PI3K for the mediation of prosurvival activity. This will inhibit apoptosis, resulting in the formation of cancer cells.[26][29]

Current Research

Cancer biotherapy via targeting ‘Ras / Ras-MAP-kinase’ signalling pathway

Recent studies have hypothesized that receptors responsible for Ras activation would be effective target for treating human cancers[24]. Based on this hypothesis, since 1995, therapies utilizing the inhibition of Ras activation have aroused a major interest. Farnesylation is a process by which small G-proteins like Ras are activated and adhered to the cell membrane. In a recent paper [30], farnesyl transferase inhibitors were used in order to block the farnesylation of Ras proteins. The results revealed promising hopes in animal models but unfortunately have not been effective in human cancer treatment[30]. The major downstream target of Ras-MAP-Kinase (MAPK) has also been taken as a subject for drug design. Sebolt and his colleagues showed that MAPK-inhibitors are effective in cancer therapy using mouse models [31] . It has been also suggested that Inhibition of the Ras-MAPK signaling pathway can serve as a potential therapy for NF1 in humans. [32]

Trk receptors can behave as signalling endosomes

In a recent publication, a hypothesized model was explained in which active Trk receptors are internalised into signaling endosomes during signalling transduction process. [33] The experiment that led to this understanding involved local application of NGF to axons and soma (cell bodies) of neuronal cells. It was shown that both ERK1/2 and ERK5 signaling cascades were activated. Surprisingly, application of NGF to neuronal cells at distance resulted only in activation of ERK5 pathway and NOT ERK1/2. It was then understood that activation of ERK5 in the cells somas required receptor internalisation due to inhibition by thermo-sensitive dynamin.[33] Further investigation was conducted by local application of specific Trk-inhibitor (K252a) at either the distal axon or cell body, which blockaded the activation of ERK5 in the cell soma in the presence of NGF. Therefore, the hypothesized model in which active Trk receptors are internalised into signalling endosomes is inevitable. Nonetheless, the mechanism through which distance affects the specificity of signalling would be the future topic of investigation. [33]

The interplay between miRNA and Trks (tropomyosin-related kinases)

MicroRNAs are tissue specific, small non-coding RNAs, which are involved in post-trancriptional-silencing mechanism (See also: miRNA Science Overview). In non-mammals, miRNAs have been discovered to be involved in developmental process of the nervous system. For instance, in Caenorhabditis elegans, miR-273 participate in a regulatory mechanism in which ensures for the morphgenesis and differentiation of receptor neurons. [34] Likewise, in mammalian brain tissue certain miRNAs have been identified, in which suggest an important role of these small molecules in modulating Trk receptors and development of nervous system. In addition, functional regulation of these miRNAs is also linked to tumorgenesis of nervous system. For instance, three neuronal miRNAs (9,125a and 125b) are found to be involved in human neuroblastoma cell proliferation by down-modulating TrkC isoform. [35]

Glossary

  • Apoptosis: Programmed cell death.
  • Autophosphorylation: is the term used to define the phosphorylation of a kinase protein catalysed by its own enzymatic activity.
  • BDNF: Brain-derived neurotrophic growth factor is a protein that promotes activation of tropomyosine receptor kinases (trk).
  • Dynamin: GTPase enzyme responsible for endocytosis in eukaryotic cells.
  • ERK: Extracellular regulated kinase.
  • Exons: Expressed regions of eukaryotic genes.
  • Farnesyl transferase inhibitors: a class of experimental cancer drug that blocks farnesylation of Ras proteins.
  • GTPases: are a large family of enzymes that can bind and hydrolyse guanosine triphosphate(GTP).
  • Isozymes: any of a group of enzymes that are similar in catalytic properties but are different in physical properties, such as isoelectric point.
  • Neurofibromatosis (NF): an inherited disorder that causes production of benign tumours on nerve tissues. There are two types of NF; NF1 and NF2. NF1 is the most common disease amongst infants, also known as Recklinghausen disease.
  • NGF: Nerve growth factor is a protein that promotes activation of tropomyosine receptor kinases (trk).
  • Phosphorylation: A process by which a phosphate group is added to a protein that is required for its cellular activation.
  • Proto-oncogene: normal cellular proteins that have the potential to cause uncontrolled cell growth when mutated.
  • Oncogene: a gene that enhances uncontrolled proliferation of cells when mutated and further expressed at high levels.
  • Ras: small G-proteins that belong to the superfamily of monomeric GTPases. They are involved in receptor-mediated signal transduction pathways.

References

  1. 1.0 1.1 EJ, Reichardt LF. “Trk receptors: roles in neuronal signal transduction”. Annu Rev Biochem. 2003;72:609-42
  2. Manning.G,. Whyte DB, Martinez R, Hunter T, Sudarsanam S. “The protein kinase complement of the human genome”. Science. 2002;298(5600):1912-34.
  3. 3.0 3.1 3.2 3.3 Huang EJ, Reichardt LF: Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001, 24. Retreived from [1]
  4. 4.0 4.1 4.2 4.3 4.4 Sofroniew MV, Howe CL, Mobley WC: Nerve growth factor signaling neuroprotection and neural repair. Annu Rev Neurosci 2001, 24: Retreived from [2]
  5. 5.0 5.1 EJ, Reichardt LF. “Trk receptors: roles in neuronal signal transduction”. Annu Rev Biochem. 2003;72:609-42. Retrieved 2 May 2009 from Pubmed
  6. 6.0 6.1 R. Urfer, P. Tsoulfas, L. O'Connell, J.A. Hongo, W. Zhao and L.G. Presta , High resolution mapping of the binding site of TrkA for nerve growth factor and TrkC for neurotrophin-3 on the second immunoglobulin-like domain of the Trk receptors. J Biol Chem 273 (1998), pp. 5829–5840 [3]
  7. 7.0 7.1 7.2 Barker PA. High affinity not in the vicinity? Neuron. 2007 Jan 4;53(1):1-4. Review retrieved from [4]
  8. 8.0 8.1 8.2 T. Pawson and P. Nash , Protein–protein interactions define specificity in signal transduction. Genes Dev 14 (2000), pp. 1027–1047. [5]
  9. 9.0 9.1 9.2 Pyle AD, Lock LF, Donovan PJ. Neurotrophins mediate human embryonic stem cell survival. Nat Biotechnology 1996;24:344–50. Retrieved 13 May 2009 from Pubmed
  10. 10.0 10.1 10.2 10.3 Melamed et al., A Novel Lymphocyte Singnaling Defect: trk A Mutation in the Syndrome of Congenital Insensitivity to Pain and Anhidrosis (CIPA). Journal of Clinical Immunology, 2004;24:(4)441-448. Retrieved on 13 May 2009 from Pubmed Cite error: Invalid <ref> tag; name "me" defined multiple times with different content Cite error: Invalid <ref> tag; name "me" defined multiple times with different content Cite error: Invalid <ref> tag; name "me" defined multiple times with different content
  11. 11.0 11.1 Patapoutian A, and Reichardt LF. Trk receptors: mediators of neurotrophin action. Current Opinion in Neurobiology 2001; 11:272–280; Retrieved May 20, 2009, from [6]
  12. Barker PA. p75NTR is positively promiscuous: novel partners and new insights. Neuron. 2004 May 27;42(4):529-33. Review. Retrieved from [7]
  13. Mankidy, R., Hastings, J., & Thackeray, J. (2003). Distinct Phospholipase C-#-Dependent Signaling Pathways in the Drosophila Eye and Wing Are Revealed by a New small wing Allele. Genetics Society of America. 164(2): 553–563.
  14. Bioengineering; Research from University of Tokyo broadens understanding of bioengineering. (2009,May). Medical Devices & Surgical Technology Week,70.
  15. PhD, Hershel Raff. Physiology Secrets. Philadelphia: Hanley & Belfus, 2002.
  16. Mankidy, R., Hastings, J., & Thackeray, J. (2003). Distinct Phospholipase C-#-Dependent Signaling Pathways in the Drosophila Eye and Wing Are Revealed by a New small wing Allele. Genetics Society of America. 164(2): 553–563.
  17. Bioengineering; Research from University of Tokyo broadens understanding of bioengineering. (2009,May). Medical Devices & Surgical Technology Week,70.
  18. 18.0 18.1 Takai, Y., Kishimoto, A., Inoue, M., & Nishizuka, Y. (1977). Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum. J. Biol. Chem., 252(21), 7603-7609. [8]
  19. Acs, P., Wang, Q., Bogi, K., Marquez, A., Lorenzo, P., Biro, T., Szallai, Z., Mushinski, F., & Blue, P. (1997). Both the Catalytic and Regulatory Domains of Protein Kinase C Chimeras Modulate the Proliferative Properties of NIH 3T3 Cells. J Biol Chem., 272(45), 28793-28799. Retrieved May 15, 2009, from Pubmed
  20. Dekker, L (2004). Protein Kinase C (Molecular Biology Intelligence Unit). New York: Springer.
  21. Signal Transduction Resource. (n.d.). Retrieved May 15, 2009, from Promega
  22. Steinberg, S. (2008). Structural Basis of Protein Kinase C Isoform Function. Physiol. Rev., 88, 1341-1378. Retrieved October 5, 2009, from Pubmed
  23. D Breitkreutz, L Braiman-Wiksman, N Daum, M F Denning, T Tennenbaum. (2007). Protein kinase C family: On the crossroads of cell signaling in skin and tumor epithelium. Journal of Cancer Research & Clinical Oncology, 133(11), 793-808. Retrieved May 16, 2009, from Pubmed
  24. 24.0 24.1 24.2 24.3 24.4 Wiesmüller L, Wittinghofer F.,“Signal Transduction pathways involving Ras. Mini Review”.Cellular Signalling.1994;6(3) 247-267.
  25. 25.0 25.1 Harvey, J., and Ashford, M.L.J. “Leptin in the CNS: much more than a satiety signal”. Neuropharmacology. 2003;44, 845-854.
  26. 26.0 26.1 Krasilnikov MA. Phoshatidylinositol-3 kinase dependent pathways: the role in control of cell growth, survival, and malignant transformation. Biochemistry. Review 2000;65(1):59-67. Retrieved May 16, 2009, from Pubmed
  27. Kapeller R, and Cantley LC. Phosphatidylinositol 3-kinase. Bioessays. 1994;16(8):565-576. Retrieved May 16, 2009, from [9]
  28. Stephens LR, Jackson TR, and Hawkins PT. Agonist-stimulated synthesis of phosphatidylinosital(3,4,5)-triphosphate: a new intracellular signaling system? Biochim Biophys Acta 1993;1179(1):27-75. Retrieved May 16, 2009, from Pubmed
  29. Kapeller R, and Cantley LC. Phosphatidylinositol 3-kinase. Bioessays. 1994;16(8):565-576. Retrieved May 16, 2009, from [10]
  30. 30.0 30.1 Kohl,N.E., Omer C.A., Conner MW., Anthony NJ, Davide JP, deSolms SJ, Giuliani EA, Gomez RP., Graham SL., Hamilton K., “Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice”. Nat Med (1995).1(8): 792-7.
  31. Sebolt,J.S,. Dudley D.T,. Herrera.R, Van Becelaere.K, Wiland A, Gowan RC, Tecle H, Barrett SD, Bridges A, Przybranowski.S,. Leopold WR. Saltiel A.R,. “Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo”. Nat Med. (1999).5(7): 810-6.
  32. Sebti S.M., Hamilton A.D,. “Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: lessons from mechanism and bench-to-bedside translational studies”. Oncogene.(2000).19(56): 6584-93.
  33. 33.0 33.1 33.2 Watson, FL., Heerssen HM, Bhattacharyya A, Klesse L, Lin MZ, Segal RA.“Neurotrophins use the Erk5 pathway to mediate a retrograde survival response”.Nat Neurosci.2001;4(10):981-8
  34. Smirnova L, Gräfe A, Seiler A, Schumacher S, Nitsch R, Wulczyn FG. “Regulation of miRNA expression during neural cell specification”. Eur J Neurosci. 2005;21(6):1469-77
  35. Miska EA, Alvarez-Saavedra E, Townsend M, Yoshii A, Sestan N, Rakic P, Constantine-Paton M, Horvitz HR. “Microarray analysis of microRNA expression in the developing mammalian brain”. Genome Biol. 2004;5(9):R68


External Link/s

MAP Kinase pathway. Cell and Molecular Biology Videos, sponsored by : Garland Science Broadcaster.

Website: http://www.garlandscience.com

Group Reflection

In our teamwork, we not only achieved a great deal of collaboration toward our common goals; the work also reflected each member’s scientific assessment of the topic. Many challenges were faced and overcome over an 11-week period. The first challenge was ambiguity over the distinction between Trk and Tyrosine-kinases. After a few weeks of debate we eventually came to understand these distinctions through an extensive search of the literature using PubMed, and now know that Trk receptors are Tropomyosin-related kinase receptors and not, as is often but erroneously supposed, Tyrosine receptor kinases. Tropomyosine-related kinase (Trk) receptors are in fact classified as a subfamily of Tyrosine-kinase (TK) receptors.


Trk receptors share some functional similarities with Tyrosine-kinase receptors in that once activated by an extracellular ligand, their intracellular domain will be also activated by phosphorylation, which then stimulates a series of signaling cascades to activate its target gene. Unlike Tyrosine-receptor kinases, which are commonly found in various types of cells, Trks are specific to neuronal cells, particularly with respect to neuronal differentiation, growth and establishment of synaptic plasticity. Each trk receptor shows an interest and affinity to a specific neutrophin (growth factor). Based on our research we are now comfortable in relating this differential specificity to the ‘splice-variants’ present in receptor gene alleles. Furthermore, multiple transduction pathways carry specific responses regulating survival and differentiation. The latter process is often gene regulation by association/dissociation of expresser/repressor protein from promoter regions. PKC, PLCy1, Ras/MAPK and PI3 are the main four pathways involved in this activity. Interestingly, recent studies have pinpointed the Ras/MAP kinase pathway as an effective target for cancer biotherapy, and it has proven to be effective in the first experimental mouse model. Although the mechanism by which trk is involved in gene regulation is now largely understood, there are still many unanswered questions associated with it.


Our group found the experience of delegation, with each member contributing only in areas where they felt comfortable doing so, to be extremely useful. We are satisfied that we have adequately communicated our proficiency on this topic to our undergraduate peers at a technical level appropriate for this audience. Overall, this collaborative project was a very rewarding exercise that has instilled us with a renewed appreciation for the value of team-work and communication.


2009 Group Projects

Group 1 Meiosis | Group 2 Cell Death - Apoptosis | Group 3 Cell Division | Group 4 Trk Receptors | Group 5 The Cell Cycle | Group 6 Golgi Apparatus | Group 7 Mitochondria | Group 8 Cell Death - Necrosis | Group 9 Nucleus | Group 10 Cell Shape