2009 Group 4 Project

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'"Tropomyosin-receptor-Kinase (Trk)"'


                                       "Under construction"
                                                

Introduction

The tropomyosin-receptor kinase (trk) belongs to the family of tyrosine-protein kinase receptors (TK), which was discovered as a proto-oncogene that consisted of seven exons of ‘non-muscle tropomyosin’ gene fused to the cytoplasmic domains of a novel ‘tyrosine-kinase’ gene. Trks are commonly associated with cell survival, proliferation, neurite growth including axons & dendrites as well as regulatory function of ion channels and neurotransmitter receptors in immature neural cells. In addition, binding of ligands to trks can affect growth, plasticity and synaptic strength of neuronal junctions in the adult nervous system (ref), although it is notable that Ligand binding does not itself illicit an action potential event. Three trk genes have been identified in mammals: trkA (proto-oncogene), which serves as an NGF receptor, trkB and trkC, that each was subsequently identified due to their high homology to trkA(ref).

--Hamid/Arash Araghi 08:39, 14 May 2009 (EST)


‘Neurotrophines; regulatory components & avtivators of tropomyosine-receptor kinase (trk)’

I can do this part-Arash




Structure

  • Trk receptors are made of an extracellular segment that binds polypeptide ligands, transmembrane helix, and cytoplasmic segment where the tyrosine kinase catalytic activity takes place.
  • The extracellular segment of the Trk receptors has various range of distinct globular domains. They include immunoglobulin-like domains, fibronectin type III-like domains, cysteine rich domains, and epidermal growth factor-like domains.

Seven subfamilies of receptor tyrosine kinases

Each of the seven subfamilies are distinct in their own ways. Please see discussion. Include the above under this heading or make a new heading for it.

--Serkan Erkan 17:12, 2 May 2009 (EST)

  • TrK receptors act as dimeric transmembrane proteins. Distally, three cysteine-rich motiffs and two Leucine rich regions form a conserved NGF binding region which is common to all TrK's near the amino terminus(in addition, TrkA is possesed of an additional NGF binding region, see TrK A).
  • Additionally, the common binding region is flanked by a pair of extracellular immunoglobulin-like domains located proximally to the cell membrane. The juxtamembrane complex contains a variable amino acid sequence suggested to determine ligand bindng affinity and specificity and may bind directly to some ligands; The localization of these peptides appears to be non-specific in tertiary NGF-TrKA complex structures however their conformation within this complex appears to indicate direct participation in complex binding.
  • Further NGF binding site affinity is generated through collaboration with the p75 protein/neurotrophin receptor (p75NTR). Furthermore, p75NTR regulates NT-3-TrkA and NT-4/5-TrkB mediated receptor activation by blocking Neurotropin ligation by circumnavigating the prequisite of these neurotropins for receptor activation.

Function

***Tyrosine receptor kinases*** play an important role in number of fundamental cellular processes such as cell migration, cell cycle, cell metabolism and survival as well as cell proliferation and differentiation. The activation of the tyrosine receptor kinases requires two processes: enhancement of intrinsic catalytic activity and creation of binding sites to recruit downstream signaling proteins. They are both achieved by the autophosphorylation of the tyrosine residues, a consequence of ligand-mediated oligomerisation. Upon their activation, tyrosine receptor kinases transduce extracellular signals to cytoplasm by autophosphorylation of the tyrosine residues on the receptors themselves and downstream signaling proteins within the cells. --Serkan Erkan 16:45, 2 May 2009 (EST)

K-ras Oncogene

The K-ras oncogene is a GTPase switch protein which is responsible for activating intracellular signalling pathways in response to extracellular growth signals. Activation of the receptor tyrosine kinase by an external signal molecule causes the Grb-2 adaptor protein to bind to the Ras guanine nucleotide exchange factor (GEF). This stimulates Ras to exchange its bound GDP for GTP and so activate several downstream signalling pathways which lead to cell division.

GTPase-activating proteins (GAPs) inactivate Ras by stimulating it to hydrolyse its bound GTP; the inactivated Ras remains tightly bound to GDP. Guanine nucleotide exchange factors (GEFs) activate Ras by stimulating it to give up its GDP; the concentration of GTP in the cytosol is 10 times greater than the concentration of GDP, and Ras rapidly binds GTP once GDP has been ejected.

Any mutation which changes the amino acid glycine at position 12 in the Ras protein blocks the binding of the GTPase–activating proteins (GAPs). If the GAPs are not able to bind Ras then it will be locked in a permanently activated state. This leads to a continual stimulation of the growth signalling pathways regulated by Ras and hence to continual cell growth (Cancer).

  • A Figure is required

--Hamid/Arash Araghi 18:30, 30 April 2009 (EST)

Role of miRNA in the regulation of Tyrosine receptor kinases

Under Construction…..

--Hamid/Arash Araghi 18:30, 30 April 2009 (EST)


Maintenance and Proliferation of undifferentiated Cell Lines

Dynamic Process

NGF binding to ligation region facilitates dimerisation of Trk Receptor monomers into the signal tranductive unit- activating the kinase unit. Phosphorylation of the autoregulatory loop tyrosines of the cytoplasmic domain further activates the kinase. Phosphorylation of an additional seven tyrosines within this region promotes signalling by providing docking sides for adaptor proteins which regulate signalling-cascade couples.

Current Research

Timeline

explain TrK Nomenclature

References

--Hamid/Arash Araghi 18:36, 30 April 2009 (EST)

--Serkan Erkan 17:57, 2 May 2009 (EST)

Glossary

Autophosphorylation is the term used to define the phosphorylation of a kinase protein catalysed by its own enzymatic activity.

GTPases are a large family of enzymes that can bind and hydrolyse guanosine triphosphate(GTP).

NGF-Nerve growth Factor.

Exons-Expressed regions of eukaryotic genes.


Include acronyms as well !

--Serkan Erkan 16:51, 2 May 2009 (EST)

2009 Group Projects

--Mark Hill 14:02, 19 March 2009 (EST) Please leave these links to all group projects at the bottom of your project page.

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