2009 Group 4 Project

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"Tyrosine Receptor Kinases (Trk)"

                                                    Draft Version
                                                

Introduction

Trk receptors are a family of tyrosine kinases commonly associated with growth and function regulation in neuronal cells. Binding of ligands to Trks can effect growth, plasticity and synaptic strength of neuronal junctions - although it is notable that Ligand binding does not itself illicit an action potential event.***REQUIRES DISAMBIGUATION***

Further points to expand on may include:

• What are Tyrosine kinase (Tk) receptors?

• What are they composed of?

• Identification & classification of human tyrosine Kinase genes in human genome project.


--Hamid/Arash Araghi 18:29, 30 April 2009 (EST)

Structure

  • 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 extracelluar immunoglobin-like domains located proximally to the cell membrane. The juxtamembrane complex contains a variable amino acid sequence suggested to determine ligand bindng affinity and specificiy 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

Trk's play numerous physiological roles in regulation of neuronal cell function: *INLUDE NON-NUEURONAL CELL FUNCTION*


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)

Glossary

Include acronyms as well !

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