A mechanism of activation of c-MET receptor tyrosine kinase

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Title: A mechanism of activation of c-MET receptor tyrosine kinase
Author: Payal Sheth
Abstract: c -MET receptor tyrosine kinase -mediated signaling governs numerous important cellular responses including cellular proliferation , differentiation , migration and apoptosis . Deregulation of these signals result in malignant behaviors , often leading to cancers . While the identity of the many signaling molecules that are activated following hepatocyte -growth factor (HGF ) -induced activation of c -MET had been established , little was known about the mechanism of activation of c -MET . From a therapeutic perspective , it is necessary to understand the detailed molecular mechanisms regulating c -MET activation to selectively target these molecules . c -MET , in presence of its cognate ligand , is oligomerized , and is autophosphorylated on specific tyrosines on its cytoplasmic domain . The phosphorylated tyrosines in specific sub -domains of c -MET cytoplasmic region perform specific functions including increase in catalytic activity and recruitment of effector molecules . Classically , it has been believed that the sole role of ligand -induced oligomerization was to autophosphorylate the receptor , thereby switching the receptor’s kinase activity on . However , in light of a recent body of evidence suggesting that certain RTKs are kinase active on cell surface in absence of ligand -induced oligomerization , we hypothesized that oligomerization could be important for other aspects of RTK activation . Using c -MET as our model system , we investigated the role of oligomerization , irrespective of its role in autophosphorylation , in regulating c -MET activation . Previous studies from our laboratory have conclusively shown that oligomerization increases c -MET’s substrate binding affinity and substrate phosphorylation kcat . The work presented here addresses the role of oligomerization in regulating c -MET’s susceptibility to dephosphorylation , another important regulator of c -MET activation . The biochemical parameters measured for c -MET are used to build a unified kinetic model for c -MET activation . The model building and its subsequent validation using cell culture experiments are described here . Furthermore , the model is probed using parameter sensitivity analyses to understand how oligomerization -induced changes in the kinetic , thermodynamic and dephosphorylation properties of c -MET work synergistically to selectively induce specific signaling from the dimeric and not the monomeric receptor . Using these data , we propose an alternative feed -forward model for c -MET activation mechanism differs from the traditional view of the RTK activation .
URI: http : / /hdl .handle .net /2152 .3 /181
Date: 2006-06-23

Citation

A mechanism of activation of c-MET receptor tyrosine kinase. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /181 .

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