Oligomerization-Induced Differential Dephosphorylation of c-Met Receptor Tyrosine Kinase

详细信息    查看全文

• 作者：Payal R. Sheth and Stanley J. Watowich
• 刊名：Biochemistry
• 出版年：2005
• 出版时间：August 23, 2005
• 年：2005
• 卷：44
• 期：33
• 页码：10984 - 10993
• 全文大小：457K
• 年卷期：v.44,no.33(August 23, 2005)
• ISSN：1520-4995

文摘

Although protein tyrosine phosphatases (PTPs) are significant negative regulators of receptortyrosine kinase (RTK)-initiated cell signaling, it is unknown how RTK oligomerization modulates theequilibrium established between kinase and phosphatase activity. To determine the impact of oligomerizationon the ability of c-MET RTK to undergo dephosphorylation, we examined the relative dephosphorylationkinetics of similarly phosphorylated dimeric TPR-MET and monomeric cytoMET. Notably, we observedthat the dephosphorylation kinetics of phosphorylated MET were significantly modulated by its oligomericstate, with the global dephosphorylation rate of TPR-MET severalfold slower than the dephosphorylationrate of monomeric cytoMET. Furthermore, there were important site-specific differences in thedephosphorylation patterns of cytoMET and TPR-MET. Reduced dephosphorylation activity was predictedto eliminate or reduce the requirement of ligand-dependent oligomerization for MET autophosphorylation.This was demonstrated by the rapid phosphorylation of unstimulated c-MET on its activation loop andcarboxy-terminal tyrosines following pervanadate treatment of cells expressing c-MET. We conclude thatthe MET oligomerization state is a critical regulator of its dephosphorylation rate. Thus, oligomerizationplays a role in modifying the receptor's kinase and dephosphorylation rates to change the equilibriumlevels of phosphorylated and dephosphorylated receptor in response to ligand stimulation, and that thismay be a general mechanism utilized by many oligomeric receptor tyrosine kinases for regulation of theiractivity.