Oligomerization-induced differential dephosphorylation of c-met receptor tyrosine kinase

Payal R. Sheth, Stanley Watowich

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Although protein tyrosine phosphatases (PTPs) are significant negative regulators of receptor tyrosine kinase (RTK)-initiated cell signaling, it is unknown how RTK oligomerization modulates the equilibrium established between kinase and phosphatase activity. To determine the impact of oligomerization on the ability of c-MET RTK to undergo dephosphorylation, we examined the relative dephosphorylation kinetics of similarly phosphorylated dimeric TPR-MET and monomeric cytoMET. Notably, we observed that the dephosphorylation kinetics of phosphorylated MET were significantly modulated by its oligomeric state, with the global dephosphorylation rate of TPR-MET severalfold slower than the dephosphorylation rate of monomeric cytoMET. Furthermore, there were important site-specific differences in the dephosphorylation patterns of cytoMET and TPR-MET. Reduced dephosphorylation activity was predicted to 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 and carboxy-terminal tyrosines following pervanadate treatment of cells expressing c-MET. We conclude that the MET oligomerization state is a critical regulator of its dephosphorylation rate. Thus, oligomerization plays a role in modifying the receptor's kinase and dephosphorylation rates to change the equilibrium levels of phosphorylated and dephosphorylated receptor in response to ligand stimulation, and that this may be a general mechanism utilized by many oligomeric receptor tyrosine kinases for regulation of their activity.

Original languageEnglish (US)
Pages (from-to)10984-10993
Number of pages10
JournalBiochemistry
Volume44
Issue number33
DOIs
StatePublished - Aug 23 2005

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Proto-Oncogene Proteins c-met
Oligomerization
Receptor Protein-Tyrosine Kinases
Phosphotransferases
Ligands
Protein Tyrosine Phosphatases
Phosphoric Monoester Hydrolases
Tyrosine
Cell signaling
Phosphorylation
Kinetics
Chemical activation
Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

Oligomerization-induced differential dephosphorylation of c-met receptor tyrosine kinase. / Sheth, Payal R.; Watowich, Stanley.

In: Biochemistry, Vol. 44, No. 33, 23.08.2005, p. 10984-10993.

Research output: Contribution to journalArticle

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