Oligomerization-induced differential dephosphorylation of c-Met receptor tyrosine kinase.
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.
Sheth
Payal R
PR
Department of Human Biological Chemistry and Genetics and Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, Texas 77555-0645, USA.
Watowich
Stanley J
SJ
D000818:Animals; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008024:Ligands; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014638:Vanadates / Q000494:pharmacology; D014709:Vero Cells
D004791:Enzyme Inhibitors; D008024:Ligands; D046912:Multiprotein Complexes; C076715:pervanadate; D014638:Vanadates; D019859:Proto-Oncogene Proteins c-met