Activation of c-Src and Fyn kinases by protein tyrosine phosphatase RPTPalpha is substrate-specific and compatible with lipid raft localization

Nathalie Vacaresse, Bente Møller, Erik Michael Danielsen, Masato Okada, Jan Sap

33 Citations (Scopus)

Abstract

Tyrosine kinases of the Src family (SFKs) function in multiple signaling pathways, raising the question of how appropriate regulation and substrate choice are achieved. SFK activity is modulated by several protein tyrosine phosphatases (PTPs), among which RPTPa and SHP2 are the best established. We studied how RPTPa affects substrate specificity and regulation of c-Src and Fyn in response to EGF and PDGF. We find that RPTPa, in a growth factor-specific manner, directs the specificity of these kinases towards a specific subset of SFK substrates, particularly the focal adhesion protein Paxillin and the lipid raft scaffolding protein Cbp/PAG. A significant fraction of RPTPa is present in lipid rafts, where its targets Fyn and Cbp/PAG reside, and growth factor-mediated SFK activation within this compartment is strictly dependent on RPTPa. Forced concentration of RPTPa into lipid rafts is compatible with activation of Fyn. Finally, RPTPa-induced phosphorylation of Paxillin and Cbp/PAG induces recruitment of the SFK inhibitory kinase Csk, indicative of negative feedback loops limiting SFK activation by RPTPa. Our findings indicate that individual- SFK-controlling PTPs play important and specific roles in dictating SFK substrate specificity and regulatory mechanism.
Original languageEnglish
JournalJournal of Biological Chemistry
ISSN0021-9258
DOIs
Publication statusPublished - 2008

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