TY - JOUR
T1 - Activation of c-Src and Fyn kinases by protein tyrosine phosphatase RPTPalpha is substrate-specific and compatible with lipid raft localization
AU - Vacaresse, Nathalie
AU - Møller, Bente
AU - Danielsen, Erik Michael
AU - Okada, Masato
AU - Sap, Jan
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
U2 - 10.1074/jbc.M807964200
DO - 10.1074/jbc.M807964200
M3 - Journal article
C2 - 18948260
SN - 0021-9258
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
ER -