The tyrosine kinase Src acts as a key regulator of cell motility by phosphorylating multiple protein substrates that control cytoskeletal and adhesion dynamics. In an earlier phosphotyrosine proteomics study, we identified a novel Rho-GTPase activating protein, now known as ARHGAP42, as a likely biologically relevant Src substrate. ARHGAP42 is a member of a family of RhoGAPs distinguished by tandem BAR-PH domains lying N-terminal to the GAP domain. Like other family members, ARHGAP42 acts preferentially as a GAP for RhoA. We show that Src principally phosphorylates ARHGAP42 on tyrosine 376 (Tyr-376) in the short linker between the BAR-PH and GAP domains. The expression of ARHGAP42 variants in mammalian cells was used to elucidate its regulation. We found that the BAR domain is inhibitory toward the GAP activity of ARHGAP42, such that BAR domain deletion resulted in decreased active GTP-bound RhoA and increased cell motility. With the BAR domain intact, ARHGAP42 GAP activity could be activated by phosphorylation of Tyr-376 to promote motile cell behavior. Thus, phosphorylation of ARHGAP42 Tyr-376 is revealed as a novel regulatory event by which Src can affect actin dynamics through RhoA inhibition.

• Klíčová slova
• Focal adhesion, GAP, GRAF, Motility, RhoA, Src, Tyrosine phosphorylation,
• MeSH
• fokální adheze metabolismus   MeSH
• fosforylace MeSH
• lidé MeSH
• myši MeSH
• pohyb buněk fyziologie   MeSH
• proteiny aktivující GTPasu genetika   metabolismus   MeSH
• Rho proteiny vázající GTP antagonisté a inhibitory   metabolismus   MeSH
• rhoA protein vázající GTP antagonisté a inhibitory   metabolismus   MeSH
• skupina kinas odvozených od src-genu metabolismus   MeSH
• tyrosin metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ARHGAP42 protein, human MeSH Prohlížeč
• proteiny aktivující GTPasu MeSH
• Rho proteiny vázající GTP MeSH
• rhoA protein vázající GTP MeSH
• RHOA protein, human MeSH Prohlížeč
• RhoA protein, mouse MeSH Prohlížeč
• skupina kinas odvozených od src-genu MeSH
• tyrosin MeSH