Open AccessARHGAP42 is activated by Src–mediated tyrosine phosphorylation to promote cell motility
Author(s) -
Weifeng Luo,
Radoslav Janoštiak,
Ondřej Tolde,
Larisa Ryzhova,
Lenka Koudelková,
Michal Dibus,
Jan Brábek,
Steven K. Hanks,
Daniel Rösel
Publication year - 2017
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.197434
Subject(s) - rhoa , biology , microbiology and biotechnology , tyrosine phosphorylation , proto oncogene tyrosine protein kinase src , phosphorylation , motility , tyrosine , gtpase activating protein , sh3 domain , sh2 domain , tyrosine kinase , gtpase , signal transduction , biochemistry , g protein
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 called 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. ARHGAP42 regulation was investigated by expression in mammalian cells. 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.