Activation of Rac1 by a Crk SH3-binding protein, DOCK180

DOCK180 is involved in integrin signaling through CrkII-p130(Cas) complexes. We have studied the involvement of DOCK180 in Rad signaling cascades. DOCK180 activated JNK in a manner dependent on Rad, Cdc42Hs, and SEK, and overexpression of DOCK180 increased the amount of GTP-bound Rad in 293T cells. Coexpression of CrkII and p130(Cas) enhanced this DOCK180-dependent activation of Rad. Furthermore, we observed direct binding of DOCK180 to Rad, but not to RhoA or Cdc42Hs. Dominant-negative Rad suppressed DOCK180-induced membrane spreading. These results strongly suggest that DOCK180 is a novel activator of Rad and involved in integrin signaling.