Hepatocyte growth factor/scatter factor (HGF) signaling depends on Crk family adapter proteins

Hepatocyte growth factor (HGF; scatter factor) is a multipotent growth and morphogenesis factor implicated in cell migration, developmental processes, and proliferation. Recent work has shown that HGF activates the receptor tyrosine kinase c-Met which phosphorylates the large docking protein Gab1, leading to the recruitment of several signaling molecules, including the Crk family adapter proteins c-Crk and Crk-like (CRKL). HEK293 (human embryonic kidney) cells treated with HGF show reduced cell adhesion. In the present study it is documented that the HGF-induced adhesion loss is blocked by disruption of the Crk/CRKL signaling through the forced expression of a dominant negative Crk/CRKLSH3(1) binding fragment (CBR) of the guanine releasing protein C3G as well as by incubation with cell-penetrating Crk/CRKLSH3(1) domain blocker peptides. CBR expression also inhibits HGF-induced activation of N-terminal c-Jun kinase (JNK) and HGF-induced activation of the small GTPase Rac. We conclude that Crk family adapters are essential mediators of HGF-induced signaling events.