Pak4, a Novel Gab1 Binding Partner, Modulates Cell Migration and Invasion by the Met Receptor

Abstract

Hepatocyte growth factor (HGF), the ligand for the Met receptor tyrosine kinase, induces epithelial cell dispersal, invasion, and morphogenesis, events that require remodeling of the actin cytoskeleton. The scaffold protein Gab1 is essential for these biological responses downstream from Met. We have identified p21-activated kinase 4 (Pak4) as a novel Gab1-interacting protein. We show that in response to HGF, Gab1 and Pak4 associate and colocalize at the cell periphery within lamellipodia. The association between Pak4 and Gab1 is dependent on Gab1 phosphorylation but independent of Pak4 kinase activity. The interaction is mediated through a region in Gab1, which displays no homology to known Gab1 interaction motifs and through the guanine exchange factor-interacting domain of Pak4. In response to HGF, Gab1 and Pak4 synergize to enhance epithelial cell dispersal, migration, and invasion, whereas knockdown of Pak4 attenuates these responses. A Gab1 mutant unable to recruit Pak4 fails to promote epithelial cell dispersal and an invasive morphogenic program in response to HGF, demonstrating a physiological requirement for Gab1-Pak4 association. These data demonstrate a novel association between Gab1 and Pak4 and identify Pak4 as a key integrator of cell migration and invasive growth downstream from the Met receptor.

Molecular background of the regional lymph node metastasis of gastric cancer (Review)

“…MET encodes a tyrosine kinase receptor that is associated with cancer progression (73,74). In a recent study, the amplification of MET was observed in patients with GC, and was indicative of the likelihood of tumor invasion and LN metastasis (75).…”

P21 activated kinases

“…This is consistent with their roles in controlling cell survival, proliferation, cytoskeletal organization, and migration. 74,[83][84][85][86][87][88][89] Neither the group A nor the group B Paks are frequently mutated in human cancer. Instead, overexpression and gene amplification of the Pak kinases, however, are commonly seen in cancer.…”

The Gab1 scaffold regulates RTK-dependent dorsal ruffle formation through the adaptor Nck

“…Met activation is also linked to pathways that modulate the actin cytoskeleton, cell adhesion and migration (Peschard and Park, 2007). These are coordinated through Gab1, where recruitment of Crk to Gab1 couples Met signalling to activation of Rap1 and Rac (Lamorte et al, 2002b;Rodrigues et al, 2005), and Gab1-Pak4 interaction is required for the localisation of Pak4 to lamellipodia and cell invasion (Paliouras et al, 2009). In epithelial colonies, Gab1 localises to lamellipodia with downstream proteins, such as Shp2, for prolonged periods (up to 15 minutes) following HGF stimulation (Frigault et al, 2008;Kallin et al, 2004;Maroun et al, 1999a).…”