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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We thank members of the Park lab for critical reading of the manuscript. We are grateful to Genentech Inc. for HGF. Gab3 was kindly provided by Larry R. Rohrschneider, Gab2 by Benjamin Neel, and Pak4S445NS447E and Pak4K350M by Audrey Minden.

G.P. was supported by a studentship from McGill University Health Centre and Faculty of Medicine, McGill University. This research was supported by an operating grant to M.P. from the National Cancer Institute of Canada with funding from the Canadian Cancer Society. M.P. holds the Diane and Sal Guerrera Chair in Cancer Genetics at McGill University.