Pak4, a novel Gab1 binding partner, modulates cell migration and invasion by the Met receptor.
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.
Paliouras
Grigorios N
GN
McGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec, Canada.
Naujokas
Monica A
MA
Park
Morag
M
D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D009024:Morphogenesis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011554:Pseudopodia / Q000187:drug effects / Q000201:enzymology; D054462:p21-Activated Kinases / Q000737:chemistry / Q000378:metabolism*
D051339:Actin Depolymerizing Factors; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D054462:p21-Activated Kinases