PAK1 and PAK2 have different roles in HGF-induced morphological responses.
Hepatocyte growth factor (HGF) stimulates dissociation of epithelial cells (scattering) and cell migration. Several Rho GTPases are required for HGF-induced scattering. PAK1 and PAK2 are members of the p21-activated kinase (PAK) family of serine/threonine kinases, and are activated by the Rho GTPases Rac and Cdc42. Here we investigate the contributions of PAK1 and PAK2 to HGF-induced motile response. HGF stimulates phosphorylation of PAK1 and PAK2. Knockdown of PAK1 inhibits HGF-stimulated migration and loss of cell-cell junctions in DU145 prostate carcinoma cells, whereas knockdown of PAK2 enhances loss of cell-cell junctions and increases lamellipodium extension but does not affect migration speed. On the other hand, in PC3 prostate carcinoma cells, which lack cell-cell junctions, knockdown of PAK1 or PAK2 reduces HGF-stimulated migration. PAK2 knockdown increases phosphorylation of PAK1, indicating that PAK2 provides a negative feedback on PAK1. We hypothesise that PAK2 acts in part via PAK1 to regulate HGF-induced scattering.
Bright
Michael D
MD
King's College London, Randall Division of Cell and Molecular Biophysics, Guy's Campus, London, SE1 1UL, UK.
Garner
Andrew P
AP
Ridley
Anne J
AJ
D002277:Carcinoma / Q000201:enzymology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D055785:Gene Knockdown Techniques; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
D017228:Hepatocyte Growth Factor; C515903:PAK1 protein, human; C515907:PAK2 protein, human; D054462:p21-Activated Kinases