title: PAK4: a pluripotent kinase that regulates prostate cancer cell adhesion.
abstract: Hepatocyte growth factor (HGF) is associated with tumour progression and increases the invasiveness of prostate carcinoma cells. Migration and invasion require coordinated reorganisation of the actin cytoskeleton and regulation of cell-adhesion dynamics. Rho-family GTPases orchestrate both of these cellular processes. p21-activated kinase 4 (PAK4), a specific effector of the Rho GTPase Cdc42, is activated by HGF, and we have previously shown that activated PAK4 induces a loss of both actin stress fibres and focal adhesions. We now report that DU145 human prostate cancer cells with reduced levels of PAK4 expression are unable to successfully migrate in response to HGF, have prominent actin stress fibres, and an increase in the size and number of focal adhesions. Moreover, these cells have a concomitant reduction in cell-adhesion turnover rates. We find that PAK4 is localised at focal adhesions, is immunoprecipitated with paxillin and phosphorylates paxillin on serine 272. Furthermore, we demonstrate that PAK4 can regulate RhoA activity via GEF-H1. Our results suggest that PAK4 is a pluripotent kinase that can regulate both actin cytoskeletal rearrangement and focal-adhesion dynamics.
authors.affiliation: Division of Cancer Studies, New Hunts House, Guy's Campus, King's College London, London SE1 1UL, UK. claire.wells@kcl.ac.uk
authors.forename: Claire M
authors.initials: CM
authors.lastname: Wells
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Whale
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
authors.forename: John R W
authors.initials: JR
authors.lastname: Masters
authors.forename: Gareth E
authors.initials: GE
authors.lastname: Jones
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D022001:Focal Adhesions / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D064067:Rho Guanine Nucleotide Exchange Factors; D054462:p21-Activated Kinases / Q000494:pharmacology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C577356:ARHGEF2 protein, human; D020662:Guanine Nucleotide Exchange Factors; D051419:Paxillin; D064067:Rho Guanine Nucleotide Exchange Factors; D017228:Hepatocyte Growth Factor; C116367:PAK4 protein, human; D054462:p21-Activated Kinases; D020742:rhoA GTP-Binding Protein
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