title: A PAK4-LIMK1 pathway drives prostate cancer cell migration downstream of HGF.
abstract: Hepatocyte growth factor (HGF) is associated with tumour progression and increases the invasiveness of prostate carcinoma cells. Cell migration and invasion requires reorganisation of the actin cytoskeleton; processes mediated by the Rho family GTPases. p21 activated kinase 4 (PAK4), an effector of the Rho family protein Cdc42, is activated downstream of HGF. We report here the novel finding that in prostate cancer cells PAK4 binds to and phosphorylates LIM kinase 1 (LIMK1) in an HGF-dependent manner. We show for the first time that variations in the level of PAK4 expression change the level of cofilin phosphorylation in cells, a change we correlate with LIMK1 activity, cell morphology and migratory behaviour. We identify for the first time a direct and localised interaction between PAK4 and LIMK1 within cells using FRET: FLIM. Moreover we show here that HGF mediates this interaction which is concentrated in small foci at the cell periphery. PAK4 and LIMK1 act synergistically to increase cell migration speed, whilst a reduction in PAK4 expression decreases cell speed. It is well established that unphosphorylated (active) cofilin is a required to drive cell migration. Our results support a model whereby HGF-stimulated cell migration also requires a cofilin phosphorylation step that is mediated by PAK4.
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, UK.
authors.forename: Tasneem
authors.initials: T
authors.lastname: Ahmed
authors.forename: Kerry
authors.initials: K
authors.lastname: Shea
authors.forename: John R W
authors.initials: JR
authors.lastname: Masters
authors.forename: Gareth E
authors.initials: GE
authors.lastname: Jones
authors.forename: Claire M
authors.initials: CM
authors.lastname: Wells
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D016764:Cell Polarity / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D054461:Lim Kinases / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D051339:Actin Depolymerizing Factors; D017228:Hepatocyte Growth Factor; C116367:PAK4 protein, human; C515892:LIMK1 protein, human; D054461:Lim Kinases; D054462:p21-Activated Kinases