title: Direct interaction between AR and PAK6 in androgen-stimulated PAK6 activation.
abstract: A p21-activated kinase 6 (PAK6) was previously identified to be an androgen receptor (AR) interacting protein through a yeast two-hybrid screening. We used hormone responsive prostate cancer LAPC4 and LNCap cell lines as models to study the signaling events associated with androgen stimulation and PAK6. An androgen-stimulated PAK6 kinase activation was observed in LAPC4 cells expressing endogenous PAK6 and in LNCap cells ectopically expressing a wild type PAK6. This activation was likely mediated through a direct interaction between AR and PAK6 since siRNA knock-down of AR in LAPC4 cells downregulated androgen-stimulated PAK6 activation. In addition, LNCap cells expressing a non-AR-interacting PAK6 mutant exhibited dampened androgen-stimulated kinase activation. As a consequence of androgen-stimulated activation, PAK6 was phosphorylated at multiple serine/threonine residues including the AR-interacting domain of PAK6. Furthermore, androgen-stimulation promoted prostate cancer cell motility and invasion were demonstrated in LNCap cells ectopically expressing PAK6-WT. In contrast, LNCap expressing non-AR-interacting mutant PAK6 did not respond to androgen stimulation with increased cell motility and invasion. Our results demonstrate that androgen-stimulated PAK6 activation is mediated through a direct interaction between AR and PAK6 and PAK6 activation promotes prostate cancer cells motility and invasion.
authors.affiliation: Urologic Research, Brigham and Women's Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Busby
authors.forename: Ciny
authors.initials: C
authors.lastname: John
authors.forename: Jianning
authors.initials: J
authors.lastname: Wei
authors.forename: Xin
authors.initials: X
authors.lastname: Yuan
authors.forename: Michael L
authors.initials: ML
authors.lastname: Lu
mesh_terms: D000728:Androgens / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054730:Protein Interaction Domains and Motifs; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; C429007:PAK6 protein, human; D054462:p21-Activated Kinases