Kaur R, Yuan X, Lu ML, Balk SP.. Increased PAK6 expression in prostate cancer and identification of PAK6 associated proteins. Prostate 68: 1510-1516
Department of Medicine, Cancer Biology Program, Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. The Prostate
(Impact Factor: 3.57).
10/2008; 68(14):1510-6. DOI: 10.1002/pros.20787
PAK6 is a member of the p21-activated kinase (PAK) family of serine/threonine kinases that was originally cloned from prostate cancer (PCa) cells as an androgen receptor interacting protein, but its cellular distribution and functions have not been established.
An affinity purified rabbit anti-PAK6 antiserum was generated to assess PAK6 protein expression. PAK6 associated proteins were identified by immunopurification of 3xFlag-tagged PAK6 followed by LC/MS/MS.
We confirmed that PAK6 protein is expressed in prostate and breast cancer cell lines. PAK6 expression in LNCaP PCa cells was not directly androgen regulated, but was markedly increased when the cells were cultured for 6-8 weeks in steroid hormone depleted medium. By immunohistochemistry, PAK6 was weakly expressed in normal prostate epithelium. Its expression was increased in primary and metastatic PCa, and was further increased in tumors that relapsed after androgen deprivation therapy. LC/MS/MS identified IQ motif containing GTPase activating protein 1 (IQGAP1) and protein phosphatase 1B (PP1B) as candidate PAK6 interacting proteins, and these findings were confirmed by coimmunoprecipitation.
These results indicate that PAK6 contributes to PCa development and progression after androgen deprivation therapy, and that it may play roles in the regulation of motility and in stress responses.
Available from: David B Sacks
- "Recently, PAK6, a less well studied member of the PAK family was identified as a putative IQGAP1 binding protein  but the functional implications were not explored. Indeed, to date, very little is known about the role of PAK6 in mammalian cells other than as an androgen receptor-interacting protein . "
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ABSTRACT: p-21 activated 6 (PAK6), first identified as interacting with the androgen receptor (AR), is over-expressed in multiple cancer tissues and has been linked to the progression of prostate cancer, however little is known about PAK6 function in the absence of AR signaling. We report here that PAK6 is specifically required for carcinoma cell–cell dissociation downstream of hepatocyte growth factor (HGF) for both DU145 prostate cancer and HT29 colon cancer cells. Moreover, PAK6 overexpression can drive cells to escape from adhesive colonies in the absence of stimulation. We have localized PAK6 to cell–cell junctions and have detected a direct interaction between the kinase domain of PAK6 and the junctional protein IQGAP1. Co-expression of IQGAP1 and PAK6 increases cell colony escape and leads to elevated PAK6 activation. Further studies have identified a PAK6/E-cadherin/IQGAP1 complex downstream of HGF. Moreover, we find that β-catenin is also localized with PAK6 in cell–cell junctions and is a novel PAK6 substrate. We propose a unique role for PAK6, independent of AR signaling, where PAK6 drives junction disassembly during HGF-driven cell–cell dissociation via an IQGAP1/E-cadherin complex that leads to the phosphorylation of β-catenin and the disruption of cell–cell adhesions.
Electronic supplementary material
The online version of this article (doi:10.1007/s00018-013-1528-5) contains supplementary material, which is available to authorized users.
Available from: Michael lu
- "This suggests a potential role of PAK6 in prostate cancer metastatic progression. It also offers a plausible mechanism for the previously reported  positive correlations between PAK6 expression and high-grade prostate cancer Since steroid hormone such as androgen has long been recognized in promoting prostate cancer progression, our results provide a direct molecular link between androgenic signal and metastasis related molecular events. "
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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.
Available from: Xuefeng Gu
- "Previous studies have demonstrated that group II PAK activity can influence cancer-cell behavior31. PAK4 is closely associated with the progression and metastasis of breast cancer32, the adhesion of prostate cancer cells33 and the migration of human gastric cancer cells34, and PAK6 is overexpressed in prostate cancer and breast cancer cell lines29,35. "
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To investigate the roles of P21-activated kinase 5 (PAK5) in proliferation and tumorigenicity of human hepatocellular carcinoma (HCC).
HCC and matched paraneoplastictis tissue samples were obtained from 30 patients. Human HCC cell lines SMMC7721, HepG2, Hep3B, SK-HEP-1, Huh-7, and liver cell line HL-7702 were examined. The expression of PAK5 gene was studied using real-time qPCR and Western blotting. Cell proliferation was quantified with the MTT assay. Cell cycle was analyzed with flow cytometry. The tumorigenicity of Lv-shRNA-transfected HepG2 cells was evaluated in BALB/cA nude mice.
The mRNA level of PAK5 was significantly higher in 25 out of 30 HCC samples compared to the matched paraneoplastic tissues. The HCC cell lines showed varying expression of PAK5 protein, and the highest level was found in the HepG2 cells. PAK5 gene silencing in HepG2 cells markedly reduced the cell proliferation and colony formation, and induced cell cycle arrest in the G1 phase. Furthermore, PAK5 gene silencing suppressed the tumor formation in nude mice, and significantly decreased the expression of HCC-related genes Cyclin D1 and beta-catenin.
PAK5 may play essential roles in the initiation and progression of human HCC. Thus, it may be an effective therapeutic target or perhaps serve as a clinical diagnostic or prognostic marker in human HCC.
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