The Scaffolding Protein RACK1 Interacts with Androgen Receptor and Promotes Cross-talk through a Protein Kinase C Signaling Pathway

Abstract

The androgen receptor (AR), a member of the nuclear hormone receptor superfamily, functions as a ligand-dependent transcription factor that regulates genes involved in cell proliferation and differentiation. Using a C-terminal region of the human AR in a yeast two-hybrid screen, we have identified RACK1 (receptor for activated Ckinase-1) as an AR-interacting protein. In this report we found that RACK1, which was previously shown to be a protein kinase C (PKC)-anchoring protein that determines the localization of activated PKCβII isoform, facilitates ligand-independent AR nuclear translocation upon PKC activation by indolactam V. We also observed RACK1 to suppress ligand-dependent and -independent AR transactivation through PKC activation. In chromatin immunoprecipitation assays, we demonstrate a decrease in AR recruitment to the AR-responsive prostate-specific antigen (PSA) promoter following stimulation of PKC. Furthermore, prolonged exposure to indolactam V, a PKC activator, caused a reduction in PSA mRNA expression in prostate cancer LNCaP cells. Finally, we found PKC activation to have a repressive effect on AR and PSA protein expression in androgen-treated LNCaP cells. Our data suggest that RACK1 may function as a scaffold for the association and modification of AR by PKC enabling translocation of AR to the nucleus but rendering AR unable to activate transcription of its target genes. The androgen receptor (AR), a member of the nuclear hormone receptor superfamily, functions as a ligand-dependent transcription factor that regulates genes involved in cell proliferation and differentiation. Using a C-terminal region of the human AR in a yeast two-hybrid screen, we have identified RACK1 (receptor for activated Ckinase-1) as an AR-interacting protein. In this report we found that RACK1, which was previously shown to be a protein kinase C (PKC)-anchoring protein that determines the localization of activated PKCβII isoform, facilitates ligand-independent AR nuclear translocation upon PKC activation by indolactam V. We also observed RACK1 to suppress ligand-dependent and -independent AR transactivation through PKC activation. In chromatin immunoprecipitation assays, we demonstrate a decrease in AR recruitment to the AR-responsive prostate-specific antigen (PSA) promoter following stimulation of PKC. Furthermore, prolonged exposure to indolactam V, a PKC activator, caused a reduction in PSA mRNA expression in prostate cancer LNCaP cells. Finally, we found PKC activation to have a repressive effect on AR and PSA protein expression in androgen-treated LNCaP cells. Our data suggest that RACK1 may function as a scaffold for the association and modification of AR by PKC enabling translocation of AR to the nucleus but rendering AR unable to activate transcription of its target genes. The androgen receptor (AR), 1The abbreviations used are: AR, androgen receptor; RACK1, receptor for activated C kinase-1; PKC, protein kinase C; PSA, prostate-specific antigen; DHT, dihydroxytestosterone; IndoV, indolactam V; GFX, GF109203X; GFP, green fluorescent protein; RFP, red fluorescent protein; RT-PCR, reverse transcriptase-polymerase chain reaction; SDM, steroid-depleted medium; ChIP, chromatin immunoprecipitation assays; TPA, 12-O-tetradecanoy phorbol-13 acetate; PBS, phosphate-buffered saline; SRC-1, steroid receptor coactivator-1. a member of the steroid hormone nuclear receptor superfamily, is a ligand-dependent transcription factor that regulates gene expression required for proliferation and differentiation of cells within the prostate and also has a role in the development and progression of prostate cancer. In its inactive state, unliganded AR is associated with heat-shock proteins from which it dissociates upon binding of the ligand, dihydrotestosterone (DHT), which is generated from testosterone by membrane-bound 5-α-reductase. Following homodimerization, AR translocates to the nucleus where it interacts with coactivators or corepressors and binds to androgen response elements (AREs) located in the promoter region of target genes triggering their transcriptional activation or repression (1Gnanapragasam V.J. Robson C.N. Leung H.Y. Neal D.E. BJU Int. 2000; 86: 1001-1013Crossref PubMed Google Scholar, 2Jenster G. Semin. Oncol. 1999; 26: 407-421PubMed Google Scholar). There is evidence to support AR cross-talk with other cellular signal transduction pathways resulting in AR ligand-independent activation and modulation of AR transactivation. There is also mounting evidence that ligand-independent activation of AR may play a role in hormone refractory prostate cancer. cAMP-dependent kinase (PKA) has been reported to mediate ligand-independent AR activation and cross-talk between AR and PKA signaling pathways resulting in androgen-independent induction of prostate-specific antigen (PSA) gene expression (3Nazareth L.V. Weigel N.L. J. Biol. Chem. 1996; 271: 19900-19907Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar, 4Sadar M.D. J. Biol. Chem. 1999; 274: 7777-7783Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar). In contrast, protein kinase C (PKC) negatively regulates AR-dependent transcription (5Darne C. Veyssiere G. Jean C. Eur. J. Biochem. 1998; 256: 541-549Crossref PubMed Scopus (48) Google Scholar). AR activation in the absence of ligand has been reported in response to the peptide hormones epidermal growth factor (EGF), keratinocyte growth factor (KGF), and insulin-like growth factor I (IGF-I), which serve as ligands for receptor-tyrosine kinases and activate downstream intracellular kinase cascades (6Culig Z. Hobisch A. Cronauer M.V. Radmayr C. Trapman J. Hittmair A. Bartsch G. Klocker H. Cancer Res. 1994; 54: 5474-5478PubMed Google Scholar). These growth factors can activate transcription from an androgen-responsive reporter construct in the absence of ligand or synergistically in conjunction with androgens. Interleukin-6 (IL-6), a multifunctional cytokine, can also stimulate ligand-independent AR activation via mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription-3 (STAT-3) signaling pathways in LNCaP human prostate cancer cells (7Ueda T. Mawji N.R. Bruchovsky N. Sadar M.D. J. Biol. Chem. 2002; 277: 38087-38094Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). Moreover, steroid receptor coactivator-1 (SRC-1) has been shown to enhance ligand-independent activation of the N-terminal domain (NTD) of the AR by IL-6 via a pathway that is dependent on MAPK in LNCaP (8Ueda T. Bruchovsky N. Sadar M.D. J. Biol. Chem. 2002; 277: 7076-7085Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar). The mechanism by which these signaling pathways affect AR function is not known. They may modulate AR via phosphorylation of either AR itself or of AR coregulators. For example, activation of the HER2/Neu MAPK pathway results in AR phosphorylation, increasing its ability to recruit coregulators and enhancing AR transactivation (9Wen Y. Hu M.C. Makino K. Spohn B. Bartholomeusz G. Yan D.H. Hung M.C. Cancer Res. 2000; 60: 6841-6845PubMed Google Scholar). Pyk2 interacts with ARA55 protein and represses AR transactivation via phosphorylation of ARA55 (10Wang X. Yang Y. Guo X. Sampson E.R. Hsu C.L. Tsai M.Y. Yeh S. Wu G. Guo Y. Chang C. J. Biol. Chem. 2002; 277: 15426-15431Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). In turn, these alternative pathways may affect AR translocation to the nucleus or transcriptional activity via interaction with scaffolding proteins that orchestrate the precise compartmentalization of signal transduction components. It is thought scaffolding proteins cluster signaling proteins thus allowing a tight control of cellular pathways as well as cross-talk between different cascades. Caveolin, a major component of caveolae membrane structures, has been implicated as a principal scaffold for many signal transduction pathways. In a study by Lu et al. (28Lu M.L. Schneider M.C. Zheng Y. Zhang X. Richie J.P. J. Biol. Chem. 2001; 276: 13442-13451Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar), caveolin was shown to interact with AR and its overexpression potentiated ligand-dependent AR activation. Recently, we identified filamin, an actin-binding protein also thought to act as a scaffold, as an AR-interacting protein that facilitates ligand-dependent AR nuclear translocation (11Ozanne D.M. Brady M.E. Cook S. Gaughan L. Neal D.E. Robson C.N. Mol. Endocrinol. 2000; 14: 1618-1626Crossref PubMed Google Scholar). In filamin-deficient M2 cells AR remained cytoplasmic even after prolonged exposure to androgen. Previous studies have also identified filamin as an interacting partner for caveolin (12Stahlhut M. van Deurs B. Mol. Biol. Cell. 2000; 11: 325-337Crossref PubMed Scopus (266) Google Scholar). Furthermore, caveolin also appears to have a role in ligand-independent estrogen receptor α nuclear translocation (13Schlegel A. Wang C. Pestell R.G. Lisanti M.P. Biochem. J. 2001; 359: 203-210Crossref PubMed Scopus (66) Google Scholar). The aim of this study was to identify novel AR-interacting proteins involved in movement or signaling from the cytoplasm to the nucleus. A yeast-two hybrid screen identified RACK1 (receptor for activated protein kinase C-1) as an AR-interacting protein. RACK1, a 36-kDa homologue of the β subunit of G proteins, is a member of the WD-40 family of proteins characterized by highly conserved internal WD-40 repeats (Trp-Asp) (14Ron D. Chen C.H. Caldwell J. Jamieson L. Orr E. D. S. A. 1994; PubMed Scopus Google Scholar, L. PubMed Scopus Google Scholar). It was identified as a protein that interacts with activated PKC and as a protein that the localization of for its function D. H. J. S. A. PubMed Scopus Google Scholar, D. Z. L. A. A. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). to its association with a of signaling proteins as A. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar), Mol. Cell. Biol. 1998; PubMed Google Scholar), β subunit J. Chang J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), G. M.D. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar), A. G. S. E. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), receptor Wang Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar, A. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar), a role of RACK1 as a or protein in intracellular signal transduction pathways has been We have found RACK1 to have a role in ligand-independent AR movement and transactivation via the PKC signaling pathway a function for this scaffolding protein in AR cross-talk with other signaling pathways. was from V, and from was from was from was from was from was as previously M.E. D.M. Gaughan L. Cook S. Neal D.E. Robson C.N. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). the and was used as in the and the data in a to the receptor for activated protein kinase C of with of the was by as previously M.E. D.M. Gaughan L. Cook S. Neal D.E. Robson C.N. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). of RACK1 of in via of from C of the used in to the RACK1 and via was via and by with yeast and on and In of and was with and from and via and used in the yeast two-hybrid the of from to the of the was to to and the was used for in interaction with and the was to the of protein in immunoprecipitation proteins and as previously M.E. D.M. Gaughan L. Cook S. Neal D.E. Robson C.N. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). from LNCaP and cells in with and and cells in of cells to the with reporter control and cells and in with that been of by with with the of as cells and for activity to the activity was for the activity to previously M.E. D.M. Gaughan L. Cook S. Neal D.E. Robson C.N. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). LNCaP cells in PBS, and in on for for with of protein after in and for and protein by for was with of and with a of to and to for with with protein was by for and in A and in was to and by by to The membrane was with was cells in cell of cells in and for in in the or absence of cells by for and on by to membrane with in for and with in in for and protein to was the of to RACK1 to was via and to on in cell of cells with and with of cells with and in with Following a cells in for a and to or with PBS, in for on and in mounting a was from LNCaP cells to the was from of reverse for The of the for the of PSA as and reverse a for for and for for with an for and a for a control was used to The by and and by cells on in for cells to androgen and PKC activator cells in steroid-depleted in steroid-depleted with or or indolactam for or Following chromatin immunoprecipitation as L. Cook S. Neal D.E. Robson C.N. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). for PSA also previously L. Cook S. Neal D.E. Robson C.N. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). RACK1 an AR-interacting two-hybrid an AR construct the and and as identified RACK1 as an AR-interacting protein The in the screen a region of from to The interaction of AR and RACK1 is in the of ligand, by an in activity in its of with AR in yeast an interaction between and the AR the upon with The in in the of that in the to the interaction or the upon ligand These data that AR interacts with RACK1 in the of RACK1 with the AR in and in the data from the yeast two-hybrid we to RACK1 interact with AR in The interaction was in transcription and of the proteins with in protein that interacts with AR the and and interaction was observed between and the transactivation domain and In with the results from the two-hybrid the of the RACK1 interaction on AR to be the and used to the interaction between RACK1 and AR in A was used to AR protein from prostate LNCaP cells to of RACK1 by LNCaP cells also with androgen to study the of ligand on the shown in a 36-kDa to RACK1 was observed in the absence and of ligand but was in control and or of of WD-40 which have been implicated in within RACK1 that of these may be for the The in the two-hybrid of the The domain of RACK1 required to interact with AR was by from the C of The for their ability to interact with in on and for and for an interaction between the proteins by these between and RACK1 was observed from the RACK1 construct the these results the in the interaction with the RACK1 in AR the of the role of RACK1 in AR movement to the nucleus was by the interacting proteins with or red fluorescent protein A report D. Z. L. A. A. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google RACK1 to act as a PKC protein that upon activation from intracellular to It has been previously a that unliganded AR is cytoplasmic but translocates to the nucleus upon of ligand V. B. C. Mol. Cell. Endocrinol. PubMed Scopus Google Scholar). nuclear translocation was also observed in this study in cells In the absence of is cytoplasmic with nuclear Following a exposure to is nuclear We the localization of in cells. was found to be cytoplasmic but also to a in cells In the state, in the by a fluorescent by androgen to from the cytoplasm to the nucleus remained in the cytoplasm et al. D. Z. L. A. A. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google RACK1 movement upon PKC activation from the to the cell cross-talk has been reported between the AR and PKC signaling pathways. The PKC signaling pathway has been reported to negatively AR-dependent we to AR translocates to the nucleus in the of RACK1 and upon PKC activation. with PKC activator indolactam V, unliganded remained cytoplasmic in the of androgen-independent nuclear translocation of was observed upon exposure to indolactam Furthermore, this movement was in the of PKC These results suggest that RACK1 has a role in ligand-independent movement of AR by activation of the PKC signaling RACK1 and of PKC AR the of RACK1 on AR transactivation in reporter the AR was the and androgen-independent prostate cancer cell in the absence and of RACK1 with shown in AR transactivation to and the of RACK1 AR transactivation to a to that observed in the absence of and we observed androgen-independent AR movement upon PKC activation and in the of RACK1, we also their effect on and -independent transcriptional activation of with PKC activator indolactam AR activity was to that observed in the absence of and upon with PKC AR activity was and a role for PKC signaling pathway in ligand-independent AR transactivation. AR transactivation a and but indolactam reporter activity and In the of the of reporter activity observed in the of AR was upon with RACK1 and A reduction was also observed upon with indolactam and The of RACK1 also AR transactivation upon with indolactam and and and These results suggest a role for appears to reverse the repression of and -independent AR activity observed upon with indolactam V. PKC a in AR to PSA PKC activation AR movement to the nucleus by RACK1 but has a repressive effect upon we to the AR is to target genes. we used chromatin immunoprecipitation in LNCaP cells an for the AR to the recruitment of the AR to the AR-responsive PSA promoter in the and absence of indolactam V. It has been previously shown that the AR associated with the PSA promoter upon androgen stimulation L. Cook S. Neal D.E. Robson C.N. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). we a decrease in AR association with the PSA promoter after of with indolactam is a decrease in AR recruitment to the promoter upon PKC activation and PKC PSA mRNA we found that PKC activation represses AR transactivation and AR recruitment to the PSA promoter we PSA expression We the effect of with indolactam for or on PSA mRNA expression in LNCaP cells by shown in prolonged exposure to indolactam caused a reduction in PSA PSA mRNA following for in to for activation of the PKC signaling pathway appears to suppress PSA mRNA PKC a on AR and PSA in LNCaP the that PKC activator may the cellular localization of AR, and nuclear of AR protein by LNCaP cells with and indolactam or and and nuclear from cells after In androgen-treated was an in nuclear AR, which of the protein in the of ligand and movement to the nucleus cells to and indolactam V, was a decrease in and nuclear AR with cell with and nuclear of AR from cells to and a in nuclear AR with cells and the PKC may reverse the repression upon PKC activation or the of ligand is AR and nuclear The cell of PSA an also the to the results for AR, exposure of cells to indolactam PSA protein expression in the of PSA protein expression is to that observed upon and cell of RACK1 remained for the of the In this we have identified RACK1 as an AR-interacting protein. RACK1 has been previously shown to be a protein that determines the localization of activated PKCβII and has as a scaffolding protein the interaction of signaling D. Z. L. A. A. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). These with the that a of scaffolding proteins filamin, and of transactivation implicated a role for RACK1 in AR function (11Ozanne D.M. Brady M.E. Cook S. Gaughan L. Neal D.E. Robson C.N. Mol. Endocrinol. 2000; 14: 1618-1626Crossref PubMed Google Scholar, M.L. Schneider M.C. Zheng Y. Zhang X. Richie J.P. J. Biol. Chem. 2001; 276: 13442-13451Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, L. S. S. Wang L. Chang C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). 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J. 2000; 14: PubMed Scopus Google that upon PKC activation RACK1 and PKCβII to the In this RACK1 in the cytoplasm AR Previous have shown RACK1 translocation to the nucleus upon PKA activation and within the AR-interacting domain in RACK1 is the of the WD-40 which has been shown to be by and its phosphorylation in the PKC activation was found to enhance phosphorylation of RACK1 and the interaction Mol. Cell. Biol. 1998; PubMed Google Scholar, M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). this also in the binding for PKC and PKC activation may this modification to RACK1 to interact with other signaling proteins as It be to RACK1 phosphorylation is for its role in AR signaling or other factors may the interaction of RACK1 and et al. A. G. M. A. A. M. M.V. D. C. J. 2000; PubMed Google an interaction of AR and with in prostate cancer cells. It may be that RACK1 in to AR following PKC activation AR Recently, et al. C. K. A. D. S. A. 2002; PubMed Scopus Google identified RACK1 as an scaffolding protein for receptor phosphorylation and function by phosphorylation of the subunit of by proteins as protein kinase proteins have been shown to PKC, and protein M.C. K. S. 1996; 271: PubMed Scopus Google Scholar). Our that RACK1 represses AR transactivation. RACK1 has also been shown to interact with the transcription factors and and their transactivation J. M. H. S. S. J. Mol. 2002; 14: Google Scholar, T. K. T. K. M. A. PubMed Scopus Google Scholar). Furthermore, RACK1 has been found to interact with protein a protein T. J. PubMed Scopus Google Scholar, M. H. D. Eur. J. Biochem. 2000; PubMed Scopus Google Scholar). nuclear RACK1 has a role in the induction of mRNA and protein expression upon exposure of cells to the I receptor for was identified as a downstream gene that is in response to the induction of by via RACK1 D. Mol. 2002; PubMed Scopus Google Scholar). in this study RACK1 was not in the it be to of RACK1 have a nuclear A of filamin has been found to with AR in the nucleus and AR transactivation by with S. A. PubMed Scopus Google Scholar). role of filamin as a nuclear transcription was filamin is as a cytoplasmic scaffolding protein. AR has also been shown to with actin-binding protein in H. Yeh S. K. Chang C. S. A. 2002; PubMed Scopus Google Scholar). A peptide of was found to in the nucleus with activated AR and enhance AR transactivation. Our studies also that PKC activation by indolactam and RACK1 have a repressive effect on AR transactivation. RACK1 may be as an AR in to PKC, which in the receptor and its transcriptional the of a to be Previous studies reported repression of gene induction by PKC activator and TPA, which was in to overexpression of and Zhang J. Oncol. Res. 1994; Google Scholar). study an of AR activity by but not by stimulation of the PKA pathway in the absence of androgen (5Darne C. Veyssiere G. Jean C. Eur. J. Biochem. 1998; 256: 541-549Crossref PubMed Scopus (48) Google Scholar). In contrast, it has been shown that AR can be activated by PKA activator in a ligand-independent (3Nazareth L.V. Weigel N.L. J. Biol. Chem. 1996; 271: 19900-19907Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar). The of by these studies that the of the promoter in the reporter gene ligand-independent activation of Our study that PKC activation represses the androgen induction of PSA protein which is in with the repression previously observed by Cancer Res. Google Scholar). The of AR to with the PSA promoter upon PKC activation is AR recruitment to the promoter these results and transactivation reporter In contrast, cross-talk between AR and PKA signal transduction pathways has been shown to androgen-independent induction of PSA gene expression by an AR-dependent pathway M.D. J. Biol. Chem. 1999; 274: 7777-7783Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar). We that upon association with RACK1, AR is by phosphorylation by PKC or which it unable to to or other coregulators and activate transcription of its target genes but has the to to the nucleus. In we have shown that upon PKC activation AR translocates to the nucleus in the absence of ligand, by scaffolding protein RACK1 but is unable to with target gene promoter and their The of these for activation of the AR may be in the progression of prostate cancer to androgen It has been that may be in prostate cancer and has been shown to have the to the of prostate cancer D. D.M. Cancer Res. 2002; Google Scholar, J. A. K. A. J. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). RACK1 has been shown to have a role in the signaling of of these PKC is required to and PKC modulate the interaction and the mechanism of repression of AR transcriptional A role for RACK1 in the of other of the also to be We for