title: Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation.
abstract: Activation of the androgen receptor (AR) may play a role in androgen-independent progression of prostate cancer. Multiple mechanisms of AR activation, including stimulation by tyrosine kinases, have been postulated. We and others have recently shown involvement of activated Cdc42-associated tyrosine kinase Ack1 in advanced human prostate cancer. Here we provide the molecular basis for interplay between Ack1 and AR in prostate cancer cells. Activated Ack1 promoted androgen-independent growth of LNCaP and LAPC-4 prostate xenograft tumors, AR recruitment to the androgen-responsive enhancer, and androgen-inducible gene expression in the absence of androgen. Heregulin-stimulated HER2 activation induced Ack1 activation and AR tyrosine phosphorylation. Ack1 knockdown inhibited heregulin-dependent AR tyrosine phosphorylation, AR reporter activity, androgen-stimulated gene expression, and AR recruitment. Ack1 was recruited to the androgen-responsive enhancers after androgen and heregulin stimulation. In 8 of 18 primary androgen-independent prostate tumor samples, tyrosine-phosphorylated AR protein was detected and correlated with the detection of tyrosine-phosphorylated Ack1. Neither was elevated in androgen-dependent tumors or benign prostate samples. Activated Ack1 phosphorylated AR protein at Tyr-267 and Tyr-363, both located within the transactivation domain. Mutation of Tyr-267 completely abrogated and mutation of Tyr-363 reduced Ack1-induced AR reporter activation and recruitment of AR to the androgen-responsive enhancer. Expression of AR point mutants inhibited Ack1-driven xenograft tumor growth. Thus, Ack1 activated by surface signals or oncogenic mechanisms may directly enhance AR transcriptional function and promote androgen-independent progression of prostate cancer. Targeting the Ack1 kinase may be a potential therapeutic strategy in prostate cancer.
authors.affiliation: Lineberger Comprehensive Cancer Center, Departments of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Nupam P
authors.initials: NP
authors.lastname: Mahajan
authors.forename: Yuanbo
authors.initials: Y
authors.lastname: Liu
authors.forename: Samarpan
authors.initials: S
authors.lastname: Majumder
authors.forename: Maria R
authors.initials: MR
authors.lastname: Warren
authors.forename: Carol E
authors.initials: CE
authors.lastname: Parker
authors.forename: James L
authors.initials: JL
authors.lastname: Mohler
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.forename: Young E
authors.initials: YE
authors.lastname: Whang
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000378:metabolism; D018450:Disease Progression; D004742:Enhancer Elements, Genetic / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D020890:Neuregulin-1 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014183:Transplantation, Heterologous
chemical_list: D000728:Androgens; D004273:DNA, Neoplasm; D020890:Neuregulin-1; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; C410798:AR protein, human; C403262:TNK2 protein, human