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Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation.

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.

Pubmed ID: 17494760

Authors

  • Mahajan NP
  • Liu Y
  • Majumder S
  • Warren MR
  • Parker CE
  • Mohler JL
  • Earp HS
  • Whang YE

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

May 15, 2007

Associated Grants

  • Agency: NCI NIH HHS, Id: CA085772
  • Agency: NCI NIH HHS, Id: CA100700
  • Agency: NCI NIH HHS, Id: CA112553
  • Agency: NCI NIH HHS, Id: CA77739
  • Agency: NCI NIH HHS, Id: K08 CA085772
  • Agency: NCI NIH HHS, Id: K08 CA085772-06
  • Agency: NCI NIH HHS, Id: R21 CA100700
  • Agency: NCI NIH HHS, Id: R21 CA100700-02

Mesh Terms

  • Androgens
  • Animals
  • Cell Line, Tumor
  • DNA, Neoplasm
  • Disease Progression
  • Enhancer Elements, Genetic
  • Enzyme Activation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice
  • Models, Genetic
  • Mutation
  • Neuregulin-1
  • Phosphorylation
  • Phosphotyrosine
  • Prostatic Neoplasms
  • Protein Binding
  • Protein Transport
  • Protein-Tyrosine Kinases
  • Receptor, ErbB-2
  • Receptors, Androgen
  • Transcription, Genetic
  • Transplantation, Heterologous