Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation.
Open accessAbstract
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.
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Ack1 can directly interact with the AR and specifically phosphorylate the AR at Tyr-267, a modification required for optimal AR recruitment to target genes at low-to no-androgen conditions.
“Ack1 can directly interact with the AR and can specifically phosphorylate the AR at Tyr-267, a modification that has been described to be required for optimal AR recruitment to target genes at low-to no-androgen conditions (59).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [59]
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- Authors
- Mahajan, N. P., Liu, Y., Majumder, S., Warren, M. R., Parker, C. E., Mohler, J. L., Earp, H. S., & Whang, Y. E.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- UNC Lineberger Comprehensive Cancer Center (US)
- Biochemistry and Biophysics,
- Roswell Park Comprehensive Cancer Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-05-15
- Volume
- 104
- Issue
- 20
- Pages
- 8438-8443
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1895968
- OpenAlex
- W2055013229
- Cited by
- 274
- References
- 26
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 9 · 2023: 17 · 2022: 28 · 2021: 9 · 2020: 11 · 2019: 13 · 2018: 11 · 2017: 11 · 2016: 11 · 2015: 15 · 2014: 19 · 2013: 24 · 2012: 21
- FWCI
- 14.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Elsa U. Pardee Foundation
- National Institutes of Health (CA77739)
- Genentech
- University of North Carolina at Chapel Hill
- National Cancer Institute (R21CA100700, CA-77739, R01CA112553, P01CA077739, CA 100700, K08CA085772, CA085772, CA112553)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- ACK1, androgen receptor, prostate cancer, androgen-independent progression, tyrosine phosphorylation, neuregulin-1, HER2, LNCaP cells, transcriptional activation
- MeSH terms
- Androgens, Animals, DNA, Neoplasm, Enhancer Elements, Genetic, Enzyme Activation, Humans, Male, Models, Genetic, Mutation, Phosphorylation, Prostatic Neoplasms, Protein Binding, Protein-Tyrosine Kinases, Receptors, Androgen, Transcription, Genetic, Transplantation, Heterologous, Gene Expression Regulation, Neoplastic, Disease Progression, Erb-b2 Receptor Tyrosine Kinases, Phosphotyrosine, Neuregulin-1, Protein Transport, Cell Line, Tumor, Mice
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