Shepherding AKT and Androgen Receptor by Ack1 Tyrosine Kinase
ABSTRACT Ack1 (also known as ACK, TNK2, or activated Cdc42 kinase) is a structurally unique non-receptor tyrosine kinase that is expressed in diverse cell types. It integrates signals from plethora of ligand-activated receptor tyrosine kinases (RTKs), for example, MERTK, EGFR, HER2, PDGFR and insulin receptor to initiate intracellular signaling cascades. Ack1 transduces extracellular signals to cytosolic and nuclear effectors such as the protein kinase AKT/PKB and androgen receptor (AR), to promote cell survival and growth. While tyrosine phosphorylation of AR at Tyr267 regulates androgen-independent recruitment of AR to the androgen-responsive enhancers and transcription of AR target genes to drive prostate cancer progression, phosphorylation of an evolutionarily conserved Tyrosine 176 in the kinase domain of AKT is essential for mitotic progression and positively correlates with breast cancer progression. In contrast to AR and AKT, Ack1-mediated phosphorylation of the tumor suppressor Wwox at Tyr287 lead to rapid Wwox polyubiquitination followed by degradation. Thus, by its ability to promote tumor growth by negatively regulating tumor suppressor such as Wwox and positively regulating pro-survival factors such as AKT and AR, Ack1 is emerging as a critical player in cancer biology. In this review, we discuss recent advances in understanding the physiological functions of Ack1 signaling in normal cells and the consequences of its hyperactivation in various cancers.
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ABSTRACT: The prostate is an accessory sex gland of the male reproductive system, which produces alkaline prostatic fluid, capable of ensuring the spermatic viability to fertilize eggs within the female reproductive system. Functionally, the prostate is under the control of androgens, such as testosterone and dihydrotestosterone (DHT), and these hormones play a key role in the maintenance of sexual behavior and male reproduction. In prostatic microenvironment, the androgens may directly orchestrate its secretory activity and coordinate events that maintain its morphological integrity. It is noteworthy a dual role of androgens regulating both proliferation and apoptosis of the epithelial cell, suggesting the androgensAndrogen Receptors: Structural Biology, Genetics and Molecular Defects, 1 edited by Silvio Socorro, 01/2014: chapter ANDROGEN RECEPTOR SIGNALING IN PROSTATE CANCER: GENETIC AND MOLECULAR ASPECTS: pages 83-106; NOVA SCIENCE PUBLISHERS., ISBN: 978-1-62948-693-2
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ABSTRACT: This review summarizes our current understanding of the role of MTA family members, particularly MTA1, with a special emphasis on prostate cancer. The interest for the role of MTA1 in prostate cancer was boosted from our initial findings of MTA1 as a component of "vicious cycle" and a member of bone metastatic signature. Analysis of human prostate tissues, xenograft and transgenic mouse models of prostate cancer, and prostate cancer cell lines has provided support for the role of MTA1 in advanced disease and its potential role in initial stages of prostate tumor progression. Recent discoveries have highlighted a critical role for MTA1 in inflammation-triggered prostate tumorigenesis, epithelial-to-mesenchymal transition, prostate cancer survival pathways, and site metastasis. Evidence for MTA1 as an upstream negative regulator of tumor suppressor genes such as p53 and PTEN has also emerged. MTA1 is involved in prostate tumor angiogenesis by regulating several pro-angiogenic factors. Evidence for MTA1 as a prognostic marker for aggressive prostate cancer and disease recurrence has been described. Importantly, pharmacological dietary agents, namely resveratrol and its analogs, are potentially applicable to prostate cancer prevention, treatment, and control of cancer progression due to their potent inhibitory effects on MTA proteins.Cancer and metastasis reviews 10/2014; DOI:10.1007/s10555-014-9519-z · 6.45 Impact Factor
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ABSTRACT: Deregulated tyrosine kinase signaling alters cellular homeostasis to drive cancer progression. The emergence of a non-receptor tyrosine kinase (non-RTK), ACK1 (also known as activated Cdc42-associated kinase 1 or TNK2) as an oncogenic kinase, has uncovered novel mechanisms by which tyrosine kinase signaling promotes cancer progression. Although early studies focused on ACK1 as a cytosolic effector of activated transmembrane RTKs, wherein it shuttles between the cytosol and the nucleus to rapidly transduce extracellular signals from the RTKs to the intracellular effectors, recent data unfold a new aspect of its functionality as an epigenetic regulator. ACK1 interacts with the estrogen receptor (ER)/histone demethylase KDM3A (JHDM2a) complex, which modifies KDM3A by tyrosine phosphorylation to regulate the transcriptional outcome at HOXA1 locus to promote the growth of tamoxifen-resistant breast cancer. It is also well established that ACK1 regulates the activity of androgen receptor (AR) by tyrosine phosphorylation to fuel the growth of hormone-refractory prostate cancers. Further, recent explosion in genomic sequencing has revealed recurrent ACK1 gene amplification and somatic mutations in a variety of human malignancies, providing a molecular basis for its role in neoplastic transformation. In this review, we will discuss the various facets of ACK1 signaling, including its newly uncovered epigenetic regulator function, which enables cells to bypass the blockade to major survival pathways to promote resistance to standard cancer treatments. Not surprisingly, cancer cells appear to acquire an 'addiction' to ACK1-mediated survival, particularly under stress conditions, such as growth factor deprivation or genotoxic insults or hormone deprivation. With the accelerated development of potent and selective ACK1 inhibitors, targeted treatment for cancers harboring aberrant ACK1 activity may soon become a clinical reality.Oncogene advance online publication, 27 October 2014; doi:10.1038/onc.2014.350.Oncogene 10/2014; DOI:10.1038/onc.2014.350 · 8.56 Impact Factor