Nonreceptor Tyrosine Kinases in Prostate

Department of Urology, University of California at Davis, Sacramento, CA 95817, USA.
Neoplasia (New York, N.Y.) (Impact Factor: 4.25). 03/2007; 9(2):90-100. DOI: 10.1593/neo.06694
Source: PubMed


Carcinoma of the prostate (CaP) is the most commonly diagnosed cancer in men in the United States. Signal transduction molecules such as tyrosine kinases play important roles in CaP. Src, a nonreceptor tyrosine kinase (NRTK) and the first proto-oncogene discovered is shown to participate in processes such as cell proliferation and migration in CaP. Underscoring NRTK's and, specifically, Src's importance in cancer is the recent approval by the US Food and Drug Administration of dasatinib, the first commercial Src inhibitor for clinical use in chronic myelogenous leukemia (CML). In this review we will focus on NRTKs and their roles in the biology of CaP.
Publicly available literature from PubMed regarding the topic of members of NRTKs in CaP was searched and reviewed.
Src, FAK, JaK1/2, and ETK are involved in processes indispensable to the biology of CaP: cell growth, migration, invasion, angiogenesis, and apoptosis.
Src emerges as a common signaling and regulatory molecule in multiple biological processes in CaP. Src's relative importance in particular stages of CaP, however, required further definition. Continued investigation of NRTKs will increase our understanding of their biological function and potential role as new therapeutic targets.

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Available from: Hsing-Jien Kung, Nov 28, 2014
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    • "Among these kinases, Src, Fyn and Yes are ubiquitously expressed in all cells while other members are tissue specific. As the most wildly studied kinase among SFKs, Src has been implicated in a variety of malignancies [3], including prostate cancer [4]. Other than Src, Fgr [5] and Lyn [6] have also been found to be involved in prostate cancer. "

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    • "CR-CaP clinical samples exhibit increased relative protein tyrosine phosphorylation levels compared to levels in AD-CaP 31. This correlates with increased activation levels on non-receptor tyrosine kinases 32 as well as receptor tyrosine kinases such as Met 33, c-Kit 34 and the EGFR family 35, 36. However, the role of AR tyrosine phosphorylation may have been underappreciated because it is not induced by androgens such as dihydrotestosterone (DHT), whereas it is induced by EGF, heregulin, IL-6 or serum 20, 37, 38. "
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    ABSTRACT: There is growing appreciation that castration-recurrent prostate cancer (CR-CaP) is driven by the continued expression of androgen receptor (AR). AR activation in CR-CaP through various mechanisms, including AR overexpression, expression of AR splice variants or mutants, increased expression of co-regulator proteins, and by post-translational modification, allows for the induction of AR-regulated genes in response to very low levels of tissue-expressed, so-called intracrine androgens, resulting in pathways that mediate CaP proliferation, anti-apoptosis and oncogenic aggressiveness. The current review focuses on the role played by Src-family (SFK) and Ack1 non-receptor tyrosine kinases in activating AR through direct phosphorylation, respectively, on tyrosines 534 or 267, and how these modifications facilitate progression to CR-CaP. The fact that SFK and Ack1 are central mediators for multiple growth factor receptor signaling pathways that become activated in CR-CaP, especially in the context of metastatic growth in the bone, has contributed to recent therapeutic trials using SFK/Ack1 inhibitors in monotherapy or in combination with antagonists of the AR activation axis.
    International journal of biological sciences 06/2014; 10(6):620-626. DOI:10.7150/ijbs.8264 · 4.51 Impact Factor
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    • "This study also reported that while levels of FYN were increased in prostate cancer, other Src kinases either did not show consistent upregulation, or were elevated to a lesser degree than FYN [65]. In prostate cancer, FYN and other SFKs have been shown to mediate extracellular interactions driven by various molecules including IL-8, c-Met, EGFR and integrins, contributing to metastatic transformation of prostate cancer [66]. Additionally, studies have reported that overexpression of FYN results in promotion of the anti-apoptotic activity of Akt [67-69], and Akt activation is detected in prostate cancer [70]. "
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    ABSTRACT: While increased COX2 expression and prostaglandin levels are elevated in human cancers, the mechanisms of COX2 regulation at the post-translational level are unknown. Initial observation that COX2 forms adduct with non-receptor tyrosine kinase FYN, prompted us to study FYN-mediated post-translational regulation of COX2. We found that FYN increased COX2 activity in prostate cancer cells DU145, independent of changes in COX2 or COX1 protein expression levels. We report that FYN phosphorylates human COX2 on Tyr 446, and while corresponding phospho-mimetic COX2 mutation promotes COX2 activity, the phosphorylation blocking mutation prevents FYN-mediated increase in COX2 activity.
    Oncotarget 05/2014; 5(12). DOI:10.18632/oncotarget.1983 · 6.36 Impact Factor
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