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Male germ cell-associated kinase is overexpressed in prostate cancer cells and causes mitotic defects via deregulation of APC/CCDH1

Oncogene volume 31, pages 2907–2918 (2012)Cite this article

Abstract

Male germ cell-associated kinase (MAK), a direct transcriptional target of androgen receptor (AR), is a co-activator of AR. In this study, we determined the activating mechanism of MAK and identified a previously unknown AR-independent role of MAK in mitosis. We found that MAK kinase activity requires dual phosphorylation of the conserved TDY motif and that the phosphorylation is dynamic during cell cycle. MAK associates with CDH1 (FZR1, fizzy/cell division cycle 20 related 1) and phosphorylates CDH1 at sites phosphorylated by cyclin-dependent kinases. When MAK is overexpressed, the binding of CDH1 to anaphase promoting complex/cyclosome decreased, resulting in an attenuation of anaphase-promoting complex/C ubiquitin ligase activity and the consequential stabilization of the CDH1 targets such as Aurora kinase A and Polo-like kinase 1. As such, overexpression of MAK leads to mitotic defects such as centrosome amplification and lagging chromosomes. Our immunohistochemistry result showed that MAK is overexpressed in prostate tumor tissues, suggesting a role of MAK in prostate carcinogenesis. Taken with our previous results, our data implicate MAK in both AR activation and chromosomal instability, acting in both early and late prostate cancer development.

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Acknowledgements

We greatly appreciate Anthony Martinez for assisting the quantitative reverse transcriptase–PCR experiment. We thank Dr Robert P Fisher in Memorial Sloan-Kettering Cancer Center for kindly providing the CCRK constructs, Dr Ai-Hong Ma and Dr Yi Guan for initiating this study. Dr Jui-Ching Wu at National Taiwan University, Dr Melanie C Bradnam and Dr Yoshihiro Izumiya at UC Davis provided helpful comments. This work is supported by NIH grants DK526529, DK078243, CA150197 and DoD grant PC093350 (to HJ Kung), as well as the DoD Postdoctoral Training Award W81XWH-08-1-0138 (to LY Wang). We also acknowledge the support of Auburn Community Cancer Endowment Fund.

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  1. Department of Biochemistry and Molecular Medicine and University of California Davis Cancer Center, School of Medicine, University of California at Davis, Sacramento, CA, USA

    L-Y Wang & H-J Kung

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Correspondence to H-J Kung.

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Wang, LY., Kung, HJ. Male germ cell-associated kinase is overexpressed in prostate cancer cells and causes mitotic defects via deregulation of APC/CCDH1. Oncogene 31, 2907–2918 (2012). https://doi.org/10.1038/onc.2011.464

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