title: Male germ cell-associated kinase is overexpressed in prostate cancer cells and causes mitotic defects via deregulation of APC/CCDH1.
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.
authors: Department of Biochemistry and Molecular Medicine and University of California Davis Cancer Center, School of Medicine, University of California at Davis, Sacramento, CA, USA.
authors: L-Y
authors: LY
authors: Wang
authors: H-J
authors: HJ
authors: Kung
mesh_terms: D020816:Amino Acid Motifs; D064173:Anaphase-Promoting Complex-Cyclosome; D064096:Aurora Kinase A; D064127:Aurora Kinases; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D043171:Chromosomal Instability; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008938:Mitosis; D010766:Phosphorylation; D011467:Prostate / Q000166:cytology / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D064173:Anaphase-Promoting Complex-Cyclosome; D064096:Aurora Kinase A; D064127:Aurora Kinases; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; D018844:Cyclin-Dependent Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; D000097869:Polo-Like Kinase 1; C577584:FZR1 protein, human; C576917:AURKA protein, human; C081931:MAK protein, human