title: Ajuba Phosphorylation by CDK1 Promotes Cell Proliferation and Tumorigenesis.
abstract: Recent studies identified the adaptor protein Ajuba as a positive regulator of Yes-associated protein (YAP) oncogenic activity through inhibiting large tumor suppressor (Lats1/2) core kinases of the Hippo pathway, a signaling pathway that plays important roles in cancer. In this study, we define a novel mechanism for phospho-regulation of Ajuba in mitosis and its biological significance in cancer. We found that Ajuba is phosphorylated in vitro and in vivo by cyclin-dependent kinase 1 (CDK1) at Ser(119) and Ser(175) during the G2/M phase of the cell cycle. Mitotic phosphorylation of Ajuba controls the expression of multiple cell cycle regulators; however, it does not affect Hippo signaling activity, nor does it induce epithelial-mesenchymal transition. We further showed that mitotic phosphorylation of Ajuba is sufficient to promote cell proliferation and anchorage-independent growth in vitro and tumorigenesis in vivo Collectively, our discoveries reveal a previously unrecognized mechanism for Ajuba regulation in mitosis and its role in tumorigenesis.
authors.affiliation: From the Eppley Institute for Research in Cancer, Fred and Pamela Buffett Cancer Center and the Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Xingcheng
authors.initials: X
authors.lastname: Chen
authors.affiliation: From the Eppley Institute for Research in Cancer, Fred and Pamela Buffett Cancer Center and the Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Seth
authors.initials: S
authors.lastname: Stauffer
authors.affiliation: From the Eppley Institute for Research in Cancer, Fred and Pamela Buffett Cancer Center and.
authors.forename: Yuanhong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: From the Eppley Institute for Research in Cancer, Fred and Pamela Buffett Cancer Center and dongj@unmc.edu.
authors.forename: Jixin
authors.initials: J
authors.lastname: Dong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D063646:Carcinogenesis; D002453:Cell Cycle; D049109:Cell Proliferation; D019926:Cyclin B / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017386:Sequence Homology, Amino Acid
chemical_list: C485608:AJUBA protein, human; D019926:Cyclin B; D060588:LIM Domain Proteins; D016203:CDC2 Protein Kinase
keywords: Hippo pathway; cell proliferation; cyclin-dependent kinase (CDK); mitosis; phosphorylation; signal transduction