title: MST2 phosphorylation at serine 385 in mitosis inhibits its tumor suppressing activity.
abstract: Mammalian sterile 20-like kinase 1/2 (MST1/2) are core tumor suppressors in the Hippo signaling pathway. MST1/2 have been shown to regulate mitotic progression. Here, we report a novel mechanism for phospho-regulation of MST2 in mitosis and its biological significance in cancer. We found that the mitotic kinase cyclin-dependent kinase 1 (CDK1) phosphorylates MST2 in vitro and in vivo at serine 385 during antimitotic drug-induced G2/M phase arrest. This phosphorylation occurs transiently during unperturbed mitosis. Mitotic phosphorylation of MST2 does not affect its kinase activity or Hippo-YAP signaling. We further showed that mitotic phosphorylation-deficient mutant MST2-S385A possesses higher activity in suppressing cell proliferation and anchorage-independent growth in vitro and tumorigenesis in vivo. Together, our findings reveal a novel layer of regulation for MST2 in mitosis and its role in tumorigenesis.
authors: Eppley Institute for Research in Cancer, Fred & Pamela Buffett Cancer Center, United States; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors: Xingcheng
authors: X
authors: Chen
authors: Eppley Institute for Research in Cancer, Fred & Pamela Buffett Cancer Center, United States.
authors: Yuanhong
authors: Y
authors: Chen
authors: Eppley Institute for Research in Cancer, Fred & Pamela Buffett Cancer Center, United States. Electronic address: dongj@unmc.edu.
authors: Jixin
authors: J
authors: Dong
mesh_terms: D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019926:Cyclin B / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D050256:Antimitotic Agents; D016203:CDC2 Protein Kinase; D019926:Cyclin B; D050505:Mutant Proteins; D010768:Phosphoserine; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; D025521:Tumor Suppressor Proteins; C097835:STK3 protein, human; D000099317:Hippo Kinases
keywords: CDK1; MST2; Mitotic phosphorylation; Tumor suppressor