CDK10/cyclin M is a protein kinase that controls ETS2 degradation and is deficient in STAR syndrome.
Cyclin-dependent kinases (CDKs) regulate a variety of fundamental cellular processes. CDK10 stands out as one of the last orphan CDKs for which no activating cyclin has been identified and no kinase activity revealed. Previous work has shown that CDK10 silencing increases ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2)-driven activation of the MAPK pathway, which confers tamoxifen resistance to breast cancer cells. The precise mechanisms by which CDK10 modulates ETS2 activity, and more generally the functions of CDK10, remain elusive. Here we demonstrate that CDK10 is a cyclin-dependent kinase by identifying cyclin M as an activating cyclin. Cyclin M, an orphan cyclin, is the product of FAM58A, whose mutations cause STAR syndrome, a human developmental anomaly whose features include toe syndactyly, telecanthus, and anogenital and renal malformations. We show that STAR syndrome-associated cyclin M mutants are unable to interact with CDK10. Cyclin M silencing phenocopies CDK10 silencing in increasing c-Raf and in conferring tamoxifen resistance to breast cancer cells. CDK10/cyclin M phosphorylates ETS2 in vitro, and in cells it positively controls ETS2 degradation by the proteasome. ETS2 protein levels are increased in cells derived from a STAR patient, and this increase is attributable to decreased cyclin M levels. Altogether, our results reveal an additional regulatory mechanism for ETS2, which plays key roles in cancer and development. They also shed light on the molecular mechanisms underlying STAR syndrome.
P2I2 Group, Protein Phosphorylation and Human Disease Unit, Station Biologique, Centre National de la Recherche Scientifique (CNRS), Unité de Service et de Recherche USR3151, 29680 Roscoff, France.
Vincent J
VJ
Guen
Carly
C
Gamble
Marc
M
Flajolet
Sheila
S
Unger
Aurélie
A
Thollet
Yoan
Y
Ferandin
Andrea
A
Superti-Furga
Pascale A
PA
Cohen
Laurent
L
Meijer
Pierre
P
Colas
D001003:Anal Canal / Q000002:abnormalities* / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000172:deficiency / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006972:Hypertelorism / Q000235:genetics* / Q000378:metabolism; D047468:Immunoprecipitation; D007668:Kidney / Q000002:abnormalities* / Q000378:metabolism; D061986:MCF-7 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D050787:Proto-Oncogene Protein c-ets-2 / Q000378:metabolism*; D013576:Syndactyly / Q000235:genetics* / Q000378:metabolism; D014034:Toes / Q000002:abnormalities*; D020798:Two-Hybrid System Techniques; D014564:Urogenital Abnormalities / Q000235:genetics* / Q000378:metabolism
C527705:CCNQ protein, human; D016213:Cyclins; C494069:ETS2 protein, human; D050787:Proto-Oncogene Protein c-ets-2; C501013:CDK10 protein, human; D018844:Cyclin-Dependent Kinases; D046988:Proteasome Endopeptidase Complex