The awakening of the CDK10/Cyclin M protein kinase

Abstract

Cyclin-dependent kinases (CDKs) play important roles in the control of fundamental cellular processes. Some of the most characterized CDKs are considered to be pertinent therapeutic targets for cancers and other diseases, and first clinical successes have recently been obtained with CDK inhibitors. Although discovered in the pre-genomic era, CDK10 attracted little attention until it was identified as a major determinant of resistance to endocrine therapy for breast cancer. In some studies, CDK10 has been shown to promote cell proliferation whereas other studies have revealed a tumor suppressor function. The recent discovery of Cyclin M as a CDK10 activating partner has allowed the unveiling of a protein kinase activity against the ETS2 oncoprotein, whose degradation is activated by CDK10/Cyclin M-mediated phosphorylation. CDK10/Cyclin M has also been shown to repress ciliogenesis and to maintain actin network architecture, through the phoshorylation of the PKN2 protein kinase and the control of RhoA stability. These findings shed light on the molecular mechanisms underlying STAR syndrome, a severe human developmental genetic disorder caused by mutations in the Cyclin M coding gene. They also pave the way to a better understanding of the role of CDK10/Cyclin M in cancer.

CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

“…To investigate the functional consequences of differential expression of cilia-related genes, we examined cilia growth and length in serum-starved Cdk10KO MEFs. Immunostaining, using ARL13B and gamma-tubulin antibodies, revealed significantly longer cilia in Cdk10KO MEFs than in WT cells ( Figures 3F and 3G), corroborating results that were reported after the silencing of Cdk10 or cyclin M by siRNA 10 (for a review, see Guen et al 33 ). BBS4, which interacts with CEP290, 34 is a BBSome component that is essential for cilia formation, 35 providing a rationale for our observation of longer cilia in Cdk10KO MEFs.…”

A homozygous deleterious CDK10 mutation in a patient with agenesis of corpus callosum, retinopathy, and deafness

“…If expressed, this mutant would be devoid of the C‐terminal bipartite nuclear localization sequence, while potentially retaining its ability to interact with CycM, two features that may phenocopy the naturally‐occurring shorter CDK10 isoforms produced from the highly complex alternative splicing events concerning the CDK10 gene (Sergère, Thuret, Le Roux, Carosella, & Leteurtre, ). As observed in a number of proteins playing multiple, complex regulatory roles, the different WT CDK10 isoforms are suspected to exert distinct, perhaps partly opposing functions (Guen, Gamble, Lees, & Colas, ). We therefore speculate that the shorter mutant CDK10 protein looses some of the functions exerted by the WT CDK10, at the advantage of other extra‐nuclear functions such as ciliogenesis inhibition.…”

Structural insights into the functional diversity of the CDK–cyclin family

“…CDK10 is implicated in regulating gene transcription, but not through RNA pol II phosphorylation. It phosphorylates diverse substrates including the ETS2 oncoprotein and the protein kinase PKN2, and mutations in its cognate cyclin, cyclin M, result in STAR syndrome, a human developmental disorder [ 10 , 11 ]. CDK10 mutant and knockout mice also show growth and developmental delays [ 12 ].…”