Abstract
CDK16 (also known as PCTAIRE1 or PCTK1) is an atypical member of the cyclin-dependent kinase (CDK) family that forms an active complex with cyclin Y (CCNY). Although both proteins have been recently implicated in cancer pathogenesis, it is still unclear how the CDK16/CCNY complex exerts its biological activity. To understand the CDK16/CCNY network, we used complementary proteomic approaches to identify potential substrates of this complex. We identified several candidates implicating the CDK16/CCNY complex in cytoskeletal dynamics, and we focused on the microtubule-associated protein regulator of cytokinesis (PRC1), an essential protein for cell division that organizes antiparallel microtubules and whose deregulation may drive genomic instability in cancer. Using analog-sensitive (AS) CDK16 generated by CRISPR-Cas9 mutagenesis in 293T cells, we found that specific inhibition of CDK16 induces PRC1 dephosphorylation at Thr481 and delocalization to the nucleus during interphase. The observation that CDK16 inhibition and PRC1 downregulation exhibit epistatic effects on cell viability confirms that these proteins can act through a single pathway. In conclusion, we identified PRC1 as the first substrate of the CDK16/CCNY complex and demonstrated that the proliferative function of CDK16 is mediated by PRC1 phosphorylation. As CDK16 is emerging as a critical node in cancer, our study reveals novel potential therapeutic targets.
Highlights
Cyclin-dependent kinase 16 (CDK16, known as PCTAIRE1 or PCTK1) is a member of the PCTAIRE family, which is a group of kinases related to the cyclin-dependent kinase (CDK) family that includes PCTAIRE-1, −2 and −31
It was recently shown that the small molecule kinase inhibitor dabrafenib (Tafinlar) targets oncogenic mutant BRAF V600E and potently inhibits CDK1617 and that this mechanism may contribute to the efficacy of this drug against BRAF wild-type (WT) tumors[18]
To identify substrates of the CDK16/cyclin Y (CCNY) CDK–cyclin complex, we examined the activity of recombinant CDK16 and CCNY in an in vitro kinase assay
Summary
Cyclin-dependent kinase 16 (CDK16, known as PCTAIRE1 or PCTK1) is a member of the PCTAIRE family, which is a group of kinases related to the CDK family that includes PCTAIRE-1, −2 and −31. CDK16 is broadly expressed in human tissues, with the highest levels found in brain and testis[2]. High levels of CDK16 expression can be found in a wide range of transformed and immortalized cell lines of epithelial origin[3,4,5]. CDK16 plays an oncogenic role that has been linked to the regulation of tumor suppressor p27 protein degradation[14], activation of the mammalian target of rapamycin pathway[15] and regulation of the WNT/βcatenin pathway[16]. It was recently shown that the small molecule kinase inhibitor dabrafenib (Tafinlar) targets oncogenic mutant BRAF V600E and potently inhibits CDK1617 and that this mechanism may contribute to the efficacy of this drug against BRAF wild-type (WT) tumors[18]
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