Cyclin-dependent kinase 1-mediated phosphorylation of YES links mitotic arrest and apoptosis during antitubulin chemotherapy.

ABSTRACT

YES is a member of the SRC family kinase (SFK) group of non-receptor tyrosine kinases, which are implicated in multiple key cellular processes involved in oncogenesis. Antitubulin agents have been widely used as chemotherapeutics for cancer patients and these drugs arrest cells in mitosis, leading to subsequent cell death. In the present study, we define a mechanism for phospho-regulation of YES that is critical for its role in response to antitubulin agents. Specifically, we found that YES is phosphorylated at multiple sites on its N-terminal unique domain by the cell cycle kinase CDK1 during antitubulin drug-induced mitotic arrest. Phosphorylation of YES occurs during normal mitosis. Deletion of YES causes arrest in prometaphase and polyploidy in a p53-independent manner. We further show that YES regulates antitubulin chemosensitivity. Importantly, mitotic phosphorylation is essential for these effects. In support of our findings, we found that YES expression is high in recurrent ovarian cancer patients. Finally, through expression profiling, we documented that YES phosphorylation affects expression of multiple cell cycle regulators. Collectively, our results reveal a previously unrecognized mechanism for controlling the activity of YES during antitubulin chemotherapeutic treatment and suggest YES as a potential target for the treatment of antitubulin-resistant cancer.