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.

YES是非受体酪氨酸激酶SRC家族激酶（SFK）组的成员，酪氨酸激酶与肿瘤发生中涉及的多个关键细胞过程有关。抗微管蛋白剂已被广泛用作癌症患者的化学疗法，这些药物将细胞停在有丝分裂中，导致随后的细胞死亡。在本研究中，我们定义了YES的磷酸调节机制，该机制对其响应抗微管蛋白的作用至关重要。具体而言，我们发现在抗微管蛋白药物诱导的有丝分裂阻滞期间，细胞周期激酶CDK1在其N末端独特结构域的多个位点磷酸化了YES。YES的磷酸化在正常的有丝分裂期间发生。删除YES会导致前中期和多倍体以p53独立的方式停滞。我们进一步表明，YES调节抗微管蛋白的化学敏感性。重要的是，有丝分裂磷酸化对于这些作用至关重要。为了支持我们的发现，我们发现在复发性卵巢癌患者中YES表达较高。最后，通过表达谱分析，我们记录了YES磷酸化影响多个细胞周期调节因子的表达。总的来说，我们的结果揭示了在抗微管蛋白化学疗法治疗期间控制YES活性的先前未被认识的机制，并表明YES是治疗抗微管蛋白抗性癌症的潜在靶标。