Cyclin-dependent kinase 1-mediated phosphorylation of YES links mitotic arrest and apoptosis during antitubulin chemotherapy
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Updated: Feb 5, 2026
Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
Published on: May 3, 2018
Zhan Wang1, Xingcheng Chen2, Mei-Zuo Zhong3
1Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Eppley Institute for Research in Cancer & Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, United States.
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.
Insights
The study reveals that cell cycle kinase CDK1 phosphorylates YES during mitotic arrest, impacting cancer cell response to antitubulin drugs. This finding highlights YES as a potential therapeutic target for overcoming cancer treatment resistance.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Non-receptor tyrosine kinases, including SRC family kinases (SFKs) like YES, play roles in oncogenesis.
- Antitubulin agents are chemotherapy drugs that induce mitotic arrest and cell death.
- Understanding kinase regulation during mitosis is crucial for cancer therapy.
Purpose of the Study:
- To elucidate the phospho-regulation of YES during antitubulin drug-induced mitotic arrest.
- To define the role of YES phosphorylation in cellular response to antitubulin chemotherapeutics.
- To investigate YES as a potential therapeutic target in cancer treatment.
Main Methods:
- Investigated YES phosphorylation by CDK1 during mitotic arrest.
- Utilized YES deletion mutants to assess effects on cell cycle progression.
- Analyzed antitubulin chemosensitivity in relation to YES activity.
- Examined YES expression in ovarian cancer patient data.
- Performed expression profiling to identify downstream targets of YES phosphorylation.
Main Results:
- YES is phosphorylated by CDK1 at its N-terminal domain during antitubulin-induced mitotic arrest and normal mitosis.
- YES deletion leads to prometaphase arrest and polyploidy independently of p53.
- YES regulates sensitivity to antitubulin chemotherapy, with mitotic phosphorylation being essential.
- High YES expression correlates with recurrent ovarian cancer.
- YES phosphorylation influences the expression of multiple cell cycle regulators.
Conclusions:
- A novel mechanism of YES phospho-regulation by CDK1 during mitotic arrest has been identified.
- YES plays a critical role in the cellular response to antitubulin chemotherapeutics.
- YES is a potential therapeutic target for overcoming resistance to antitubulin-based cancer therapies.
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