Clear cell renal carcinoma essentially requires CDKL3 for oncogenesis

• 成果类型: Article
• 署名作者: Ma, Lanjing; Pang, Zhongqiu; Zhang, Haijiao; Yang, Xueling; Zheng, Shaoqin; Chen, Yi; Ding, Weijie; Han, Qing; Zhang, Xi; Cao, Liu; Fei, Teng; Wang, Qiang; Gao, Daming; He, Aina; Hu, Ke-Bang; Li, Xuexin; Sheng, Ren
• 署名单位: Northeastern University - China; NewYork-Presbyterian Hospital; Columbia University; Northeastern University - China; China Medical University; South China University of Technology; Chinese Academy of Sciences; Center for Excellence in Molecular Cell Science, CAS; Shanghai Jiao Tong University; Jilin University; China Medical University; China Medical University; China Medical University; Karolinska Institutet
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12001
• DOI: 10.1073/pnas.2415244122
• 发表日期: 2025-02-18
• 关键词: cyclin d1; independent role; kinase; phosphorylation; akt; activation; cancer; akt/pkb; pbrm1; resistance

摘要

Clear cell renal cell carcinoma (ccRCC) is the predominant human renal cancer with surging incidence and fatality lately. Hyperactivation of hypoxia- inducible factor (HIF) and mammalian target of rapamycin (mTOR) signaling are the common signatures in ccRCC. Herein, we employed spontaneous ccRCC model to demonstrate the indispensability of an underappreciated Ser/Thr kinase, CDKL3, in the initiation and progression of ccRCC. Ablation of CDKL3 does not affect normal kidney, but abrogates Akt-mTOR hyperactivity and thoroughly prevents the formation and growth of the HIF- agitated ccRCC in vivo. Remarkable clinical correlations also supported the oncogenic role of CDKL3. Mechanism- wise, cytosolic CDKL3 unexpectedly behaves as the adaptor to physically potentiate mTORC2- dependent Akt activation without functioning through kinase activity. And mTORC2 can phosphorylate and stabilize CDKL3 to form apositive feedback loop to sustain the cancer- favored Akt-mTOR overactivation. Together, we revealed the pathological importance and molecular mechanism of CDKL3- mediated Akt-mTOR axis in ccRCC initiation and progression.