Clear cell renal carcinoma essentially requires CDKL3 for oncogenesis
Abstract
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 a positive 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Lanjing Ma
College of Life and Health Sciences, Northeastern University
Zhongqiu Pang
College of Life and Health Sciences, Northeastern University
Haijiao Zhang
College of Life and Health Sciences, Northeastern University
Xueling Yang
College of Life and Health Sciences, Northeastern University
Shaoqin Zheng
College of Life and Health Sciences, Northeastern University
Yi Chen
Weijie Ding
College of Life and Health Sciences, Northeastern University
Qing Han
Xi Zhang
Liu Cao
Computational Biology Department, School of Computer Science
Teng Fei
College of Life and Health Sciences, Northeastern University
Qiang Wang
Daming Gao
State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences
Aina He
Department of Oncology, the Sixth People’s Hospital, School of Medicine, Shanghai Jiaotong University
Ke-Bang Hu
Department of Urology, The First Hospital of Jilin University
Xuexin Li
Department of General Surgery, The Fourth Affiliated Hospital, China Medical University
Ren Sheng
College of Life and Health Sciences, Northeastern University