DCLK1 autoinhibition and activation in tumorigenesis

Linna Cheng; Zejing Yang; Wenhao Guo; Chengyong Wu; Shufang Liang; Aiping Tong; Zhongwei Cao; Rick F Thorne; Sheng-Yong Yang; Yamei Yu; Qiang Chen

doi:10.1016/j.xinn.2021.100191

DCLK1 autoinhibition and activation in tumorigenesis

Innovation (Camb). 2021 Nov 26;3(1):100191. doi: 10.1016/j.xinn.2021.100191. eCollection 2022 Jan 25.

Authors

Linna Cheng^{1

2}, Zejing Yang¹, Wenhao Guo³, Chengyong Wu¹, Shufang Liang¹, Aiping Tong¹, Zhongwei Cao¹, Rick F Thorne⁴, Sheng-Yong Yang¹, Yamei Yu¹, Qiang Chen¹

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
² Institute of Hematology, Henan Key Laboratory of Stem Cell Differentiation and Modification, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou 450003, China.
³ Department of Abdominal Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
⁴ Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical Science, Zhengzhou University, Zhengzhou 450003, China.

Abstract

Doublecortin-like kinase 1 (DCLK1) is upregulated in many tumors and is a marker for tumor stem cells. Accumulating evidence suggests DCLK1 constitutes a promising drug target for cancer therapy. However, the regulation of DCLK1 kinase activity is poorly understood, particularly the function of its autoinhibitory domain (AID), and, moreover, no physiological activators of DCLK1 have presently been reported. Here we determined the first DCLK1 kinase structure in the autoinhibited state and identified the neuronal calcium sensor HPCAL1 as an activator of DCLK1. The C-terminal AID functions to block the ATP-binding site and is competitive with ATP. HPCAL1 binds directly to the AID in a Ca²⁺-dependent manner, which releases the autoinhibition. We also analyzed cancer-associated mutations occurring in the AID and elucidate how these mutations disrupt DCLK1 autoinhibition to elicit kinase activity upregulation. Our results present a molecular mechanism for autoinhibition and activation of DCLK1 kinase activity and provide insights into DCLK1-associated tumorigenesis.

Keywords: DCLK1; HPCAL1; autoinhibition; kinase; tumorigenesis.