DCLK1 autoinhibition and activation in tumorigenesis

• Published in: Innovation (New York, NY) Vol. 3; no. 1; p. 100191
• Main Authors: Cheng, Linna, Yang, Zejing, Guo, Wenhao, Wu, Chengyong, Liang, Shufang, Tong, Aiping, Cao, Zhongwei, Thorne, Rick F., Yang, Sheng-Yong, Yu, Yamei, Chen, Qiang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.01.2022; Elsevier
• Subjects: autoinhibition; DCLK1; HPCAL1; kinase; tumorigenesis; HPCAL1; kinase; tumorigenesis; autoinhibition; DCLK1
• ISSN: 2666-6758; 2666-6758
• DOI: 10.1016/j.xinn.2021.100191

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. [Display omitted] •The first reported DCLK1 kinase structure in the autoinhibited state•The C-terminal autoinhibitory domain functions to block the ATP-binding site•Cancer-associated mutations significantly upregulate DCLK1 kinase activity•HPCAL1 activates DCLK1 kinase activity in a Ca2+-dependent manner