Cheng Linna, Yang Zejing, Guo Wenhao, Wu Chengyong, Liang Shufang, Tong Aiping, Cao Zhongwei, Thorne Rick F, Yang Sheng-Yong, Yu Yamei, Chen Qiang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
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.
Innovation (Camb). 2021 Nov 26;3(1):100191. doi: 10.1016/j.xinn.2021.100191. eCollection 2022 Jan 25.
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 Ca-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.
双皮质素样激酶1（DCLK1）在许多肿瘤中表达上调，是肿瘤干细胞的标志物。越来越多的证据表明，DCLK1是一种很有前景的癌症治疗药物靶点。然而，人们对DCLK1激酶活性的调节了解甚少，尤其是其自身抑制结构域（AID）的功能，此外，目前尚未报道DCLK1的生理激活剂。在这里，我们确定了处于自身抑制状态的首个DCLK1激酶结构，并鉴定出神经元钙传感器HPCAL1是DCLK1的激活剂。C末端AID的功能是阻断ATP结合位点，并与ATP竞争。HPCAL1以钙依赖的方式直接与AID结合，从而解除自身抑制。我们还分析了AID中发生的癌症相关突变，并阐明这些突变如何破坏DCLK1的自身抑制，从而导致激酶活性上调。我们的结果揭示了DCLK1激酶活性自身抑制和激活的分子机制，并为DCLK1相关的肿瘤发生提供了见解。
