Start Over

DCLK1 autoinhibition and activation in tumorigenesis.

Authors :: Cheng L
Yang Z
Guo W
Wu C
Liang S
Tong A
Cao Z
Thorne RF
Yang SY
Yu Y
Chen Q
Source :: Innovation (Cambridge (Mass.)) [Innovation (Camb)] 2021 Nov 26; Vol. 3 (1), pp. 100191. Date of Electronic Publication: 2021 Nov 26 (Print Publication: 2022).
Publication Year :: 2021
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 Ca <superscript>2+</superscript> -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.<br />Competing Interests: The authors declare no competing interests.<br /> (© 2021 The Authors.)