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DCLK1 autoinhibition and activation in tumorigenesis

Linna Cheng1,2, Zejing Yang1, Wenhao Guo3

  • 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.

Innovation (Cambridge (Mass.))
|January 3, 2022
PubMed

Insights

Doublecortin-like kinase 1 (DCLK1) activity in cancer is regulated by its autoinhibitory domain. Neuronal calcium sensor HPCAL1 activates DCLK1 by binding to this domain, offering new therapeutic strategies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Doublecortin-like kinase 1 (DCLK1) is upregulated in various tumors and marks tumor stem cells.
  • DCLK1 is a promising drug target for cancer therapy, but its kinase activity regulation is poorly understood.
  • The autoinhibitory domain (AID) and physiological activators of DCLK1 remain largely uncharacterized.

Purpose of the Study:

  • To elucidate the molecular mechanism of DCLK1 kinase activity regulation.
  • To identify physiological activators of DCLK1.
  • To understand how cancer-associated mutations affect DCLK1 activity.

Main Methods:

  • Determined the first crystal structure of DCLK1 in its autoinhibited state.
  • Identified HPCAL1 as a Ca2+-dependent activator of DCLK1.
  • Analyzed cancer-associated mutations in the DCLK1 AID.

Main Results:

  • The C-terminal AID blocks the ATP-binding site and is competitive with ATP.
  • HPCAL1 binds to the AID in a Ca2+-dependent manner, releasing autoinhibition.
  • Cancer-associated mutations in the AID disrupt autoinhibition, leading to upregulated kinase activity.

Conclusions:

  • A molecular mechanism for DCLK1 autoinhibition and activation by HPCAL1 has been established.
  • Understanding DCLK1 regulation provides insights into DCLK1-associated tumorigenesis.
  • DCLK1 and its activator HPCAL1 represent potential therapeutic targets for cancer treatment.
Keywords:
DCLK1HPCAL1autoinhibitionkinasetumorigenesis

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