Autoregulatory control of microtubule binding in doublecortin-like kinase 1
- University of California, United States
- N Molecular Systems, Inc., United States
Abstract
The microtubule-associated protein, doublecortin-like kinase 1 (DCLK1), is highly expressed in a range of cancers and is a prominent therapeutic target for kinase inhibitors. The physiological roles of DCLK1 kinase activity and how it is regulated remain elusive. Here, we analyze the role of mammalian DCLK1 kinase activity in regulating microtubule binding. We find that DCLK1 autophosphorylates a residue within its C-terminal tail to restrict its kinase activity and prevent aberrant hyperphosphorylation within its microtubule-binding domain. Removal of the C-terminal tail or mutation of this residue causes an increase in phosphorylation within the doublecortin domains, which abolishes microtubule binding. Therefore, autophosphorylation at specific sites within DCLK1 have diametric effects on the molecule's association with microtubules. Our results suggest a mechanism by which DCLK1 modulates its kinase activity to tune its microtubule-binding affinity. These results provide molecular insights for future therapeutic efforts related to DCLK1's role in cancer development and progression.
Data availability
All data generated or analyzed during this study are included in the manuscript or as source files. Data has been deposited in Dryad Digital Repository and can be currently accessed at https://doi.org/10.25338/B8T634.
Article and author information
Author details
Kassandra M Ori-McKenney
Funding
National Institutes of Health (1R35GM133688)
- Kassandra M Ori-McKenney
Pew Charitable Trusts (A19-0406)
- Kassandra M Ori-McKenney
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Agulto et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Autoregulatory control of microtubule binding in doublecortin-like kinase 1
eLife 10:e60126.
https://doi.org/10.7554/eLife.60126
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