La Trobe
Carli et al_Review.pdf (2.39 MB)

Structure-Guided Prediction of the Functional Impact of DCLK1 Mutations on Tumorigenesis

Download (2.39 MB)
journal contribution
posted on 2023-09-08, 06:24 authored by Annalisa Leandra Elena CarliAnnalisa Leandra Elena Carli, JM Hardy, H Hoblos, Matthias ErnstMatthias Ernst, IS Lucet, Michael BuchertMichael Buchert
Doublecortin-like kinase 1 (DCLK1) is a functional serine/threonine (S/T)-kinase and a member of the doublecortin family of proteins which are characterized by their ability to bind to microtubules (MTs). DCLK1 is a proposed cancer driver gene, and its upregulation is associated with poor overall survival in several solid cancer types. However, how DCLK1 associates with MTs and how its kinase function contributes to pro-tumorigenic processes is poorly understood. This review builds on structural models to propose not only the specific functions of the domains but also attempts to predict the impact of individual somatic missense mutations on DCLK1 functions. Somatic missense mutations in DCLK1 are most frequently located within the N-terminal MT binding region and likely impact on the ability of DCLK1 to bind to αβ-tubulin and to polymerize and stabilize MTs. Moreover, the MT binding affinity of DCLK1 is negatively regulated by its auto-phosphorylation, and therefore mutations that affect kinase activity are predicted to indirectly alter MT dynamics. The emerging picture portrays DCLK1 as an MT-associated protein whose interactions with tubulin heterodimers and MTs are tightly controlled processes which, when disrupted, may confer pro-tumorigenic properties.


This research was funded by the National Health and Medical Research Council of Australia (NHMRC) Senior Research Fellowship (1079257), Program Grant (1092788) and Investigator Grant (1173814) to M.E., NHMRC Investigator Grant (2008096) to J.M.H., NHMRC Project Grant (1162058) to I.S.L., NHMRC Project Grant (1143020) and a La Trobe University (LTU) RFA Understanding Disease grant to M.B. An LTU PhD scholarship (LTUFRS) to A.L.E.C., a WEHI Alan W Harris Scholarship to H.H. The Operational Infrastructure Support Program, Victorian Government, Australia, to the Olivia Newton-John Cancer Research Institute and Walter & Eliza Hall Institute. The contents of this published material are solely the responsibility of the individual authors and do not reflect the views of the NHMRC or funding partners.


Publication Date








Article Number








Rights Statement

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (