Structure-Guided Prediction of the Functional Impact of DCLK1 Mutations on Tumorigenesis
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 su...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-03-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/3/990 |
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| author | Annalisa L. E. Carli Joshua M. Hardy Hanadi Hoblos Matthias Ernst Isabelle S. Lucet Michael Buchert |
| author_facet | Annalisa L. E. Carli Joshua M. Hardy Hanadi Hoblos Matthias Ernst Isabelle S. Lucet Michael Buchert |
| author_sort | Annalisa L. E. Carli |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T06:54:02Z |
| format | Article |
| id | doaj.art-e3d165ad1af54d03b44552f5860586ff |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T06:54:02Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-e3d165ad1af54d03b44552f5860586ff2023-11-17T09:48:35ZengMDPI AGBiomedicines2227-90592023-03-0111399010.3390/biomedicines11030990Structure-Guided Prediction of the Functional Impact of DCLK1 Mutations on TumorigenesisAnnalisa L. E. Carli0Joshua M. Hardy1Hanadi Hoblos2Matthias Ernst3Isabelle S. Lucet4Michael Buchert5Cancer Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, AustraliaACRF Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, AustraliaACRF Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, AustraliaCancer Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, AustraliaACRF Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, AustraliaCancer Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, AustraliaDoublecortin-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.https://www.mdpi.com/2227-9059/11/3/990DCLK1DCXcrystal structurecryo-EMmissense mutationscancer |
| spellingShingle | Annalisa L. E. Carli Joshua M. Hardy Hanadi Hoblos Matthias Ernst Isabelle S. Lucet Michael Buchert Structure-Guided Prediction of the Functional Impact of DCLK1 Mutations on Tumorigenesis Biomedicines DCLK1 DCX crystal structure cryo-EM missense mutations cancer |
| title | Structure-Guided Prediction of the Functional Impact of DCLK1 Mutations on Tumorigenesis |
| title_full | Structure-Guided Prediction of the Functional Impact of DCLK1 Mutations on Tumorigenesis |
| title_fullStr | Structure-Guided Prediction of the Functional Impact of DCLK1 Mutations on Tumorigenesis |
| title_full_unstemmed | Structure-Guided Prediction of the Functional Impact of DCLK1 Mutations on Tumorigenesis |
| title_short | Structure-Guided Prediction of the Functional Impact of DCLK1 Mutations on Tumorigenesis |
| title_sort | structure guided prediction of the functional impact of dclk1 mutations on tumorigenesis |
| topic | DCLK1 DCX crystal structure cryo-EM missense mutations cancer |
| url | https://www.mdpi.com/2227-9059/11/3/990 |
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