Carli Annalisa L E, Hardy Joshua M, Hoblos Hanadi, Ernst Matthias, Lucet Isabelle S, Buchert Michael
Cancer Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia.
School of Cancer Medicine, La Trobe University, Bundoora, VIC 3086, Australia.
Biomedicines. 2023 Mar 22;11(3):990. doi: 10.3390/biomedicines11030990.
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.
双皮质素样激酶1（DCLK1）是一种功能性丝氨酸/苏氨酸（S/T）激酶，属于双皮质素蛋白家族成员，其特点是能够与微管（MT）结合。DCLK1被认为是一种癌症驱动基因，其上调与多种实体癌类型的总体生存率低有关。然而，人们对DCLK1如何与微管结合以及其激酶功能如何促进肿瘤发生过程知之甚少。本综述基于结构模型，不仅提出了各结构域的具体功能，还试图预测个别体细胞错义突变对DCLK1功能的影响。DCLK1中的体细胞错义突变最常位于N端微管结合区域，可能影响DCLK1与αβ-微管蛋白结合以及使微管聚合和稳定的能力。此外，DCLK1的微管结合亲和力受其自身磷酸化的负调控，因此预计影响激酶活性的突变会间接改变微管动力学。新出现的情况表明，DCLK1是一种与微管相关的蛋白，其与微管蛋白异二聚体和微管的相互作用是受到严格控制的过程，一旦被破坏，可能赋予促肿瘤特性。
