Wang Yong, Liu Xinping, Liu Zheng, Hua Shasha, Jiang Kai
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Medical Research Institute, Wuhan University, Wuhan, 430071, China.
Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430071, China.
Cell Insight. 2024 Oct 11;4(1):100210. doi: 10.1016/j.cellin.2024.100210. eCollection 2025 Feb.
Tumor suppressor protein Adenomatous polyposis coli protein (APC) is an EB-binding and microtubule (MT) plus end-tracking protein; however, how exactly APC regulates MT dynamics remains elusive. Here, we show that in LLC-PK1 cells, APC and KIF2A, an MT depolymerase, form a complex clustering at the cell edge and destabilize MTs at the MT plus ends. Further biochemical characterization and mutational analysis reveal key residues for the APC-KIF2A interaction. In addition, APC counteracts the major MT-stabilizer CLASPs at MT plus ends and promotes directional cell migration via modulating cell adhesion force. Reconstitution experiments demonstrate that APC potentiates KIF2A-induced MT catastrophes and antagonizes the stabilizing effect of CLASP2 . In summary, APC functions as a positive regulator of MT-destabilizer and a negative regulator of MT-stabilizer to orchestrate MT dynamics.
肿瘤抑制蛋白腺瘤性息肉病大肠杆菌蛋白（APC）是一种与EB结合且追踪微管（MT）正端的蛋白；然而，APC究竟如何调节MT动力学仍不清楚。在此，我们表明在LLC-PK1细胞中，APC与一种MT解聚酶KIF2A形成复合物，聚集在细胞边缘，并使MT正端的MT不稳定。进一步的生化特性分析和突变分析揭示了APC与KIF2A相互作用的关键残基。此外，APC在MT正端对抗主要的MT稳定蛋白CLASPs，并通过调节细胞粘附力促进细胞定向迁移。重组实验表明，APC增强了KIF2A诱导的MT灾难，并拮抗CLASP2的稳定作用。总之，APC作为MT不稳定蛋白的正调节因子和MT稳定蛋白的负调节因子来协调MT动力学。
