MT1-MMP plays a crucial role in promoting the cellular invasion of cancer cells by degrading the extracellular matrix to create a path for migration. During this process, its localization at the leading edge of migrating cells is critical, and it is achieved by targeted transport of MT1-MMP-containing vesicles along microtubules by kinesin superfamily motor proteins (KIFs). Here we identified three KIFs involved in MT1-MMP vesicle transport: KIF3A, KIF13A, and KIF9. Knockdown of KIF3A and KIF13A effectively inhibited MT1-MMP-dependent collagen degradation and invasion, while knockdown of KIF9 increased collagen degradation and invasion. Our data suggest that KIF3A/KIF13A dependent MT1-MMP vesicles transport takes over upon KIF9 knockdown. Live-cell imaging analyses have indicated that KIF3A and KIF13A coordinate to transport the same MT1-MMP-containing vesicles from the trans-Golgi to the endosomes, and KIF13A alone transports the vesicle from the endosome to the plasma membrane. Taken together, we have identified a unique interplay between three KIFs to regulate leading edge localization of MT1-MMP and MT1-MMP-dependent cancer cell invasion.

MT1-MMP通过降解细胞外基质创造迁移路径，在促进癌细胞的细胞侵袭方面发挥着至关重要的作用。在这个过程中，它在迁移细胞前沿的定位是至关重要的，它是通过驱动蛋白超家族运动蛋白 (KIF) 沿着微管靶向运输含有 MT1-MMP 的囊泡来实现的。在这里，我们确定了三个参与 MT1-MMP 囊泡运输的 KIF：KIF3A、KIF13A 和 KIF9。KIF3A 和 KIF13A 的敲低有效地抑制了 MT1-MMP 依赖的胶原蛋白降解和侵袭，而 KIF9 的敲低增加了胶原蛋白的降解和侵袭。我们的数据表明，KIF3A/KIF13A 依赖的 MT1-MMP 囊泡转运接管了 KIF9 的敲除。反式高尔基体到内体，仅 KIF13A 将囊泡从内体运输到质膜。总之，我们已经确定了三种 KIF 之间的独特相互作用，以调节 MT1-MMP 的前沿定位和 MT1-MMP 依赖性癌细胞侵袭。