Kopp Petra, Lammers Reiner, Aepfelbacher Martin, Woehlke Günther, Rudel Thomas, Machuy Nikolaus, Steffen Walter, Linder Stefan
Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Ludwig-Maximilians-Universität, 80336 Munich, Germany.
Mol Biol Cell. 2006 Jun;17(6):2811-23. doi: 10.1091/mbc.e05-11-1010. Epub 2006 Mar 22.
Microtubules are important for the turnover of podosomes, dynamic, actin-rich adhesions implicated in migration and invasion of monocytic cells. The molecular basis for this functional dependency, however, remained unclear. Here, we show that contact by microtubule plus ends critically influences the cellular fate of podosomes in primary human macrophages. In particular, we identify the kinesin KIF1C, a member of the Kinesin-3 family, as a plus-end-enriched motor that targets regions of podosome turnover. Expression of mutation constructs or small interfering RNA-/short hairpin RNA-based depletion of KIF1C resulted in decreased podosome dynamics and ultimately in podosome deficiency. Importantly, protein interaction studies showed that KIF1C binds to nonmuscle myosin IIA via its PTPD-binding domain, thus providing an interface between the actin and tubulin cytoskeletons, which may facilitate the subcellular targeting of podosomes by microtubules. This is the first report to implicate a kinesin in podosome regulation and also the first to describe a function for KIF1C in human cells.
微管对于足体的周转很重要，足体是单核细胞迁移和侵袭过程中富含肌动蛋白的动态黏附结构。然而，这种功能依赖性的分子基础仍不清楚。在这里，我们表明微管正端的接触对原代人类巨噬细胞中足体的细胞命运有至关重要的影响。特别是，我们鉴定出驱动蛋白KIF1C，它是驱动蛋白-3家族的成员，是一种在正端富集的马达蛋白，靶向足体周转区域。突变体构建体的表达或基于小干扰RNA/短发夹RNA的KIF1C缺失导致足体动态性降低，并最终导致足体缺乏。重要的是，蛋白质相互作用研究表明，KIF1C通过其PTPD结合结构域与非肌肉肌球蛋白IIA结合，从而在肌动蛋白和微管蛋白细胞骨架之间提供了一个界面，这可能有助于微管对足体进行亚细胞靶向定位。这是第一份表明驱动蛋白参与足体调节的报告，也是第一份描述KIF1C在人类细胞中功能的报告。
