Medical Research Council, Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK.
Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
EMBO Rep. 2019 Sep;20(9):e47495. doi: 10.15252/embr.201847495. Epub 2019 Jul 24.
The concerted action of many protein kinases helps orchestrate the error-free progression through mitosis of mammalian cells. The roles and regulation of some prominent mitotic kinases, such as cyclin-dependent kinases, are well established. However, these and other known mitotic kinases alone cannot account for the extent of protein phosphorylation that has been reported during mammalian mitosis. Here we demonstrate that CK1α, of the casein kinase 1 family of protein kinases, localises to the spindle and is required for proper spindle positioning and timely cell division. CK1α is recruited to the spindle by FAM83D, and cells devoid of FAM83D, or those harbouring CK1α-binding-deficient FAM83D knockin mutations, display pronounced spindle positioning defects, and a prolonged mitosis. Restoring FAM83D at the endogenous locus in FAM83D cells, or artificially delivering CK1α to the spindle in FAM83D cells, rescues these defects. These findings implicate CK1α as new mitotic kinase that orchestrates the kinetics and orientation of cell division.
许多蛋白激酶的协同作用有助于协调哺乳动物细胞有丝分裂过程中的无错误进展。一些突出的有丝分裂激酶(如细胞周期蛋白依赖性激酶)的作用和调节已经得到很好的确立。然而,这些和其他已知的有丝分裂激酶本身并不能解释在哺乳动物有丝分裂过程中已经报道的蛋白质磷酸化的程度。在这里,我们证明了蛋白激酶家族中的 CK1α 定位于纺锤体,并且对于正确的纺锤体定位和及时的细胞分裂是必需的。FAM83D 将 CK1α 招募到纺锤体上,而缺乏 FAM83D 的细胞或携带 CK1α 结合缺陷的 FAM83D 基因突变的细胞则显示出明显的纺锤体定位缺陷,并延长有丝分裂。在 FAM83D 细胞中恢复内源性位点的 FAM83D 或在 FAM83D 细胞中人为地将 CK1α 递送到纺锤体上,可挽救这些缺陷。这些发现表明 CK1α 是一种新的有丝分裂激酶,它协调细胞分裂的动力学和方向。