Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
Nat Cell Biol. 2022 May;24(5):723-736. doi: 10.1038/s41556-022-00886-z. Epub 2022 Apr 25.
The disassembly of integrin-containing focal adhesions (FAs) at mitotic entry is essential for cell rounding, mitotic retraction fibre formation, bipolar spindle positioning and chromosome segregation. The mechanism that drives FA disassembly at mitotic entry is unknown. Here, we show that the CDK1-cyclin B1 complex phosphorylates the integrin activator kindlin, which results in the recruitment of the cullin 9-FBXL10 ubiquitin ligase complex that mediates kindlin ubiquitination and degradation. This molecular pathway is essential for FA disassembly and cell rounding, as phospho-inhibitory mutations of the CDK1 motif prevent kindlin degradation, FA disassembly and mitotic cell rounding. Conversely, phospho-mimetic mutations promote kindlin degradation in interphase, accelerate mitotic cell rounding and impair mitotic retraction fibre formation. Despite the opposing effects on kindlin stability, both types of mutations cause severe mitotic spindle defects, apoptosis and aneuploidy. Thus, the exquisite regulation of kindlin levels at mitotic entry is essential for cells to progress accurately through mitosis.
在有丝分裂开始时，含整合素的粘着斑（FA）的解体对于细胞变圆、有丝分裂回缩纤维的形成、双极纺锤体定位和染色体分离是必不可少的。驱动 FA 在有丝分裂开始时解体的机制尚不清楚。在这里，我们表明 CDK1-cyclinB1 复合物磷酸化整合素激活因子韧蛋白，导致募集 cullin9-FBXL10 泛素连接酶复合物，介导韧蛋白泛素化和降解。该分子途径对于 FA 解体和细胞变圆是必不可少的，因为 CDK1 模体的磷酸化抑制突变阻止了韧蛋白的降解、FA 的解体和有丝分裂细胞的变圆。相反，磷酸模拟突变促进了有丝分裂细胞的变圆，加速了有丝分裂细胞的变圆，并损害了有丝分裂回缩纤维的形成。尽管这两种突变对韧蛋白稳定性有相反的影响，但都会导致严重的有丝分裂纺锤体缺陷、细胞凋亡和非整倍体。因此，在有丝分裂开始时，对韧蛋白水平的精确调节对于细胞准确地通过有丝分裂是必不可少的。
