Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Cell Rep. 2024 Aug 27;43(8):114510. doi: 10.1016/j.celrep.2024.114510. Epub 2024 Jul 16.
Ubiquitination is an essential regulator of cell division. The kinase Polo-like kinase 1 (PLK1) promotes protein degradation at G2/M phase through the E3 ubiquitin ligase Skp1-Cul1-F box (SCF). However, the magnitude to which PLK1 shapes the mitotic proteome is uncharacterized. Combining quantitative proteomics with pharmacologic PLK1 inhibition revealed a widespread, PLK1-dependent program of protein breakdown at G2/M. We validated many PLK1-regulated proteins, including substrates of the cell-cycle E3 SCF, demonstrating that PLK1 promotes proteolysis through at least two distinct E3 ligases. We show that the protein-kinase-A-anchoring protein A-kinase anchor protein 2 (AKAP2) is cell-cycle regulated and that its mitotic degradation is dependent on the PLK1/βTrCP signaling axis. Expression of a non-degradable AKAP2 mutant resulted in actin defects and aberrant mitotic spindles, suggesting that AKAP2 degradation coordinates cytoskeletal organization during mitosis. These findings uncover PLK1's far-reaching role in shaping the mitotic proteome post-translationally and have potential implications in malignancies where PLK1 is upregulated.
泛素化是细胞分裂的重要调节因子。激酶 Polo 样激酶 1（PLK1）通过 E3 泛素连接酶 Skp1-Cul1-F 盒（SCF）在 G2/M 期促进蛋白降解。然而，PLK1 对有丝分裂蛋白质组的影响程度尚未确定。定量蛋白质组学与药理学 PLK1 抑制相结合，揭示了 G2/M 期广泛存在的、依赖于 PLK1 的蛋白质降解程序。我们验证了许多 PLK1 调节的蛋白质，包括细胞周期 E3 SCF 的底物，证明 PLK1 通过至少两种不同的 E3 连接酶促进蛋白水解。我们表明，蛋白激酶 A 锚定蛋白 A-激酶锚定蛋白 2（AKAP2）是细胞周期调节的，其有丝分裂降解依赖于 PLK1/βTrCP 信号轴。非降解性 AKAP2 突变体的表达导致肌动蛋白缺陷和有丝分裂纺锤体异常，表明 AKAP2 降解在有丝分裂过程中协调细胞骨架组织。这些发现揭示了 PLK1 在翻译后塑造有丝分裂蛋白质组方面的广泛作用，并可能对 PLK1 上调的恶性肿瘤具有潜在影响。
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