<br>蛋白质组学分析揭示了 PLK1 依赖性 G2/M 降解程序并将 PKA-AKAP2 与细胞周期控制联系起来,bioRxiv - Cell Biology

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蛋白质组学分析揭示了 PLK1 依赖性 G2/M 降解程序并将 PKA-AKAP2 与细胞周期控制联系起来
bioRxiv - Cell Biology Pub Date : 2023-10-12 , DOI: 10.1101/2023.10.11.561963
Ryan D Mouery _{1,

2} , Carolyn Hsu ₂ , Thomas Bonacci _{2,

3} , Derek L Bolhuis ₄ , Xianxi Wang _{2,

3} , Christine A Mills ₅ , E Drew Toomer _{2,

3} , Owen G Canterbury ₃ , Kevin C Robertson _{2,

3} , Timothy B Branigan ₆ , Nicholas G Brown _{2,

3} , Laura E Herring _{2,

3,

5} , Michael J Emanuele _{2,

3}

Affiliation

泛素-蛋白酶体系统的靶向蛋白质降解是调节细胞分裂的重要机制。激酶 PLK1 通过促进底物与 E3 泛素连接酶 SCF-βTrCP 的结合来协调细胞周期 G2/M 期的蛋白质降解。然而，PLK1 塑造有丝分裂蛋白质组的程度尚未得到表征。将深入的定量蛋白质组学与药理学 PLK1 抑制 (PLK1i) 相结合，我们鉴定了 200 多种蛋白质，其丰度在 G2/M 时因 PLK1i 而增加。我们验证了许多新的 PLK1 调节蛋白，包括细胞周期 E3 SCF-Cyclin F 的几种底物，证明 PLK1 通过至少两种不同的 SCF 家族 E3 连接酶促进蛋白水解。此外，我们发现蛋白激酶 A 锚定蛋白 AKAP2 受细胞周期调节，其有丝分裂降解依赖于 PLK1/βTrCP 信号轴。相互作用组分析表明，AKAP2 最强的相互作用因子在调节增殖的信号网络中发挥作用，包括 MAPK、AKT 和 Hippo。总而言之，我们的数据表明 PLK1 协调 G2/M 期广泛的蛋白质分解程序。我们提出，PLK1 介导的动态蛋白水解变化将增殖信号与细胞分裂过程中的核心细胞周期机制整合在一起。这对于 PLK1 异常调节的恶性肿瘤具有潜在影响。

"点击查看英文标题和摘要"

Proteomic Analysis Reveals a PLK1-Dependent G2/M Degradation Program and Links PKA-AKAP2 to Cell Cycle Control

Targeted protein degradation by the ubiquitin-proteasome system is an essential mechanism regulating cellular division. The kinase PLK1 coordinates protein degradation at the G2/M phase of the cell cycle by promoting the binding of substrates to the E3 ubiquitin ligase SCF-βTrCP. However, the magnitude to which PLK1 shapes the mitotic proteome has not been characterized. Combining deep, quantitative proteomics with pharmacologic PLK1 inhibition (PLK1i), we identified more than 200 proteins whose abundances were increased by PLK1i at G2/M. We validate many new PLK1-regulated proteins, including several substrates of the cell cycle E3 SCF-Cyclin F, demonstrating that PLK1 promotes proteolysis through at least two distinct SCF-family E3 ligases. Further, we found that the protein kinase A anchoring protein AKAP2 is cell cycle regulated and that its mitotic degradation is dependent on the PLK1/βTrCP-signaling axis. Interactome analysis revealed that the strongest interactors of AKAP2 function in signaling networks regulating proliferation, including MAPK, AKT, and Hippo. Altogether, our data demonstrate that PLK1 coordinates a widespread program of protein breakdown at G2/M. We propose that dynamic proteolytic changes mediated by PLK1 integrate proliferative signals with the core cell cycle machinery during cell division. This has potential implications in malignancies where PLK1 is aberrantly regulated.

更新日期：2023-10-12

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