Regulation of the DLC3 tumor suppressor by a novel phosphoswitch,iScience

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Regulation of the DLC3 tumor suppressor by a novel phosphoswitch
iScience ( IF 4.6 ) Pub Date : 2024-06-06 , DOI: 10.1016/j.isci.2024.110203
Yannick Frey ₁ , Cristiana Lungu _{1,

2} , Florian Meyer ₁ , Franziskus Hauth ₃ , Daniel Hahn ₁ , Corinna Kersten ₁ , Vivien Heller ₁ , Mirita Franz-Wachtel ₄ , Boris Macek ₄ , Igor Barsukov ₃ , Monilola A Olayioye _{1,

2}

Affiliation

Deleted in liver cancer 3 (DLC3) is a Rho GTPase-activating protein (RhoGAP) that plays a crucial role in maintaining adherens junction integrity and coordinating polarized vesicle transport by modulating Rho activity at the plasma membrane and endomembranes. By employing bioinformatical sequence analysis, in vitro experiments, and in cellulo assays we here identified a polybasic region (PBR) in DLC3 that facilitates the association of the protein with cellular membranes. Within the PBR, we mapped two serines whose phosphorylation can alter the electrostatic character of the region. Consequently, phosphomimetic mutations of these sites impaired the membrane association of DLC3. Furthermore, we found a new PBR-dependent localization of DLC3 at the midbody region, where the protein locally controlled Rho activity. Here, the phosphorylation-dependent regulation of DLC3 appeared to be required for proper cytokinesis. Our work thus provides a novel mechanism for spatiotemporal termination of Rho signaling by the RhoGAP protein DLC3.

中文翻译：

新型磷酸化开关对 DLC3 抑癌基因的调节

肝癌缺失 3 （DLC3）是一种 Rho GTP 酶激活蛋白（RhoGAP），通过调节质膜和内膜的 Rho 活性，在维持粘附连接完整性和协调极化囊泡转运方面起着至关重要的作用。通过采用生物信息序列分析、体外实验和纤维素测定，我们在这里确定了 DLC3 中的多碱基区（PBR），该区域促进蛋白质与细胞膜的结合。在 PBR 中，我们绘制了两个丝氨酸，其磷酸化可以改变该区域的静电特性。因此，这些位点的模拟磷酸化突变损害了 DLC3 的膜结合。此外，我们在中间体区域发现了 DLC3 的新 PBR 依赖性定位，该蛋白质局部控制 Rho 活性。在这里，DLC3 的磷酸化依赖性调节似乎是适当胞质分裂所必需的。因此，我们的工作为 RhoGAP 蛋白 DLC3 的时空终止 Rho 信号传导提供了一种新的机制。

更新日期：2024-06-06

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