Functional analysis of the DLC tumor suppressor family in 3D cell culture models
Final Report Abstract
Deleted in Liver Cancer 3 (DLC3) is a still poorly characterized Rho GTPase-activating protein (GAP) with potential tumor-suppressive function. Work from our lab has shown that DLC3 plays an important GAP-dependent role in maintaining cell-cell adhesions and in controlling endocytic membrane transport. For this, it is crucial that DLC3 is recruited to the respective membranes where it ensures proper 3D epithelial morphogenesis and endosomal trafficking. In fact, we previously reported the PDZ adaptor proteins Scribble and SNX27 to facilitate recruitment of DLC3 to cell contacts and endosomal membranes, respectively. Together with our biophysical partners, we now identified within an intrinsically disordered region in DLC3 a polybasic region (PBR) mediating the interaction with membranes and provide evidence that the structural and membrane binding properties of the PBR are regulated by phosphorylation. Using stable cell lines expressing wild type, PBR deleted, phosphomimetic, or phosphodeficient DLC3, the phosphorylation of the PBR is shown to act as a molecular switch, regulating membrane binding to cell contacts. Strikingly, during cell division, we observed a PBR-dependent recruitment to the cleavage furrow and midbody where spatiotemporal Rho signaling was controlled by DLC3 to ensure proper cytokinesis. In this project, we therefore not only unraveled a PBR-dependent regulation of DLC3 localization that involves phosphorylation, but also revealed a thus far unknown role for DLC3 during cell division.
Publications
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Golgi screen identifies the RhoGEF Solo as a novel regulator of RhoB and endocytic transport. Traffic, 24(4), 162-176.
Lungu, Cristiana; Meyer, Florian; Hörning, Marcel; Steudle, Jasmin; Braun, Anja; Noll, Bettina; Benz, David; Fränkle, Felix; Schmid, Simone; Eisler, Stephan A. & Olayioye, Monilola A.
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Regulation of the DLC3 tumor suppressor by a novel phosphoswitch. iScience, 27(7), 110203.
Frey, Yannick; Lungu, Cristiana; Meyer, Florian; Hauth, Franziskus; Hahn, Daniel; Kersten, Corinna; Heller, Vivien; Franz-Wachtel, Mirita; Macek, Boris; Barsukov, Igor & Olayioye, Monilola A.
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Regulation and functions of the DLC family of RhoGAP proteins: Implications for development and cancer. Cellular Signalling, 125, 111505.
Frey, Yannick; Lungu, Cristiana & Olayioye, Monilola A.
