Regulation of the DLC3 tumor suppressor by a novel phosphoswitch
Yannick Frey,
Cristiana Lungu,
Florian Meyer,
Franziskus Hauth,
Daniel Hahn,
Corinna Kersten,
Vivien Heller,
Mirita Franz-Wachtel,
Boris Macek,
Igor Barsukov,
Monilola A. Olayioye
Affiliations
Yannick Frey
University of Stuttgart, Institute of Cell Biology and Immunology, Stuttgart, Germany
Cristiana Lungu
University of Stuttgart, Institute of Cell Biology and Immunology, Stuttgart, Germany; University of Stuttgart, Stuttgart Research Center Systems Biology, Stuttgart, Germany
Florian Meyer
University of Stuttgart, Institute of Cell Biology and Immunology, Stuttgart, Germany
Franziskus Hauth
University of Liverpool, Institute of Systems, Molecular and Integrative Biology, Department of Biochemistry, Cell and Systems Biology, Liverpool, UK
Daniel Hahn
University of Stuttgart, Institute of Cell Biology and Immunology, Stuttgart, Germany
Corinna Kersten
University of Stuttgart, Institute of Cell Biology and Immunology, Stuttgart, Germany
Vivien Heller
University of Stuttgart, Institute of Cell Biology and Immunology, Stuttgart, Germany
Mirita Franz-Wachtel
Proteome Center Tübingen, University of Tübingen, Tübingen, Germany
Boris Macek
Proteome Center Tübingen, University of Tübingen, Tübingen, Germany
Igor Barsukov
University of Liverpool, Institute of Systems, Molecular and Integrative Biology, Department of Biochemistry, Cell and Systems Biology, Liverpool, UK
Monilola A. Olayioye
University of Stuttgart, Institute of Cell Biology and Immunology, Stuttgart, Germany; University of Stuttgart, Stuttgart Research Center Systems Biology, Stuttgart, Germany; Corresponding author
Summary: 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.
