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Vol. 20, Issue 20, 4400-4411, October 15, 2009

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DLC1 Activation Requires Lipid Interaction through a Polybasic Region Preceding the RhoGAP Domain

Patrik Erlmann^*, Simone Schmid^*, Florian A. Horenkamp, Matthias Geyer, Thomas G. Pomorski, and Monilola A. Olayioye^*

*Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany; Department of Physical Biochemistry, Max-Planck-Institute of Molecular Physiology, 44227 Dortmund, Germany; and Department of Plant Biology and Biotechnology, University of Copenhagen, 871 Frederiksberg C, Denmark

Submitted March 26, 2009; Revised August 13, 2009; Accepted August 18, 2009
Monitoring Editor: David G. Drubin

Deleted in Liver Cancer 1 (DLC1) is a GTPase-activating protein (GAP) with specificity for RhoA, RhoB, and RhoC that is frequently deleted in various tumor types. By inactivating these small GTPases, DLC1 controls actin cytoskeletal remodeling and biological processes such as cell migration and proliferation. Here we provide evidence that DLC1 binds to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P₂) through a previously unrecognized polybasic region (PBR) adjacent to its RhoGAP domain. Importantly, PI(4,5)P₂-containing membranes are shown to stimulate DLC1 GAP activity in vitro. In living cells, a DLC1 mutant lacking an intact PBR inactivated Rho signaling less efficiently and was severely compromised in suppressing cell spreading, directed migration, and proliferation. We therefore propose that PI(4,5)P₂ is an important cofactor in DLC1 regulation in vivo and that the PBR is essential for the cellular functions of the protein.

Address correspondence to: Dr. Monilola A. Olayioye (monilola.olayioye{at}izi.uni-stuttgart.de).

Abbreviations used: DLC, deleted in liver cancer; FRET, fluorescence resonance energy transfer; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; PA, phosphatidic acid; PBR, polybasic region; PC, phosphatidylcholine; PI, phosphatidylinositol; PI(3,5)P₃, phosphatidylinositol-3,4,5-trisphosphate; PI(4)P, phosphatidylinositol-4-phosphate; PI(4)P₂, phosphatidylinositol-4,5-bisphosphate; PLC-1, phospholipase C 1; PS, phosphatidylserine; SAM, sterile motif; START, StAR-related lipid transfer