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First published online 9 December 2008
doi: 10.1242/jcs.036251

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DLC1 interacts with 14-3-3 proteins to inhibit RhoGAP activity and block nucleocytoplasmic shuttling

Rolf-Peter Scholz^*, Jennifer Regner^*,, Anke Theil, Patrik Erlmann, Gerlinde Holeiter, Ruth Jähne, Simone Schmid, Angelika Hausser and Monilola A. Olayioye

University of Stuttgart, Institute of Cell Biology and Immunology, Allmandring 31, 70569 Stuttgart, Germany

Author for correspondence (e-mail: monilola.olayioye{at}izi.uni-stuttgart.de)

Accepted 29 September 2008

Deleted in liver cancer 1 (DLC1) is a Rho-GTPase-activating protein (GAP) that is downregulated in various tumor types. In vitro, DLC1 specifically inactivates the small GTPases RhoA, RhoB and RhoC through its GAP domain and this appears to contribute to its tumor suppressor function in vivo. Molecular mechanisms that control DLC1 activity have not so far been investigated. Here, we show that phorbol-ester-induced activation of protein kinase C and protein kinase D stimulates association of DLC1 with the phosphoserine/phosphothreonine-binding 14-3-3 adaptor proteins via recognition motifs that involve Ser327 and Ser431. Association with 14-3-3 proteins inhibits DLC1 GAP activity and facilitates signaling by active Rho. We further show that treatment of cells with phorbol ester or coexpression of 14-3-3 proteins, blocks DLC1 nucleocytoplasmic shuttling, probably by masking a previously unrecognized nuclear localization sequence. The binding to 14-3-3 proteins is thus a newly discovered mechanism by which DLC1 activity is regulated and compartmentalized.

Key words: Rho GTPases, Actin cytoskeleton, Protein kinases C and D, Serine phosphorylation, Tumor suppressor

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