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J. Biol. Chem., Vol. 283, Issue 41, 27891-27903, October 10, 2008

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The Diaphanous-related Formin FHOD1 Associates with ROCK1 and Promotes Src-dependent Plasma Membrane Blebbing^*

Sebastian Hannemann, Ricardo Madrid^¶||, Jana Stastna, Thomas Kitzing^**, Judith Gasteier, André Schönichen, Jerome Bouchet^¶, Alberto Jimenez^||, Matthias Geyer, Robert Grosse^**, Serge Benichou^¶, and Oliver T. Fackler¹

From the Department of Virology and ^**Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France, ^¶INSERM U567, 75014 Paris, France, ^||Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid and Consejo Superior de Investigaciones Científicas, Cantoblanco, 28049 Madrid, Spain, and Abteilung Physikalische Biochemie, Max-Planck-Institut für Molekulare Physiologie, 44227 Dortmund, Germany

Diaphanous-related formins (DRFs) mediate GTPase-triggered actin rearrangements to regulate central cellular processes, such as cell motility and cytokinesis. The DRF FHOD1 interacts with the Rho-GTPase Rac1 and mediates formation of actin stress fibers in its deregulated form; the physiologically relevant activities and molecular mechanisms of endogenous FHOD1, however, are still unknown. Here we report that FHOD1 physically associates via the N-terminal part of its FH2 domain with the central domain of ROCK1. Although FHOD1 does not affect the kinase activity of ROCK1, the DRF is an efficient substrate for phosphorylation by ROCK1. Co-expression of FHOD1 and ROCK1 results in the generation of nonapoptotic plasma membrane (PM) blebs, to which the DRF is efficiently recruited. Blebbing induced by FHOD1 and ROCK1 depends on F-actin integrity, the Rho-ROCK cascade, and Src activity and is reminiscent of the recently described PM blebs triggered by expression of Src homology 4 (SH4) domain PM targeting signals. Consistently, endogenous FHOD1 is required in SH4 domain expressing cells for efficient PM blebbing and rounded cell morphology in two-dimensional cultures or three-dimensional matrices, respectively. Efficient association of FHOD1 with ROCK1, as well as recruitment of the DRF to blebs, depends on Src activity, suggesting that the functional interaction between both proteins is regulated by Src. These results define a role for endogenous FHOD1 in SH4 domain-induced blebbing and suggest that its activity is regulated by ROCK1 in a Src-dependent manner.

Received for publication, March 6, 2008 , and in revised form, July 3, 2008.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants Fa 378/6-1 (to O. T. F.), Ge 976/4-1 (to M. G.), Gr 2111/1-3 (to R. G.), and GRK1188 (to S. H. and J. S.) and grants from the French Agency for AIDS Research (to S. B.), Sidaction (to S. B., R. M., and J. B.), and the Ministerio de Educacion y Cultura, Ramon y Cajal program (to R. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed. Tel.: 49-6221-561322; Fax: 49-6221-565003; E-mail: oliver_fackler{at}med.uni-heidelberg.de.

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