title: Activation of the Rac-binding partner FHOD1 induces actin stress fibers via a ROCK-dependent mechanism.
abstract: Diaphanous related formins (DRFs) are part of the formin protein family that control morphogenesis, embryonic differentiation, cytokinesis, and cell polarity. DRFs organize the cytoskeleton in eukaryotic cells via the interaction with specific members of the Rho family of small GTPases including Rho, Rac, and Cdc42. This is best understood for Rho, which transmits signals to the actin cytoskeleton through the cooperation of its DRF effector mDia with ROCK (Rho-associated kinase). Here, we show that a constitutive active form of the Rac-interacting DRF FHOD1 (formin homology 2 domain containing 1) associates with F-actin in NIH3T3 cells, resulting in the formation of thick actin fibers. Cytoskeletal changes induced by FHOD1 correlated with the induction of serum response element transcription and were mediated by formin homology domains 1 and 2 of FHOD1. FHOD1-induced effects required the activity of the Rho-ROCK cascade that is targeted at a level downstream of Rho by the DRF. However, when the functional interaction of FHOD1 with individual GTPases was addressed, Rac but not Rho or Cdc42 bound to FHOD1 in cells and induced its recruitment to actin filaments and lamellipodia/membrane ruffles. Furthermore, activated FHOD1 interfered with lamellipodia formation. These results indicate that FHOD1 acts as an effector of Rac in actin rearrangements and transcriptional regulation and may provide a link for the Rac-dependent activation of the Rho cascade.
authors.affiliation: Institute for Hygiene, Department of Virology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Gasteier
authors.forename: Ricardo
authors.initials: R
authors.lastname: Madrid
authors.forename: Ellen
authors.initials: E
authors.lastname: Krautkrämer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schröder
authors.forename: Walter
authors.initials: W
authors.lastname: Muranyi
authors.forename: Serge
authors.initials: S
authors.lastname: Benichou
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Fackler
mesh_terms: D016475:3T3 Cells; D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D003599:Cytoskeleton / Q000378:metabolism; D005326:Fetal Proteins / Q000378:metabolism*; D000080865:Formins; D020558:GTP Phosphohydrolases / Q000737:chemistry; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011554:Pseudopodia / Q000737:chemistry; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases
chemical_list: D000199:Actins; C120021:FHOD1 protein, human; D005326:Fetal Proteins; D000080865:Formins; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D009687:Nuclear Proteins; D049452:Green Fluorescent Proteins; D005982:Glutathione Transferase; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020558:GTP Phosphohydrolases; D020744:rac GTP-Binding Proteins