title: The RhoGAP activity of OPHN1, a new F-actin-binding protein, is negatively controlled by its amino-terminal domain.
abstract: Recent human genetic approaches showed that mutations in three genes encoding OPHN1, PAK3, and alphaPIX cause nonspecific X-linked mental retardation. These three proteins act to modulate Rho GTPase signaling pathways and may participate in neuronal morphogenesis by regulating the actin cytoskeleton. Here we showed that the Oligophrenin-1 gene is expressed in the developing spinal cord and later in brain areas that are characterized by high synaptic plasticity. At the cellular level OPHN1 is expressed in both glial and neuronal cells where it colocalizes with actin, notably at the tip of growing neurites. This interaction seems to be direct through a novel uncharacterized domain in the carboxyl-terminal end of OPHN1. Overexpression experiments in fibroblasts showed that the OPHN1 RhoGAP domain regulates in vivo the actin cytoskeleton by inhibition of Rho pathways. Interestingly the amino-terminal domain of OPHN1 inhibits the RhoGAP activity through an as yet unknown mechanism, suggesting that OPHN1 may be tightly regulated in vivo.
authors.affiliation: Institut Cochin, INSERM U567, CNRS UMR8104, Université Paris V René Descartes, IFR116, 24 rue du Fg St Jacques, 75014, Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Fauchereau
authors.forename: Ulrike
authors.initials: U
authors.lastname: Herbrand
authors.forename: Philippe
authors.initials: P
authors.lastname: Chafey
authors.forename: Alexander
authors.initials: A
authors.lastname: Eberth
authors.forename: Annette
authors.initials: A
authors.lastname: Koulakoff
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Vinet
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Ahmadian
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Pierre
authors.initials: P
authors.lastname: Billuart
mesh_terms: D016475:3T3 Cells; D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002490:Central Nervous System / Q000002:abnormalities* / Q000166:cytology / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D025461:Feedback, Physiological / Q000235:genetics; D005333:Fetus; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016501:Neurites / Q000378:metabolism* / Q000648:ultrastructure; D009457:Neuroglia / Q000378:metabolism* / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C498439:Ophn1 protein, mouse; D010750:Phosphoproteins; C085379:rho GTPase-activating protein; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein