title: alpha2beta1 integrin controls association of Rac with the membrane and triggers quiescence of endothelial cells.
abstract: Integrin receptors and their extracellular matrix ligands provide cues to cell proliferation, survival, differentiation and migration. Here, we show that alpha2beta1 integrin, when ligated to the basement membrane component laminin-1, triggers a proliferation arrest in primary endothelial cells. Indeed, in the presence of strong growth signals supplied by growth factors and fibronectin, alpha2beta1 engagement alters assembly of mature focal adhesions by alpha5beta1 and leads to impairment of downstream signaling and cell-cycle arrest in the G1 phase. Although the capacity of alpha5beta1 to signal for GTP loading of Rac is preserved, the joint engagement of alpha2beta1 interferes with membrane anchorage of Rac. Adapting the 'split-ubiquitin' sensor to screen for membrane-proximal alpha2 integrin partners, we identified the CD9 tetraspanin and further establish its requirement for destabilization of focal adhesions, control of Rac subcellular localization and growth arrest induced by alpha2beta1 integrin. Altogether, our data establish that alpha2beta1 integrin controls endothelial cell commitment towards quiescence by triggering a CD9-dependent dominant signaling.
authors.affiliation: INSERM, U634, Faculté de Médecine, 27 Avenue de Valombrose, Nice, F-06107, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Cailleteau
authors.forename: Soline
authors.initials: S
authors.lastname: Estrach
authors.forename: Raphael
authors.initials: R
authors.lastname: Thyss
authors.forename: Laurent
authors.initials: L
authors.lastname: Boyer
authors.forename: Anne
authors.initials: A
authors.lastname: Doye
authors.forename: Barbara
authors.initials: B
authors.lastname: Domange
authors.forename: Nils
authors.initials: N
authors.lastname: Johnsson
authors.forename: Eric
authors.initials: E
authors.lastname: Rubinstein
authors.forename: Claude
authors.initials: C
authors.lastname: Boucheix
authors.forename: Teni
authors.initials: T
authors.lastname: Ebrahimian
authors.forename: Jean-Sebastien
authors.initials: JS
authors.lastname: Silvestre
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lemichez
authors.forename: Guerrino
authors.initials: G
authors.lastname: Meneguzzi
authors.forename: Amel
authors.initials: A
authors.lastname: Mettouchi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005353:Fibronectins / Q000494:pharmacology; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism; D006801:Humans; D038982:Integrin alpha2beta1 / Q000819:agonists / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000819:agonists / Q000378:metabolism; D007797:Laminin / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D060245:Tetraspanin 29; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C554869:CD9 protein, human; C554870:Cd9 protein, mouse; D005353:Fibronectins; D038982:Integrin alpha2beta1; D039081:Integrin alpha5beta1; D007797:Laminin; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D060245:Tetraspanin 29; C121346:laminin 1; D016222:Fibroblast Growth Factor 2; D020744:rac GTP-Binding Proteins