title: Tetraspanin CD151 stimulates adhesion-dependent activation of Ras, Rac, and Cdc42 by facilitating molecular association between β1 integrins and small GTPases.
abstract: Tetraspanin CD151 associates with laminin-binding α(3)β(1)/α(6)β(1) integrins in epithelial cells and regulates adhesion-dependent signaling events. We found here that CD151 plays a role in recruiting Ras, Rac1, and Cdc42, but not Rho, to the cell membrane region, leading to the formation of α(3)β(1)/α(6)β(1) integrin-CD151-GTPases complexes. Furthermore, cell adhesion to laminin enhanced CD151 association with β(1) integrin and, thereby, increased complex formation between the β(1) family of integrins and small GTPases, Ras, Rac1, and Cdc42. Adhesion receptor complex-associated small GTPases were activated by CD151-β(1) integrin complex-stimulating adhesion events, such as α(3)β(1)/α(6)β(1) integrin-activating cell-to-laminin adhesion and homophilic CD151 interaction-generating cell-to-cell adhesion. Additionally, FAK and Src appeared to participate in this adhesion-dependent activation of small GTPases. However, engagement of laminin-binding integrins in CD151-deficient cells or CD151-specific siRNA-transfected cells did not activate these GTPases to the level of cells expressing CD151. Small GTPases activated by engagement of CD151-β(1) integrin complexes contributed to CD151-induced cell motility and MMP-9 expression in human melanoma cells. Importantly, among the four tetraspanin proteins that associate with β(1) integrin, only CD151 exhibited the ability to facilitate complex formation between the β(1) family of integrins and small GTPases and stimulate β(1) integrin-dependent activation of small GTPases. These results suggest that CD151 links α(3)β(1)/α(6)β(1) integrins to Ras, Rac1, and Cdc42 by promoting the formation of multimolecular complexes in the membrane, which leads to the up-regulation of adhesion-dependent small GTPase activation.
authors: Medical and Bio-Material Research Center, School of Medicine, Kangwon National University, Chunchon, Kangwon-do 200-701, Korea.
authors: In-Kee
authors: IK
authors: Hong
authors: Doo-Il
authors: DI
authors: Jeoung
authors: Kwon-Soo
authors: KS
authors: Ha
authors: Young-Myeong
authors: YM
authors: Kim
authors: Hansoo
authors: H
authors: Lee
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D007797:Laminin / Q000737:chemistry; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013347:Subcellular Fractions; D060185:Tetraspanin 24 / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D019012:Integrin beta1; D007797:Laminin; D034741:RNA, Small Interfering; D060185:Tetraspanin 24; D020780:Matrix Metalloproteinase 9; D020559:Monomeric GTP-Binding Proteins; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D018631:ras Proteins