Two synergistic activation mechanisms of alpha2beta1 integrin-mediated collagen binding.
Activation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate (TPA) induces ligand-independent aggregation of a cell surface collagen receptor, alpha2beta1 integrin. Concomitantly, TPA increases the avidity of alpha2beta1 for collagen and the number of conformationally activated alpha2beta1 integrins. The structural change was shown using a monoclonal antibody 12F1 that recognizes the "open" (active) conformation of the inserted domain in the alpha2 subunit (alpha2I). Amino acid residue Glu-336 in alpha2 subunit is proposed to mediate the interaction between alpha2I domain and beta1 subunit. Glu-336 seems to regulate a switch between open and "closed" conformations, since the mutation alpha2E336A inhibited the TPA-related increase in the number of 12F1 positive integrins. E336A also reduced cell adhesion to collagen. However, E336A did not prevent the TPA-related increase in adhesion to collagen or alpha2beta1 aggregation. Thus, alpha2beta1 integrin avidity is regulated by two synergistic mechanisms, first an alpha2E336-dependent switch to the open alpha2I conformation, and second an alpha2E336-independent mechanism temporally associated with receptor aggregation.
Connors
Wendy L
WL
Department of Biochemistry and Food Chemistry, University of Turku, Turku, Finland.
Jokinen
Johanna
J
White
Daniel J
DJ
Puranen
J Santeri
JS
Kankaanpää
Pasi
P
Upla
Paula
P
Tulla
Mira
M
Johnson
Mark S
MS
Heino
Jyrki
J
D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D002448:Cell Adhesion; D024042:Collagen Type I / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D038982:Integrin alpha2beta1 / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D009154:Mutation / Q000235:genetics; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects*; D011493:Protein Kinase C / Q000378:metabolism; D038981:Receptors, Collagen / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002273:Carcinogens; D024042:Collagen Type I; D038982:Integrin alpha2beta1; D008024:Ligands; D038981:Receptors, Collagen; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate