Specific integrin alpha and beta chain phosphorylations regulate LFA-1 activation through affinity-dependent and -independent mechanisms.
Integrins are adhesion receptors that are crucial to the functions of multicellular organisms. Integrin-mediated adhesion is a complex process that involves both affinity regulation and cytoskeletal coupling, but the molecular mechanisms behind this process have remained incompletely understood. In this study, we report that the phosphorylation of each cytoplasmic domain of the leukocyte function-associated antigen-1 integrin mediates different modes of integrin activation. alpha Chain phosphorylation on Ser1140 is needed for conformational changes in the integrin after chemokine- or integrin ligand-induced activation or after activation induced by active Rap1 (Rap1V12). In contrast, the beta chain Thr758 phosphorylation mediates selective binding to 14-3-3 proteins in response to inside-out activation through the T cell receptor, resulting in cytoskeletal rearrangements. Thus, site-specific phosphorylation of the integrin cytoplasmic domains is important for the dynamic regulation of these complex receptors in cells.
Fagerholm
Susanna C
SC
Division of Biochemistry, Faculty of Biosciences, University of Helsinki, FIN-00014 Helsinki, Finland.
Hilden
Tiina J
TJ
Nurmi
Susanna M
SM
Gahmberg
Carl G
CG
D048948:14-3-3 Proteins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D019556:COS Cells; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D018925:Chemokines / Q000378:metabolism; D002522:Chlorocebus aethiops; D002846:Chromatography, Affinity; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D016023:Integrins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D012694:Serine / Q000737:chemistry; D016608:Talin / Q000737:chemistry; D013997:Time Factors; D014162:Transfection
D048948:14-3-3 Proteins; D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D018925:Chemokines; D018076:DNA, Complementary; C065289:ICAM2 protein, human; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D011506:Proteins; D011994:Recombinant Proteins; C102467:SDF2 protein, human; D016608:Talin; D018799:Intercellular Adhesion Molecule-1; D012694:Serine