Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins.
Although critical for development, immunity, wound healing, and metastasis, integrins represent one of the few classes of plasma membrane receptors for which the basic signaling mechanism remains a mystery. We investigated cytoplasmic conformational changes in the integrin LFA-1 (alphaLbeta2) in living cells by measuring fluorescence resonance energy transfer between cyan fluorescent protein-fused and yellow fluorescent protein-fused alphaL and beta2 cytoplasmic domains. In the resting state these domains were close to each other, but underwent significant spatial separation upon either intracellular activation of integrin adhesiveness (inside-out signaling) or ligand binding (outside-in signaling). Thus, bidirectional integrin signaling is accomplished by coupling extracellular conformational changes to an unclasping and separation of the alpha and beta cytoplasmic domains, a distinctive mechanism for transmitting information across the plasma membrane.
D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D040881:CD11a Antigen / Q000737:chemistry*; D018821:CD18 Antigens / Q000737:chemistry*; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D003593:Cytoplasm / Q000737:chemistry*; D019281:Dimerization; D031541:Fluorescence Resonance Energy Transfer; D049452:Green Fluorescent Proteins; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008024:Ligands; D008164:Luminescent Proteins; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D019718:Receptors, CXCR4 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D015398:Signal Transduction; D016608:Talin / Q000737:chemistry / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D040881:CD11a Antigen; D018821:CD18 Antigens; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D008024:Ligands; D008164:Luminescent Proteins; D016169:Lymphocyte Function-Associated Antigen-1; D019718:Receptors, CXCR4; D011993:Recombinant Fusion Proteins; D016608:Talin; C054562:yellow fluorescent protein, Bacteria; D018799:Intercellular Adhesion Molecule-1; D049452:Green Fluorescent Proteins