Bidirectional Transmembrane Signaling by Cytoplasmic Domain Separation in Integrins

• Published in: Science (American Association for the Advancement of Science) 2003-09, Vol.301 (5640), p.1720-1725
• Main Authors: Kim, Minsoo, Carman, Christopher V., Springer, Timothy A.
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal; Bacterial Proteins; Biological and medical sciences; CD11a Antigen - chemistry; CD18 Antigens - chemistry; Cell Adhesion; Cell interaction; Cell interactions; Cell Membrane - metabolism; Cell membranes; Cell physiology; Cellular biology; Chemokine CXCL12; Chemokines, CXC - metabolism; Cytoplasm - chemistry; Dimerization; Ecosystems; Epiphytes; Fluorescence; Fluorescence Resonance Energy Transfer; Fundamental and applied biological sciences. Psychology; Green Fluorescent Proteins; Humans; Immunity (Disease); Individualized Instruction; Integrins; Intercellular Adhesion Molecule-1 - metabolism; K562 cells; Least Squares Statistics; Ligands; Luminescent Proteins; Lymphocyte Function-Associated Antigen-1 - chemistry; Lymphocyte Function-Associated Antigen-1 - metabolism; Marine ecosystems; Membranes; Molecular and cellular biology; Physiological aspects; Plasma; Protein Conformation; Protein Structure, Tertiary; Proteins; Receptors; Receptors, CXCR4 - metabolism; Recombinant Fusion Proteins - chemistry; Signal Transduction; T lymphocytes; Talin - chemistry; Talin - metabolism; Transfection; Tumor Cells, Cultured
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1084174

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 ($\alpha_{L}\beta_2$) in living cells by measuring fluorescence resonance energy transfer between cyan fluorescent protein-fused and yellow fluorescent protein-fused αLand β2cytoplasmic 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 α and β cytoplasmic domains, a distinctive mechanism for transmitting information across the plasma membrane.