Sci. STKE, 17 September 2002
Receptors Integrin Signals from Both Sides Now
Two new studies shed light on the mechanisms by which integrins "integrate" information from both sides of the plasma membrane. The integrins, a family of heterodimeric transmembrane receptors with large extracellular domains and small cytoplasmic tails, play a key role in transducing information about the extracellular matrix into responses affecting cell motility, growth, and survival (outside-in signaling). Cytoplasmic signals regulate integrin clustering and ligand-binding affinity to integrate these responses with information from other signaling pathways (inside-out signaling). Vinogradova et al. used nuclear magnetic resonance (NMR) to demonstrate interactions between the cytoplasmic tails of the integrin αIIb and β3 subunits and, using highly soluble fusion constructs, to determine the structure of the αIIb-β3 cytoplasmic tail complex. Interactions between the tail domains were abolished by mutations that constitutively activated the αIIbβ3 receptor and were disrupted by a cytoskeletal protein domain that enhanced ligand binding. Takagi et al. used electron microscopy, as well as analytical gel filtration, to demonstrate global conformational rearrangements of integrin αVβ3 extracellular domains under various activating and inactivating conditions. Solution-phase binding assays, combined with the mutational introduction of disulfide bonds into integrins expressed in cells, showed that conditions favoring a highly bent conformation were associated with a low affinity for ligands, whereas ligand binding or dissociation of the COOH termini favored an extended conformation with high affinity for ligands. These studies support a "switchblade" model of integrin activation, in which inside-out signals promote dissociation of the cytoplasmic tails, enhancing ligand affinity and leading to an intermediate conformation, which, like ligand binding itself, favors assumption of the high-affinity active form.
O. Vinogradova, A. Velyvis, A. Velyviene, B. Hu, T. A. Haas, E. F. Plow, J. Qin, A structural mechanism of integrin αIIbβ3 "inside-out" activation as regulated by its cytoplasmic face. Cell 110, 587-597 (2002). [Online Journal]
J. Takagi, B. M. Petre, T. Watz, T. A. Springer, Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 110, 599-611 (2002). [Online Journal]
Citation: Integrin Signals from Both Sides Now. Sci. STKE 2002, tw337 (2002).
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882