Disruption of disulfide restriction at integrin knees induces activation and ligand-independent signaling of α4β7.

Control of integrin activation and signaling plays crucial roles in cell adhesion, spreading and migration. Here, we report that selective breakage of two conserved disulfide bonds located at the knees of integrin α₄C589-C594 and β₇C494-C526 activated α₄β₇. This activated integrin had a unique structure that was different from the typical extended conformation of active integrin. In addition, these activated α₄β₇ integrins spontaneously clustered on the cell membrane and triggered integrin downstream signaling independent of ligand binding. Although these disulfide bonds were not broken during α₄β₇ activation by inside-out signaling or Mn²⁺, they could be specifically reduced by 0.1 mM dithiothreitol, a reducing strength that could be produced in vivo under certain conditions. Our findings reveal a novel mechanism of integrin activation under specific reducing conditions by which integrin can signal and promote cell spreading in the absence of ligand. [ABSTRACT FROM AUTHOR]