Research ArticleIntegrins

Kindlin-3 disrupts an intersubunit association in the integrin LFA1 to trigger positive feedback activation by Rap1 and talin1

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Science Signaling  08 Jun 2021:
Vol. 14, Issue 686, eabf2184
DOI: 10.1126/scisignal.abf2184

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Linking inside-out and outside-in signaling

Integrins link the cytoskeleton to the extracellular matrix and mediate both outside-in signaling, which transduces cellular responses to ligands, and inside-out signaling, which controls ligand affinity. Talins and kindlins associate with the intracellular domains of integrins and coordinate bidirectional signaling. Using single-molecule imaging of lymphocytes, Kondo et al. found that ligand binding to the integrin LFA1 induced transient interactions with talin1, which recruited kindlin-3, led to a conformational change in LFA1, and stabilized talin1 binding. These effects stimulated the inside-out signaling mediator Rap1, causing LFA1 to adopt an open, high-affinity conformation. In migrating lymphocytes, the association of talin1 and kindlin-3 with LFA1 corresponded to LFA1 adopting the high-affinity conformation in the body of the cell but remaining in a low-affinity conformation at the leading edge. Thus, kindlin-3 mediates positive feedback in the ligand-induced conversion of LFA1 from a low-affinity conformation to a high-affinity conformation.

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