Kindlin-3 is essential for integrin activation and platelet aggregation

Abstract

Integrin-mediated platelet adhesion and aggregation are essential for sealing injured blood vessels and preventing blood loss, and excessive platelet aggregation can initiate arterial thrombosis, causing heart attacks and stroke. To ensure that platelets aggregate only at injury sites, integrins on circulating platelets exist in a low-affinity state and shift to a high-affinity state (in a process known as integrin activation or priming) after contacting a wounded vessel. The shift is mediated through binding of the cytoskeletal protein Talin to the beta subunit cytoplasmic tail. Here we show that platelets lacking the adhesion plaque protein Kindlin-3 cannot activate integrins despite normal Talin expression. As a direct consequence, Kindlin-3 deficiency results in severe bleeding and resistance to arterial thrombosis. Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis.

Toward correlating structure and mechanics of platelets

“…For example, talin and kindlin binding to the integrin cytoplasmic domain was associated with an extended integrin conformation. [28][29][30][31] The observed integrin receptors on the platelet surface allowed us to address the question of integrin conformation. We measured the distance between the globular head domain of individual integrins and the cell membrane (Fig.…”

Distinct regulatory mechanisms control integrin adhesive processes during tissue morphogenesis

“…We generated another activating mutation in the TM domain, L796R, which mimics talininduced conformational changes by shortening the length of transmembrane domain that is buried in the plasma membrane . We also introduced a deactivating mutation, N840A, in the distal NPxY motif, which in vertebrates is required to mediate binding of various signaling molecules, notably kindlins, which are required for inside-out integrin activation (Moser et al, 2008;Harburger et al, 2009). In addition, we generated a truncation mutant, 804*stop, which lacks the majority of the cytoplasmic tail (Fig.…”

Platelets at the vascular interface

“…collagen, and/or locally generated soluble agonists, e.g thrombin, triggers intracellular signaling cascades that ultimately lead to the inside-out activation of integrins. Important in this process is the recruitment of the FERM-domain containing proteins, TALIN[2,3] and KINDLIN3[4], to the integrin cytoplasmic tail [5]. Once bound, TALIN triggers conformational changes that increase integrin ligand-binding affinity[6], while KINDLIN3 promotes multivalent ligand binding by increasing the local density (avidity) of TALIN-activated integrins[7].…”