Talin is required for integrin-mediated platelet function in hemostasis and thrombosis

Abstract

Integrins are critical for hemostasis and thrombosis because they mediate both platelet adhesion and aggregation. Talin is an integrin-binding cytoplasmic adaptor that is a central organizer of focal adhesions, and loss of talin phenocopies integrin deletion in Drosophila. Here, we have examined the role of talin in mammalian integrin function in vivo by selectively disrupting the talin1 gene in mouse platelet precursor megakaryocytes. Talin null megakaryocytes produced circulating platelets that exhibited normal morphology yet manifested profoundly impaired hemostatic function. Specifically, platelet-specific deletion of talin1 led to spontaneous hemorrhage and pathological bleeding. Ex vivo and in vitro studies revealed that loss of talin1 resulted in dramatically impaired integrin αIIbβ3-mediated platelet aggregation and β1 integrin–mediated platelet adhesion. Furthermore, loss of talin1 strongly inhibited the activation of platelet β1 and β3 integrins in response to platelet agonists. These data establish that platelet talin plays a crucial role in hemostasis and provide the first proof that talin is required for the activation and function of mammalian α2β1 and αIIbβ3 integrins in vivo.

A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function

“…Whether these platelets contain full-length FlnA or a truncated form, as shown for talin (Priddle et al, 1998), remains to be investigated. The high efficiency of gene inactivation is similar to that described for the widely used megakaryocytespecific Pf4-Cre transgenic mouse and posits the GATA1-Cre mouse as a strong alternative for studies in megakaryocytes and platelets (Léon et al, 2007;Petrich et al, 2007;Tiedt et al, 2007;Hitchcock et al, 2008;Wen et al, 2009).…”

Subcellular Localization of Talin Is Regulated by Inter-domain Interactions

“…Affinity modulation of integrins for their ligands and the connection of most integrins to the actin cytoskeleton are mediated by adaptors that bind to the integrin cytoplasmic domains (1)(2)(3)(4). Among the numerous proteins that associate with integrin cytoplasmic domains, talin has emerged as a central player in both affinity modulation and integrin-actin cytoskeleton linkage (5)(6)(7)(8)(9)(10)(11)(12)(13).…”

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].…”