Talin is required for integrin-mediated platelet function in hemostasis and thrombosis.
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 alphaIIbbeta3-mediated platelet aggregation and beta1 integrin-mediated platelet adhesion. Furthermore, loss of talin1 strongly inhibited the activation of platelet beta1 and beta3 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 alpha2beta1 and alphaIIbbeta3 integrins in vivo.
Petrich
Brian G
BG
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Marchese
Patrizia
P
Ruggeri
Zaverio M
ZM
Spiess
Saskia
S
Weichert
Rachel A M
RA
Ye
Feng
F
Tiedt
Ralph
R
Skoda
Radek C
RC
Monkley
Susan J
SJ
Critchley
David R
DR
Ginsberg
Mark H
MH
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D006487:Hemostasis; D006720:Homozygote; D038982:Integrin alpha2beta1 / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D040201:Platelet Membrane Glycoprotein IIb / Q000096:biosynthesis; D016608:Talin / Q000502:physiology*; D013927:Thrombosis
D038982:Integrin alpha2beta1; D019012:Integrin beta1; D039661:Integrin beta3; D016023:Integrins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D040201:Platelet Membrane Glycoprotein IIb; D016608:Talin