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PMID:18278053

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Citation

Moser, M, Nieswandt, B, Ussar, S, Pozgajova, M and Fässler, R (2008) Kindlin-3 is essential for integrin activation and platelet aggregation. Nat. Med. 14:325-30

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.

Links

PubMed Online version:10.1038/nm1722

Keywords

Animals; Chimera; Cytoskeletal Proteins/genetics; Cytoskeletal Proteins/metabolism; Gene Deletion; Hepatocytes/metabolism; Integrins/metabolism; Mice; Osteoporosis; Platelet Aggregation/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:ITB3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8K1B8

F

Seeded From UniProt

complete

MOUSE:ITB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8K1B8

F

Seeded From UniProt

complete

MOUSE:URP2

enables

GO:0005178: integrin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:URP2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P09055

F

Seeded From UniProt

complete

MOUSE:URP2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O54890

F

Seeded From UniProt

complete

MOUSE:URP2

involved_in

GO:0033622: integrin activation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:URP2

involved_in

GO:0070527: platelet aggregation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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