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PMID:20713593

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Citation

Falet, H, Pollitt, AY, Begonja, AJ, Weber, SE, Duerschmied, D, Wagner, DD, Watson, SP and Hartwig, JH (2010) A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function. J. Exp. Med. 207:1967-79

Abstract

Filamin A (FlnA) cross-links actin filaments and connects the Von Willebrand factor receptor GPIb-IX-V to the underlying cytoskeleton in platelets. Because FlnA deficiency is embryonic lethal, mice lacking FlnA in platelets were generated by breeding FlnA(loxP/loxP) females with GATA1-Cre males. FlnA(loxP/y) GATA1-Cre males have a macrothrombocytopenia and increased tail bleeding times. FlnA-null platelets have decreased expression and altered surface distribution of GPIbalpha because they lack the normal cytoskeletal linkage of GPIbalpha to underlying actin filaments. This results in approximately 70% less platelet coverage on collagen-coated surfaces at shear rates of 1,500/s, compared with wild-type platelets. Unexpectedly, however, immunoreceptor tyrosine-based activation motif (ITAM)- and ITAM-like-mediated signals are severely compromised in FlnA-null platelets. FlnA-null platelets fail to spread and have decreased alpha-granule secretion, integrin alphaIIbbeta3 activation, and protein tyrosine phosphorylation, particularly that of the protein tyrosine kinase Syk and phospholipase C-gamma2, in response to stimulation through the collagen receptor GPVI and the C-type lectin-like receptor 2. This signaling defect was traced to the loss of a novel FlnA-Syk interaction, as Syk binds to FlnA at immunoglobulin-like repeat 5. Our findings reveal that the interaction between FlnA and Syk regulates ITAM- and ITAM-like-containing receptor signaling and platelet function.

Links

PubMed PMC2931168 Online version:10.1084/jem.20100222

Keywords

Amino Acid Motifs; Animals; Blood Platelets/cytology; Blood Platelets/metabolism; Cell Adhesion; Female; Filamins; Intracellular Signaling Peptides and Proteins/metabolism; Male; Mice; Mice, Knockout; Nerve Tissue Proteins/deficiency; Nerve Tissue Proteins/metabolism; Phosphotyrosine/metabolism; Protein Binding; Protein-Tyrosine Kinases/metabolism; Signal Transduction; Syk Kinase; Thrombocytosis/genetics; Thrombocytosis/metabolism

Significance

Annotations

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

HUMAN:KSYK

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P21333

F

Seeded From UniProt

complete

HUMAN:FLNA

enables

GO:0019900: kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P43405

F

Seeded From UniProt

complete

MOUSE:FLNA

involved_in

GO:0032231: regulation of actin filament bundle assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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