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

Research output: Contribution to journalArticle

Authors

  • H Falet
  • AJ Begonja
  • SJ Weber
  • D Duerschmeid
  • DD Wagner
  • JH Hartwig

Colleges, School and Institutes

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 GPIb. because they lack the normal cytoskeletal linkage of GPIb. to underlying actin filaments. This results in similar to 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 alpha IIb beta 3 activation, and protein tyrosine phosphorylation, particularly that of the protein tyrosine kinase Syk and phospholipase C-gamma 2, 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.

Details

Original languageEnglish
Pages (from-to)1967-1979
Number of pages13
JournalThe Journal of Experimental Medicine
Volume207
Issue number9
Publication statusPublished - 30 Aug 2010