Rapid tyrosine phosphorylation and activation of Bruton's tyrosine/Tec kinases in platelets induced by collagen binding or CD32 cross-linking

Atsushi Oda, Yasuo Ikeda, Hans D. Ochs, Brian Druker, Katsutsohi Ozaki, Makoto Handa, Tadashi Ariga, Yukio Sakiyama, Owen N. Witte, Matthew I. Wah

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

Stimulation of the platelet nonintegrin collagen receptor, glycoprotein VI, evokes a signaling response similar to that induced by antigen receptor activation in B and T lymphocytes. A key transducer of the lymphocyte signaling pathways is the Bruton's tyrosine kinase (Btk)/Tec kinase family, which connects receptors to the elevation of intracellular-free calcium levels. An important signaling function for Btk in collagen-induced platelet activation in vitro was recently demonstrated by other researchers using Btk- deficient platelets from patients with X-linked agammaglobulinemia (XLA). Since Btk-deficiency does not induce an overt platelet-based bleeding disorder in vivo, collagen receptor responses may include other Btk/Tec kinase family members in normal platelets. Both Btk and Tec had increased tyrosine following stimulation of collagen receptors or CD32 crosslinking. Data from kinetic analyses and inhibitor studies and the use of phosphopeptide-specific antibodies recognizing 2 Btk regulatory phosphorylated tyrosine residues suggest a mechanism for coordinate recruitment of Btk and Tec through the immunoreceptor tyrosine-based activation motif, Src family kinases, and phosphatidylinositol 3-kinase. In XLA platelets, collagen treatment increased tyrosine phosphorylation of Tec and several other signaling proteins, including Lyn, Fyb, Slp-76, and the Wiskott-Aldrich syndrome protein. This indicates that important elements of the collagen signaling pathway proximal and distal to Btk and Tec are preserved despite the lack of functional Btk. The results are consistent with the conclusion that activation of Tec may sustain XLA platelet function in vivo, while some in vitro assays of nonintegrin collagen receptor signaling through the Btk/Tec kinase family reflect the additive dosage of the transducers. (C) 2000 by The American Society of Hematology.

Original languageEnglish (US)
Pages (from-to)1663-1670
Number of pages8
JournalBlood
Volume95
Issue number5
Publication statusPublished - Mar 1 2000
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Hematology

Cite this