title: Interaction of Bruton's tyrosine kinase and protein kinase Ctheta in platelets. Cross-talk between tyrosine and serine/threonine kinases.
abstract: The nonreceptor Bruton's tyrosine kinase (Btk) has been previously shown to associate physically and functionally with members of the protein kinase C (PKC) family of serine/threonine kinases in a variety of cell types. Here we show evidence for a novel interaction between Btk and PKCtheta; in platelets activated through the adhesion receptors GP Ib-V-IX and GP VI. Alboaggregin A, a snake venom component capable of activating both receptors in combination, leads to tyrosine phosphorylation of Btk downstream of Src family kinases. Inhibition of Btk by the selective antagonist LFM-A13 causes a reduction in calcium entry, although secretion of 5-hydroxytryptamine is potentiated. Btk is also phosphorylated on threonine residues in a PKC-dependent manner and associates with PKCtheta; upon platelet activation by either alboaggregin A or activation of GP Ib-V-IX alone by von Willebrand factor/ristocetin. PKCtheta; in turn becomes tyrosine-phosphorylated in a manner dependent upon Src family and Btk kinase activity. Inhibition of Btk activity by LFM-A13 leads to enhancement of PKCtheta; activity, whereas nonselective inhibition of PKC activity by bisindolylmaleimide I leads to reduction in Btk activity. We propose a reciprocal feedback interaction between Btk and PKCtheta; in platelets, in which PKCtheta; positively modulates activity of Btk, which in turn feeds back negatively upon PKCtheta;.
authors.affiliation: Department of Pharmacology, School of Medical Sciences, University Walk, Bristol BS8 1TD, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Crosby
authors.forename: Alastair W
authors.initials: AW
authors.lastname: Poole
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D001792:Blood Platelets / Q000201:enzymology* / Q000378:metabolism*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D003435:Crotalid Venoms / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry* / Q000378:metabolism*; D008954:Models, Biological; D004676:Myelin Basic Protein / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000737:chemistry* / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
chemical_list: D003435:Crotalid Venoms; D007527:Isoenzymes; D004676:Myelin Basic Protein; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; C112003:alboaggregin A; D013912:Threonine; D012701:Serotonin; D014443:Tyrosine; D012694:Serine; D005982:Glutathione Transferase; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D016392:Proto-Oncogene Proteins pp60(c-src); C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D002118:Calcium