Platelet activation: new aspects.

Work on growth factor receptors in other cells has led to the concept that tyrosine phosphorylation of receptor cytoplasmic domains leads to recruitment of signaling molecules to appropriate sub-membrane locations. Complexes of molecules are assembled through structural motifs that mediate phosphotyrosine-SH2 domain and SH3-proline-rich domain interactions. These interactions lead to activation of signaling molecules, especially activation of members of the Ras superfamily that in turn mediate downstream effects on gene regulation, vesicle movement, and cytoskeletal reorganizations. In platelets, signaling occurs primarily through members of the seven transmembrane-hererotrimeric G-protein coupled family of receptors and through adhesion receptors. The most rapid are of growth in recent years has been the realization that signaling through both G-protein coupled receptors and adhesion receptors is dependent on tyrosine kinase activation, recruitment of complexes of SH2, SH3, and proline-rich signaling molecules to appropriate locations in the cell, and on activation of members of the Ras superfamily of proteins. Because neither G-protein coupled receptors nor adhesion receptors have intrinsic tyrosine kinase activity, mechanisms presumably exist for using non-receptor kinases to initiate tyrosine phosphorylation reactions that in turn lead to the recruitment of signaling molecules. As discussed in this article, many tyrosine kinases exist in platelets and some of these are known to be tyrosine phosphorylated and activated following platelet activation. The theme that is emerging is that these tyrosine kinases may serve to phosphorylate submembranous proteins including receptors for cytoplasmic domains or components of the submembranous cytoskeleton of adhesion-receptor cytoskeleton complexes that can then recruit and activate appropriate signaling molecules. The challenge in future years will be to identity the way in which the activation of tyrosine kinase(s) is induced by receptor activation, identify the tyrosine kinase(s) involved, and identify the way in which specific members of the Ras superfamily activate downstream effectors to induce the responses of platelets to activation.