The platelet membrane is lined by a membrane skeleton. It associates with the transmembrane receptors and with the intracellular network of cytoplasmic actin filaments. This structure may regulate properties of receptors and play a role in signal transduction. Information are used to generate transgenic mice in which the GP Ib- IX complex contains full length human GP Ibeta Alpha or a form that cannot associate with actin-binding protein.
In Specific Aim 1, these transgenic mice will be used to test the hypotheses that association of GP Ib-IX with the cytoskeleton regulates its ability to bind von Willebrand factor, that attachment of GP Ib-IX to the cytoskeleton regulates signaling in platelets, and that the size and shape of platelets are dependent on the association of the cytoskeleton with GP Ib-IX.
In Specific Aim 2, experiments are to determine whether pp60c-src associates with a protein in the membrane skeleton of unstimulated platelets or in the integrin-rich cytoskeletal structures that form in aggregating cells.
Specific Aim 3 is to test this hypothesis. It is anticipated that these studies will provide insight into the role of teh GP Ib-IX cytoskeletal interaction in regulating functions of GP Ib-IX and properties of the plasma membrane, and of the cytoskeleton in regulating signal transduction mechanisms in platelets. Because many of the signaling mechanisms occuring in platelets occur in other cell types, the studies may provide an increased understanding of the function of the cytoskeleton in regulating signaling mechanisms in other cells.
| O'Toole, Timothy E; Bialkowska, Katarzyna; Li, Xiaohong et al. (2011) Tiam1 is recruited to ?1-integrin complexes by 14-3-3? where it mediates integrin-induced Rac1 activation and motility. J Cell Physiol 226:2965-78 |
