Hematopoietic reconstitution of SLP-76 corrects hemostasis and platelet signaling through alpha IIb beta 3 and collagen receptors

Mice deficient in the hematopoietic cell-specific adapter protein SLP-76 de monstrate a failure of T cell development and fetal hemorrhage. Although SL P-76-deficient platelets manifest defective collagen receptor signaling, th is alone may not explain the observed bleeding diathesis. Because alpha IIb beta3, the platelet fibrinogen receptor, is required for normal hemostasis , we explored a potential role for SLP-76 in alpha IIb beta3 signaling. Int eraction of soluble or immobilized fibrinogen with normal human or murine p latelets triggers: rapid tyrosine phosphorylation of SLP-76. Moreover, plat elet adhesion to fibrinogen stimulates actin rearrangements, filopodial and lamellipodial extension, and localization of tyrosine phosphorylated prote ins to the cell periphery. In contrast, SLP-76-deficient murine platelets b ind fibrinogen normally, but spread poorly and exhibit reduced levels of ph osphotyrosine. The in vivo bleeding diathesis as well as the defects in pla telet responses to fibrinogen and collagen are reversed by retroviral trans duction of SLP-76 into bone marrow derived from SLP-76-deficient mice. Thes e studies establish that SLP-76 functions downstream of alpha IIb beta3 and collagen receptors in platelets. Furthermore, expression of SLP-76 in hema topoietic cells, including platelets, plays a necessary role in hemostasis.