Mice deficient in the hematopoietic cell-specific adapter
protein SLP-76 demonstrate a failure of T cell development and fetal
hemorrhage. Although SLP-76-deficient platelets manifest defective
collagen receptor signaling, this alone may not explain the observed
bleeding diathesis. Because alpha IIb beta 3, the platelet
fibrinogen receptor, is required for normal hemostasis, we explored a potential role for SLP-76 in alpha IIb beta 3 signaling. Interaction of soluble or immobilized
fibrinogen with normal human or murine platelets triggers rapid
tyrosine phosphorylation of SLP-76. Moreover, platelet adhesion to
fibrinogen stimulates actin rearrangements, filopodial and lamellipodial extension, and localization of
tyrosine phosphorylated
proteins to the cell periphery. In contrast, SLP-76-deficient murine platelets bind
fibrinogen normally, but spread poorly and exhibit reduced levels of
phosphotyrosine. The in vivo
bleeding diathesis as well as the defects in platelet responses to
fibrinogen and
collagen are reversed by retroviral transduction of SLP-76 into bone marrow derived from SLP-76-deficient mice. These studies establish that SLP-76 functions downstream of alpha IIb beta 3 and
collagen receptors in platelets. Furthermore, expression of SLP-76 in hematopoietic cells, including platelets, plays a necessary role in hemostasis.