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 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.
Judd
B A
BA
University of Iowa Program in Molecular Biology, Iowa City, IA 52242, USA.
Myung
P S
PS
Leng
L
L
Obergfell
A
A
Pear
W S
WS
Shattil
S J
SJ
Koretzky
G A
GA
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D005340:Fibrinogen / Q000378:metabolism; D006410:Hematopoiesis; D006487:Hemostasis / Q000502:physiology*; D006801:Humans; D016023:Integrins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology*; D011485:Protein Binding; D038981:Receptors, Collagen; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D016023:Integrins; D010750:Phosphoproteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D038981:Receptors, Collagen; C092947:SLP-76 signal Transducing adaptor proteins; D014443:Tyrosine; D005340:Fibrinogen