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Hematopoietic reconstitution of SLP-76 corrects hemostasis and platelet signaling through alpha IIb beta 3 and collagen receptors.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2000 Oct 24; Vol. 97 (22), pp. 12056-61. - Publication Year :
- 2000
-
Abstract
- 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.
- Subjects :
- Adaptor Proteins, Signal Transducing
Animals
Fibrinogen metabolism
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Phenotype
Phosphorylation
Protein Binding
Receptors, Collagen
Tyrosine metabolism
Blood Platelets physiology
Hematopoiesis
Hemostasis physiology
Integrins physiology
Phosphoproteins physiology
Platelet Glycoprotein GPIIb-IIIa Complex physiology
Signal Transduction physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 97
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 11050236
- Full Text :
- https://doi.org/10.1073/pnas.97.22.12056