Judd B A, Myung P S, Leng L, Obergfell A, Pear W S, Shattil S J, Koretzky G A
University of Iowa Program in Molecular Biology, Iowa City, IA 52242, USA.
Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12056-61. doi: 10.1073/pnas.97.22.12056.
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.
缺乏造血细胞特异性衔接蛋白SLP - 76的小鼠表现出T细胞发育失败和胎儿出血。尽管缺乏SLP - 76的血小板表现出胶原受体信号传导缺陷，但仅此一点可能无法解释所观察到的出血素质。由于血小板纤维蛋白原受体αIIbβ3是正常止血所必需的，我们探讨了SLP - 76在αIIbβ3信号传导中的潜在作用。可溶性或固定化纤维蛋白原与正常人或小鼠血小板的相互作用会触发SLP - 76的快速酪氨酸磷酸化。此外，血小板与纤维蛋白原的粘附刺激肌动蛋白重排、丝状伪足和片状伪足延伸，以及酪氨酸磷酸化蛋白在细胞周边的定位。相比之下，缺乏SLP - 76的小鼠血小板能正常结合纤维蛋白原，但铺展能力差且磷酸酪氨酸水平降低。通过将SLP - 76逆转录病毒转导到来自缺乏SLP - 76小鼠的骨髓中，可逆转体内出血素质以及血小板对纤维蛋白原和胶原反应的缺陷。这些研究表明，SLP - 76在血小板中αIIbβ3和胶原受体的下游发挥作用。此外，SLP - 76在包括血小板在内的造血细胞中的表达在止血中起必要作用。
