SHPS-1 negatively regulates integrin αIIbβ3 function through CD47 without disturbing FAK phosphorylation
SHPS-1 negatively regulates integrin αIIbβ3 function through CD47 without disturbing FAK phosphorylation
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DOI：
10.1111/j.1538-7836.2005.01235.x
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发表时间：
2005-04-01
影响因子：
10.4
通讯作者：
Tomiyama, A
中科院分区：
文献类型：
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作者：
Kato, H;Honda, S;Tomiyama, A
CD 47（整合素相关蛋白）作为血小板反应蛋白-1（TSP-1）和含Src同源2结构域的蛋白酪氨酸磷酸酶底物-1（SHPS-1）的受体，并且TSP-1/CD 47相互作用被认为增强整合素介导的血小板功能。在这里，采用SHPS-1-in-尿苷肽（1g）作为配体，我们新证明了CD 47作为血小板功能的抑制性受体。SHPS- 1 -IG的结合仅由CD 47介导，因为CD 47缺陷型血小板不能结合鼠SHPS- 1-IG。人SHPS- 1 /CD 47相互作用在低浓度下可抑制多种激动剂诱导的血小板聚集。此外，在细胞表面表达的人SHPS-1和可溶性SHPS-1-IG能显著抑制血小板在固定纤维蛋白原上的铺展，但不能抑制血小板与固定纤维蛋白原的初始粘附.同样，在细胞表面表达的鼠SHPS-1和鼠SHPS-1-IG都不能抑制血小板的扩散或CD 47缺陷.我们进一步研究了血小板在固定纤维蛋白原上铺展期间信号蛋白的酪氨酸磷酸化。出乎意料的是，SHPS-1抑制α（Hb）β（3-）介导的血小板扩散，而不干扰粘着斑激酶（FAK）酪氨酸磷酸化。进一步的研究表明，SHPS-1抑制α-辅肌动蛋白（FAK的下游效应物）的酪氨酸磷酸化，但不抑制corneum。因此，SHPS-1/CD 47相互作用可能通过干扰FAK的下游通路来抑制α（IIb）β（3）介导的由外向内信号传导。综上所述，我们的数据表明，SHPS-1通过CD 47，特别是α（IIb）β（3）介导的由外向内信号传导负调节血小板功能。
CD47 (integrin-associated protein) serves as a receptor for thrombospondin-1 (TSP-1) and Src homology 2 domain-containing protein tyrosine phosphatase substrate-l (SHPS-1), and the TSP-1/CD47 interaction has been believed to augment integrin-mediated platelet function. Here, employing SHPS-1-in-uriunoglobulin (1g) as a ligand, we have newly demonstrated that CD47 acts as an inhibitory receptor for platelet function. The binding of SHPS- 1 -Ig was solely mediated by CD47, because CD47-deficient platelets failed to bind murine SHPS- 1-Ig. The human SHPS- 1 /CD47 interaction inhibited the platelet aggregation induced by several kinds of agonists at a low concentration. Moreover, human SHPS- I expressed on the cell surface as well as soluble SHPS-1-Ig markedly inhibited the platelet spreading on, but not initial adhesion to, immobilized fibrinogen. Again, neither murine SHPS- I expressed on the cell surface nor murine SHPS-1-Ig inhibited the spreading orCD47deficient platelets. We further investigated the tyrosine phosphorylation of signaling proteins during platelet spreading on immobilized fibrinogen. Unexpectedly, SHPS-1 inhibited alpha(Hb)beta(3-)mediated platelet spreading without disturbing focal adhesion kinase (FAK) tyrosine phosphorylation. Further examination revealed that SHPS-1 inhibited the tyrosine phosphorylation of alpha-actinin, a downstream effector of FAK, but not of cortactin. Thus, it is likely that the SHPS-1/CD47 interaction inhibits alpha(IIb)beta(3)-mediated outside-in signaling by interfering with the downstream pathway of FAK. Taken together, our data suggest that SHPS-l negatively regulates platelet function via CD47, especially alpha(IIb)beta(3)-Mediated outside-in signaling.