Ectodomain shedding of SHPS-1 and its role in regulation of cell migration
Ectodomain shedding of SHPS-1 and its role in regulation of cell migration
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DOI：
10.1074/jbc.m313085200
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发表时间：
2004-07-02
影响因子：
4.8
通讯作者：
Matozaki, T
中科院分区：
文献类型：
--
作者：
Ohnishi, H;Kobayashi, H;Matozaki, T
SHPS-1是一种跨膜蛋白，其胞质区域经历酪氨酸磷酸化，然后结合蛋白酪氨酸磷酸酶SHP-2。SHPS-1-SHP-2复合物的形成涉及细胞迁移的调节。此外，SHPS-1及其配体CD 47构成细胞间识别系统，有助于通过细胞-细胞接触抑制细胞迁移。SHPS-1的胞外结构域现在已经显示在可能由金属蛋白酶介导的反应中从细胞脱落。该过程通过蛋白激酶C或Ras的活化来促进，并且释放的胞外域表现出最小的CD 47结合活性。金属蛋白酶催化重组SHPS-1-Fc融合蛋白的体外切割，并且主要切割位点定位于SHPS-1的质膜区域。一个SHPS-1突变体的强制表达抵抗胞外域脱落损害细胞迁移，细胞扩散和重组的肌动蛋白细胞骨架。它还增加了由细胞粘附触发的桩蛋白和FAK的酪氨酸磷酸化。这些结果表明SHPS-1的胞外结构域的脱落在该蛋白调节细胞迁移和扩散中起重要作用。
SHPS-1 is a transmembrane protein whose cytoplasmic region undergoes tyrosine phosphorylation and then binds the protein-tyrosine phosphatase SHP-2. Formation of the SHPS-1-SHP-2 complex is implicated in regulation of cell migration. In addition, SHPS-1 and its ligand CD47 constitute an intercellular recognition system that contributes to inhibition of cell migration by cell-cell contact. The ectodomain of SHPS-1 has now been shown to be shed from cells in a reaction likely mediated by a metalloproteinase. This process was promoted by activation of protein kinase C or of Ras, and the released ectodomain exhibited minimal CD47-binding activity. Metalloproteinases catalyzed the cleavage of a recombinant SHPS-1-Fc fusion protein in vitro, and the primary cleavage site was localized to the juxtamembrane region of SHPS-1. Forced expression of an SHPS-1 mutant resistant to ectodomain shedding impaired cell migration, cell spreading, and reorganization of the actin cytoskeleton. It also increased the tyrosine phosphorylation of paxillin and FAK triggered by cell adhesion. These results suggest that shedding of the ectodomain of SHPS-1 plays an important role in regulation of cell migration and spreading by this protein.