Integrin αvβ3 is a pleiotrophin receptor required for pleiotrophin-induced endothelial cell migration through receptor protein tyrosine phosphatase β/ζ
Integrin αvβ3 is a pleiotrophin receptor required for pleiotrophin-induced endothelial cell migration through receptor protein tyrosine phosphatase β/ζ
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DOI：
10.1096/fj.08-117564
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发表时间：
2009-05-01
期刊：
影响因子：
4.8
通讯作者：
Papadimitriou, Evangelia
中科院分区：
文献类型：
--
作者：
Mikelis, Constantinos;Sfaelou, Evanthia;Papadimitriou, Evangelia
我们先前已经证明，血管生成生长因子多效生长因子（PTN）通过与其受体蛋白酪氨酸磷酸酶β/ζ（RPTP β/ζ）结合诱导内皮细胞迁移。在这项研究中，我们发现，针对α（v）β（3）而不是α（5）β（1）整联蛋白的单克隆抗体以浓度依赖性方式消除了PTN诱导的人内皮细胞迁移。发现整合素α（v）β（3）以不依赖于RGD的方式直接与PTN相互作用，而对应于β（3）整合素胞外结构域特异性环的合成肽（（CYD）-C-177-MKTTC 184）抑制PTN-alpha（v）β（3）相互作用并完全消除PTN诱导的内皮细胞迁移。有趣的是，alpha（v）beta（3）也被发现与RPTP beta/zeta直接相互作用，并且PTN诱导的β（3）整联蛋白的Y 773磷酸化依赖于RPTP beta/zeta和下游c-src激酶激活。中期因子被发现与RPTP β/zeta相互作用，但不与α（v）β（3）相互作用，并引起细胞迁移的小但统计学显著的减少。在同一细胞系中，PTN降低了表达RPTP beta/zeta但不表达alpha（v）beta（3）的不同胶质瘤细胞系的迁移，而它刺激了在细胞膜上表达alpha（v）beta（3）的U87 MG细胞的迁移。β 3的过度表达或下调分别刺激或消除PTN对细胞迁移的影响。总的来说，这些数据表明alpha（v）beta（3）是决定PTN对细胞迁移的刺激或抑制作用的关键分子。Mikelis，C.，Sfaelou，E.，Kaghoumpa，M.，Kieffer，N.，Papadimitriou，E.整合素α（v）β（3）是一种多效生长因子受体，通过受体蛋白酪氨酸磷酸酶β/ζ诱导内皮细胞迁移。FASEB J. 23，1459-1469（2009）
We have previously shown that the angiogenic growth factor pleiotrophin (PTN) induces migration of endothelial cells through binding to its receptor protein tyrosine phosphatase beta/zeta (RPTP beta/zeta). In this study, we show that a monoclonal antibody against alpha(v)beta(3) but not alpha(5)beta(1) integrin abolished PTN-induced human endothelial cell migration in a concentration-dependent manner. Integrin alpha(v)beta(3) was found to directly interact with PTN in an RGD-independent manner, whereas a synthetic peptide corresponding to the specificity loop of the beta(3) integrin extracellular domain ((CYD)-C-177-MKTTC184) inhibited PTN-alpha(v)beta(3) interaction and totally abolished PTN-induced endothelial cell migration. Interestingly, alpha(v)beta(3) was also found to directly interact with RPTP beta/zeta, and PTN-induced Y773 phosphorylation of beta(3) integrin was dependent on both RPTP beta/zeta and the downstream c-src kinase activation. Midkine was found to interact with RPTP beta/zeta, but not with alpha(v)beta(3), and caused a small but statistically significant decrease in cell migration. In the same line, PTN decreased migration of different glioma cell lines that express RPTP beta/zeta but do not express alpha(v)beta(3), while it stimulated migration of U87MG cells that express alpha(v)beta(3) on their cell membrane. Overexpression or down-regulation of beta 3 stimulated or abolished, respectively, the effect of PTN on cell migration. Collectively, these data suggest that alpha(v)beta(3) is a key molecule that determines the stimulatory or inhibitory effect of PTN on cell migration.-Mikelis, C., Sfaelou, E., Koutsioumpa, M., Kieffer, N., Papadimitriou, E. Integrin alpha(v)beta(3) is a pleiotrophin receptor required for pleiotrophin-induced endothelial cell migration through receptor protein tyrosine phosphatase beta/zeta. FASEB J. 23, 1459-1469 (2009)