Signaling through JAM-1 and ανβ3 is required for the angiogenic action of bFGF:: dissociation of the JAM-1 and ανβ3 complex
Signaling through JAM-1 and ανβ3 is required for the angiogenic action of bFGF:: dissociation of the JAM-1 and ανβ3 complex
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DOI：
10.1182/blood-2003-04-1114
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发表时间：
2003-09-15
期刊：
影响因子：
20.3
通讯作者：
Naik, UP
中科院分区：
文献类型：
--
作者：
Naik, MU;Mousa, SA;Naik, UP
生长因子诱导的新生血管是实体瘤生长和转移的基础，因此受到广泛关注。这一多步骤过程需要通过生长因子受体和整合素进行广泛的信号传导。在参与该过程的整合素中，整合素α（v）β（3）对碱性成纤维细胞生长因子（bFGF）诱导的血管生成具有特异性。在这里，我们表明，连接粘附分子1/A（JAM-1/A）和α（v）β（3）形成一个复合物，在碱性成纤维细胞生长因子的情况下。JAM-1通常位于静止内皮细胞的细胞-细胞连接处，在bFGF处理后重新分布到细胞表面。阻断JAM-1的细胞外结构域可抑制bFGF诱导的内皮细胞形态、增殖和血管生成。此外，JAM-1胞质结构域中的突变阻断bFGF诱导的促分裂原活化蛋白（MAP）激酶活化并消除其诱导内皮细胞管形成的能力，表明通过JAM-1的信号传导是bFGF诱导的信号传导的关键。免疫沉淀分析表明，bFGF信号传导使JAM-1 α（v）β（3）复合物解离，允许通过JAM-1和α（v）β（3）进行信号传导。此外，阻断JAM-1或alpha（v）beta（3）抑制bFGF诱导的MAP激酶活化。因此，我们的研究结果表明，通过JAM-1和alpha（v）beta（3）的信号传导对于bFGF诱导的血管生成是必要的。
Growth factor-induced neovascularization has received a great deal of attention because it is fundamental to the growth and metastasis of solid tumors. This multistep process requires extensive signaling through growth factor receptors and integrins. Among the integrins involved in this process, integrin alpha(v)beta(3) is specific to basic fibroblast growth factor (bFGF)induced angiogenesis. Here we show that junctional adhesion molecule 1/A (JAM-1/A) and alpha(v)beta(3) form a complex in the absence of bFGF. JAM-1, which is normally localized at the cell-cell junctions of quiescent endothelial cells, redistributes to the cell surface on bFGF treatment. Blockage of the extracellular domain of JAM-1 inhibits bFGF-Induced endothelial cell morphology, proliferation, and angio-genesis. Additionally, mutation in the JAM-1 cytoplasmic domain blocks bFGF-induced mitogen-activated protein (MAP) kinase activation and ablates its ability to induce endothelial cell tube formation, suggesting that signaling through JAM-1 is key to bFGF-induced signaling. immunoprecipitation analysis suggests that bFGF signaling dissociates the JAM-1alpha(v)beta(3) complex, allowing for signaling through JAM-1 and of alpha(v)beta(3). In addition, blockage of either JAM-1 or alpha(v)beta(3) inhibits bFGF-induced MAP kinase activation. Thus, our results suggest that signaling through JAM-1 and alpha(v)beta(3) is necessary for bFGF-induced angiogenesis.