Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis
Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis
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DOI：
10.1182/blood.v95.11.3403.011k07_3403_3411
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发表时间：
2000-06-01
期刊：
影响因子：
20.3
通讯作者：
Claesson-Welsh, L
中科院分区：
文献类型：
--
作者：
Dixelius, J;Larsson, H;Claesson-Welsh, L
内皮抑素对应于胶原XVIII的c端片段，是一种有效的血管生成抑制剂。内皮抑素可抑制成纤维细胞生长因子-2 （FGF-2）诱导的鸡绒毛膜尿囊膜血管生成，但内皮抑素突变体R158/270A不具有抑制作用，缺乏肝素结合能力。内皮细胞内化内皮抑素，小鼠成纤维细胞内化内皮抑素。内皮素处理小鼠脑内皮（IBE）细胞减少了S期细胞的比例，而内皮素处理的胶原凝胶中生长受阻的IBE细胞显示出增强的管状形态发生，过度表达Shb（一种与血管他汀诱导的凋亡有关的适应蛋白）的IBE细胞在内皮素和FGF-2的作用下，显示出凋亡增加和胶原凝胶中管状形态发生减少。细胞凋亡的诱导依赖于内皮抑素的肝素结合能力和Shb与Src同源2 （SH2）结构域的表达。内皮抑素治疗10分钟或24小时可诱导Shb的酪氨酸磷酸化和多蛋白复合物的形成。在内皮他汀处理的细胞中，Shb SH2结构域融合蛋白沉淀了一个125 kd的磷酸酪氨酸蛋白。125-kd成分要么含有内在的酪氨酸激酶活性，要么与酪氨酸激酶复合物发生。总之，我们的数据表明，内皮抑素诱导酪氨酸激酶活性，并增强fgf处理的内皮细胞的凋亡。（血液。2000;95:3403-3411）(C) 2000由美国血液学会。
Endostatin, which corresponds to the C-terminal fragment of collagen XVIII, is a potent inhibitor of angiogenesis. Fibroblast growth factor-2 (FGF-2)-induced angiogenesis in the chicken chorioallantoic membrane was inhibited by endostatin, but not by an endostatin mutant R158/270A, lacking heparin-binding ability. Endostatin was internalized by endothelial cells, but not by mouse fibroblasts. Treatment of murine brain endothelial (IBE) cells with endostatin reduced the proportion of cells in S phase, whereas growth-arrested IBE cells in collagen gels treated with endostatin displayed enhanced tubular morphogenesis, IBE cells overexpressing Shb, an adaptor protein implicated in angiostatin-induced apoptosis, displayed elevated apoptosis and decreased tubular morphogenesis in collagen gels in response to endostatin when added together with FGF-2, Induction of apoptosis was dependent on the heparin-binding ability of endostatin and the expression of Shb with a functional Src homology 2 (SH2)-domain. Endostatin treatment for 10 minutes or 24 hours induced tyrosine phosphorylation of Shb and formation of multiprotein complexes. An Shb SH2 domain fusion protein precipitated a 125-kd phosphotyrosyl protein in endostatin-treated cells. The 125-kd component either contained intrinsic tyrosine kinase activity or occurred in complex with a tyrosine kinase, In conclusion, our data show that endostatin induces tyrosine kinase activity and enhanced apoptosis in FGF-treated endothelial cells. (Blood. 2000;95:3403-3411) (C) 2000 by The American Society of Hematology.