Anchorage of VEGF to the extracellular matrix conveys differential signaling responses to endothelial cells

被引:241
作者
Chen, Tom T. [1 ]
Luque, Alfonso [1 ]
Lee, Sunyoung [1 ]
Anderson, Sean M. [2 ]
Segura, Tatiana [2 ]
Iruela-Arispe, M. Luisa [1 ,3 ,4 ]
机构
[1] Univ Calif Los Angeles, Dept Mol Cellular & Dev Biol, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, Dept Chem & Biomol Engn, Los Angeles, CA 90095 USA
[3] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA
[4] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA
基金
美国国家卫生研究院;
关键词
GROWTH-FACTOR RECEPTOR-2; VASCULAR-PERMEABILITY; BIOLOGICAL-ACTIVITY; PROXIMITY LIGATION; INDUCED ACTIVATION; TYROSINE-KINASE; SPLICE VARIANTS; NITRIC-OXIDE; IN-SITU; TRANSDUCTION;
D O I
10.1083/jcb.200906044
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
VEGF can be secreted in multiple isoforms with variable affinity for extracellular proteins and different abilities to induce vascular morphogenesis, but the molecular mechanisms behind these effects remain unclear. Here, we show molecular distinctions between signaling initiated from soluble versus matrix-bound VEGF, which mediates a sustained level of VEGFR2 internalization and clustering. Exposure of endothelial cells to matrix-bound VEGF elicits prolonged activation of VEGFR2 with differential phosphorylation of Y1214, and extended activation kinetics of p38. These events require association of VEGFR2 with. 1 integrins. Matrix-bound VEGF also promotes reciprocal responses on. 1 integrin by inducing its association with focal adhesions; a response that is absent upon exposure to soluble VEGF. Inactivation of. 1 integrin blocks the prolonged phosphorylation of Y1214 and consequent activation of p38. Combined, these results indicate that when in the context of extracellular matrix, activation of VEGFR2 is distinct from that of soluble VEGF in terms of recruitment of receptor partners, phosphorylation kinetics, and activation of downstream effectors.
引用
收藏
页码:595 / 609
页数:15
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