Heterogeneity in VEGF Receptor-2 Mobility and Organization on the Endothelial Cell Surface Leads to Diverse Models of Activation by VEGF.
Heterogeneity in VEGF Receptor-2 Mobility and Organization on the Endothelial Cell Surface Leads to Diverse Models of Activation by VEGF.
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DOI：
10.1016/j.celrep.2020.108187
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发表时间：
2020-09-29
期刊：
影响因子：
8.8
通讯作者：
Jaqaman K
中科院分区：
文献类型：
--
作者：
da Rocha-Azevedo B;Lee S;Dasgupta A;Vega AR;de Oliveira LR;Kim T;Kittisopikul M;Malik ZA;Jaqaman K
细胞表面受体的动态纳米结构在信号转导中起着重要作用。我们通过结合活体内皮细胞内源性VEGFR-2的单分子成像和多尺度计算分析，确定了这种组织及其与血管内皮细胞(ECs)中关键的受体酪氨酸激酶VEGFR-2激活的关系。我们发现，VEGFR-2表面可以是可移动的，也可以表现出有限的迁移率，可以是单体或非单体，两者之间存在复杂的相互作用。这种基本的异质性导致了导致VEGFR-2被血管内皮生长因子激活的步骤序列的异质性。具体地说，我们发现，血管内皮生长因子可以与单体和非单体VEGFR-2结合，并且当与单体VEGFR-2结合时，其对二聚的影响取决于VEGFR-2的流动性。我们的研究强调了细胞表面受体组织的动态和异质性，以及需要多尺度的、基于单分子的分析来确定其与受体激活和信号传递的关系。Da Rocha-Azevedo等人。表明VEGFR-2在内皮细胞表面表现出移动性和相互作用的异质性。VEGF激活VEGFR-2的步骤顺序取决于VEGFR-2的基础状态。因此，血管内皮生长因子激活VEGFR-2的模型不是单一的，而是多种共存的。
The dynamic nanoscale organization of cell surface receptors plays an important role in signaling. We determine this organization and its relation to activation of VEGF receptor-2 (VEGFR-2), a critical receptor tyrosine kinase in endothelial cells (ECs), by combining single-molecule imaging of endogenous VEGFR-2 in live ECs with multiscale computational analysis. We find that surface VEGFR-2 can be mobile or exhibit restricted mobility and be monomeric or non-monomeric, with a complex interplay between the two. This basal heterogeneity results in heterogeneity in the sequence of steps leading to VEGFR-2 activation by VEGF. Specifically, we find that VEGF can bind to monomeric and non-monomeric VEGFR-2 and that, when binding to monomeric VEGFR-2, its effect on dimerization depends on the mobility of VEGFR-2. Our study highlights the dynamic and heterogeneous nature of cell surface receptor organization and the need for multiscale, single-molecule-based analysis to determine its relationship to receptor activation and signaling. da Rocha-Azevedo et al. show that VEGFR-2 exhibits mobility and interaction heterogeneity on the endothelial cell surface. The sequence of steps leading to VEGFR-2 activation by VEGF depends on the basal state of VEGFR-2. Thus, there is not one model but multiple co-existing models of VEGFR-2 activation by VEGF.
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影响因子：
64.5
作者：
Freeman SA;Vega A;Riedl M;Collins RF;Ostrowski PP;Woods EC;Bertozzi CR;Tammi MI;Lidke DS;Johnson P;Mayor S;Jaqaman K;Grinstein S
通讯作者：
Grinstein S
血管内皮钙粘蛋白控制着细胞内室的VEGFR-2内在化和信号传导。
影响因子：
7.8
作者：
Lampugnani, Maria Grazia;Orsenigo, Fabrizio;Gagliani, Maria Cristina;Tacchetti, Carlo;Dejana, Elisabetta
通讯作者：
Dejana, Elisabetta
影响因子：
4
作者：
Githaka, John Maringa;Vega, Anthony R.;Touret, Nicolas
通讯作者：
Touret, Nicolas
影响因子：
4.6
作者：
Karaman, Sinem;Leppanen, Veli-Matti;Alitalo, Kari
通讯作者：
Alitalo, Kari
影响因子：
3.7
作者：
Imoukhuede PI;Popel AS
通讯作者：
Popel AS