Integrin β3 crosstalk with VEGFR accommodating tyrosine phosphorylation as a regulatory switch.
Integrin β3 crosstalk with VEGFR accommodating tyrosine phosphorylation as a regulatory switch.
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DOI：
10.1371/journal.pone.0031071
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Byzova TV
中科院分区：
文献类型：
--
作者：
West XZ;Meller N;Malinin NL;Deshmukh L;Meller J;Mahabeleshwar GH;Weber ME;Kerr BA;Vinogradova O;Byzova TV
整合素通过将细胞内机制与周围的细胞外基质相连，介导细胞黏附、迁移和存活。先前的研究表明，在血管内皮生长因子（VEGF）诱导的血管生成过程中，β3整合素与VEGF 2型受体（VEGFR2）之间的相互作用至关重要。在此，我们提供了β3和VEGFR2胞质尾区（CTs）直接关联的体外证据。具体而言，VEGFR2中801YLSI附近的膜近端基序介导其与未磷酸化的β3CT结合，在整合素结合构象中形成一个α - 螺旋转角。我们还发现，β3的Y747磷酸化会增强上述相互作用。为了证明β3磷酸化在内皮细胞功能中的重要性，我们合成了模拟β3CT的Y747磷酸化和未磷酸化的膜透性肽。我们发现，含有磷酸化Y747而非F747的肽能显著抑制VEGF诱导的信号传导和血管生成。此外，磷酸化Y747肽仅在野生型细胞中有抑制作用，而在β3整合素基因敲除细胞或表达两个酪氨酸被苯丙氨酸取代的β3整合素敲入细胞中则无此作用，这证明了其特异性。重要的是，这些肽对成纤维细胞生长因子受体信号传导无影响。总体而言，这些数据为整合素与VEGFR2之间依赖磷酸化的相互作用提供了新的机制见解。
Integrins mediate cell adhesion, migration, and survival by connecting intracellular machinery with the surrounding extracellular matrix. Previous studies demonstrated the importance of the interaction between β3 integrin and VEGF type 2 receptor (VEGFR2) in VEGF-induced angiogenesis. Here we present in vitro evidence of the direct association between the cytoplasmic tails (CTs) of β3 and VEGFR2. Specifically, the membrane-proximal motif around 801YLSI in VEGFR2 mediates its binding to non-phosphorylated β3CT, accommodating an α-helical turn in integrin bound conformation. We also show that Y747 phosphorylation of β3 enhances the above interaction. To demonstrate the importance of β3 phosphorylation in endothelial cell functions, we synthesized β3CT-mimicking Y747 phosphorylated and unphosphorylated membrane permeable peptides. We show that a peptide containing phospho-Y747 but not F747 significantly inhibits VEGF-induced signaling and angiogenesis. Moreover, phospho-Y747 peptide exhibits inhibitory effect only in WT but not in β3 integrin knock-out or β3 integrin knock-in cells expressing β3 with two tyrosines substituted for phenylalanines, demonstrating its specificity. Importantly, these peptides have no effect on fibroblast growth factor receptor signaling. Collectively these data provide novel mechanistic insights into phosphorylation dependent cross-talk between integrin and VEGFR2.
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影响因子：
3.3
作者：
Boettiger, D;Huber, F;Blystone, S
通讯作者：
Blystone, S
影响因子：
4
作者：
Chandhoke, SK;Williams, M;Blystone, SD
通讯作者：
Blystone, SD
影响因子：
13.6
作者：
Napione, Lucia;Cascone, Ilaria;Bussolino, Federico
通讯作者：
Bussolino, Federico
DOI：
10.1073/pnas.0914318107
发表时间：
2010-02-09
影响因子：
11.1
作者：
Leppanen, Veli-Matti;Prota, Andrea E.;Alitalo, Kari
通讯作者：
Alitalo, Kari
整联蛋白信号传导对于病理血管生成至关重要。
影响因子：
15.3
作者：
Mahabeleshwar, Ganapati H.;Feng, Weiyi;Phillips, David R.;Byzova, Tatiana V.
通讯作者：
Byzova, Tatiana V.