The efficacy of receptor tyrosine kinase EphA2 autophosphorylation increases with EphA2 oligomer size.
The efficacy of receptor tyrosine kinase EphA2 autophosphorylation increases with EphA2 oligomer size.
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DOI：
10.1016/j.jbc.2022.102370
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发表时间：
2022-10
影响因子：
4.8
通讯作者：
Hristova, Kalina
中科院分区：
文献类型：
--
作者：
Zapata-Mercado, Elmer;Biener, Gabriel;McKenzie, Daniel M.;Wimley, William C.;Pasquale, Elena B.;Raicu, Valerica;Hristova, Kalina
受体酪氨酸激酶(RTK)EphA2在上皮细胞和内皮细胞中表达，控制细胞-细胞连接的组装。EphA2还与包括癌症在内的许多疾病有关。与大多数以二聚体为主的RTK不同，EphA2在与配体结合时很容易形成高阶低聚物。在这里，我们研究了EphA2信号特性与多个配体诱导的EphA2寡聚体大小之间的相关性，这些配体包括广泛使用的ewitinA1-Fc配体、可溶性单体m-ewitinA1和新型工程多肽配体。我们使用荧光强度波动(FIF)光谱来表征不同配体诱导的EphA2寡聚体数量。有趣的是，我们发现不同的单体和二聚体配体导致EphA2寡聚体的大小分布有很大的不同。我们对FIF亮度分布参数和EphA2信号参数的比较表明，EphA2对酪氨酸588的磷酸化效果与EphA2平均寡聚体大小有关。酪氨酸588是一种有助于EphA2激活的自动磷酸化反应。然而，我们发现，其他特征，如AKT抑制效果和配体偏向系数，似乎与EphA2寡聚体的大小无关。综上所述，这项工作强调了FIF在RTK信号研究中的效用，并证明了EphA2信号复合体的结构和信号特征之间的定量关联。
The receptor tyrosine kinase (RTK) EphA2 is expressed in epithelial and endothelial cells and controls the assembly of cell–cell junctions. EphA2 has also been implicated in many diseases, including cancer. Unlike most RTKs, which signal predominantly as dimers, EphA2 readily forms high-order oligomers upon ligand binding. Here, we investigated if a correlation exists between EphA2 signaling properties and the size of the EphA2 oligomers induced by multiple ligands, including the widely used ephrinA1-Fc ligand, the soluble monomeric m-ephrinA1, and novel engineered peptide ligands. We used fluorescence intensity fluctuation (FIF) spectrometry to characterize the EphA2 oligomer populations induced by the different ligands. Interestingly, we found that different monomeric and dimeric ligands induce EphA2 oligomers with widely different size distributions. Our comparison of FIF brightness distribution parameters and EphA2 signaling parameters reveals that the efficacy of EphA2 phosphorylation on tyrosine 588, an autophosphorylation response contributing to EphA2 activation, correlates with EphA2 mean oligomer size. However, we found that other characteristics, such as the efficacy of AKT inhibition and ligand bias coefficients, appear to be independent of EphA2 oligomer size. Taken together, this work highlights the utility of FIF in RTK signaling research and demonstrates a quantitative correlation between the architecture of EphA2 signaling complexes and signaling features.
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影响因子：
7.7
作者：
Huang, Yongjian;Bharill, Shashank;Kuriyan, John
通讯作者：
Kuriyan, John
DOI：
10.1146/annurev-pharmtox-011112-140226
发表时间：
2015
影响因子：
12.5
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Barquilla A;Pasquale EB
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作者：
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通讯作者：
Novick, Steven
影响因子：
37.8
作者：
Finney AC;Funk SD;Green JM;Yurdagul A Jr;Rana MA;Pistorius R;Henry M;Yurochko A;Pattillo CB;Traylor JG;Chen J;Woolard MD;Kevil CG;Orr AW
通讯作者：
Orr AW