Eph receptor function is modulated by heterooligomerization of A and B type Eph receptors
Eph receptor function is modulated by heterooligomerization of A and B type Eph receptors
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DOI：
10.1083/jcb.201104037
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发表时间：
2011-12-12
影响因子：
7.8
通讯作者：
Lackmann, Martin
中科院分区：
文献类型：
--
作者：
Janes, Peter W.;Griesshaber, Bettina;Lackmann, Martin
Eph受体与邻近细胞上的肝配蛋白配体相互作用，以促进正常和致癌发育过程中的组织模式，其中非计划表达和体细胞突变有助于肿瘤进展。 EphA 和 B 亚型分别优先结合 A 型和 B 型肝配蛋白，形成通过同型 Eph-Eph 相互作用传播的受体复合物。我们现在证明 EphA 和 B 受体共聚，这样一种受体的特异性连接促进了另一种受体的募集和交叉激活。值得注意的是，激酶失活突变体 EphA3 与野生型 EphB2 的共表达可以引起交叉激活或交叉抑制，具体取决于相对表达。我们的研究结果表明，细胞对肝配蛋白接触的反应是由给定细胞上的 EphA/EphB 受体谱决定的，而不是由单个 Eph 亚类决定的。重要的是，它们意味着在共表达不同 Eph 的肿瘤细胞中，一种亚型的功能突变可能会导致表型，这是异型而非同型 Eph 簇信号改变的结果。
Eph receptors interact with ephrin ligands on adjacent cells to facilitate tissue patterning during normal and oncogenic development, in which unscheduled expression and somatic mutations contribute to tumor progression. EphA and B subtypes preferentially bind A- and B-type ephrins, respectively, resulting in receptor complexes that propagate via homotypic Eph-Eph interactions. We now show that EphA and B receptors cocluster, such that specific ligation of one receptor promotes recruitment and cross-activation of the other. Remarkably, coexpression of a kinase-inactive mutant EphA3 with wild-type EphB2 can cause either cross-activation or cross-inhibition, depending on relative expression. Our findings indicate that cellular responses to ephrin contact are determined by the EphA/EphB receptor profile on a given cell rather than the individual Eph subclass. Importantly, they imply that in tumor cells coexpressing different Ephs, functional mutations in one subtype may cause phenotypes that are a result of altered signaling from heterotypic rather from homotypic Eph clusters.