Mechanisms of Cross-talk Between EphrinB and Alternate Signaling Pathways

在正常发育过程中，许多组织的祖细胞经历进行性的 限制多能性、上皮-间充质转化、增殖、迁移 和差异化。这些事件中的大多数（如果不是全部的话）涉及细胞间的修饰， 细胞-基质粘附，以及这些粘附系统的异常修饰， 与肿瘤的形成有关。受体酪氨酸激酶的Eph家族和它们的 配体肝配蛋白在多种癌症中经常过度表达，包括 乳腺癌、小细胞肺癌和胃肠癌、黑素瘤和神经母细胞瘤。使用 在非洲爪蟾胚胎系统中，我们已经证明了由细胞内的 ephrinB的结构域影响细胞-细胞粘附，并且这种活性可以通过 与活化的FGF受体相互作用。跨膜ephrinB 1蛋白是一种 一种双向信号分子，通过其胞质结构域发出信号， 细胞运动进入眼区，而成纤维细胞生长因子的激活 受体（FGFR）抑制这些运动和视网膜命运。在非洲爪蟾胚胎中，ephrinB 1 在视网膜前体细胞通过与视网膜前体细胞的相互作用进入眼区中的作用。 支架蛋白Dishevelled（Dsh）。然而，FGFR可能调节这一点的机制 细胞运动未知。在这里，我们提出的证据表明，FGFR诱导的视网膜抑制， 命运取决于肝配蛋白B1胞内结构域的磷酸化。我们 表明ephrinB 1内酪氨酸324和325的磷酸化破坏了 ephrinB 1/Dsh相互作用，从而调节依赖于 平面细胞极性（PCP）途径。这些结果提供了深入了解FGF如何 在正常发育过程中，许多组织的祖细胞经历渐进性的增殖， 限制多能性、上皮-间充质转化、增殖、迁移 和差异化。这些事件中的大多数（如果不是全部的话）涉及细胞间的修饰， 细胞-基质粘附，以及这些粘附系统的异常修饰， 与肿瘤的形成有关。受体酪氨酸激酶的Eph家族和它们的 配体肝配蛋白在多种癌症中经常过度表达，包括 乳腺癌、小细胞肺癌和胃肠癌、黑素瘤和神经母细胞瘤。使用 在非洲爪蟾胚胎系统中，我们已经证明了由细胞内的 ephrinB的结构域影响细胞-细胞粘附，并且这种活性可以通过 与活化的FGF受体相互作用。跨膜ephrinB 1蛋白是一种 一种双向信号分子，通过其胞质结构域发出信号， 细胞运动进入眼区，而成纤维细胞生长因子的激活 受体（FGFR）抑制这些运动和视网膜命运。在非洲爪蟾胚胎中，ephrinB 1 在视网膜前体细胞通过与视网膜前体细胞的相互作用进入眼区中的作用。 支架蛋白Dishevelled（Dsh）。然而，FGFR可能调节这一点的机制 细胞运动未知。在这里，我们提出的证据表明，FGFR诱导的视网膜抑制， 命运取决于肝配蛋白B1胞内结构域的磷酸化。我们 表明ephrinB 1内酪氨酸324和325的磷酸化破坏了 ephrinB 1/Dsh相互作用，从而调节依赖于 平面细胞极性（PCP）途径。这些结果提供了深入了解FGF如何 信号传导调节ephrinB 1对眼区内视网膜祖细胞运动的控制。

During normal development progenitor cells of many tissues undergo progressive restriction of pluripotency, epithelial-to-mesenchymal transition, proliferation, migration, and differentiation. Most, if not all, of these events involve modifications of cell-cell and cell-matrix adhesion, and abnormal modifications of these adhesion systems are often associated with the formation of tumors. The Eph family of receptor tyrosine kinases and their ligands, the ephrins, are frequently over-expressed in a wide variety of cancers, including breast, small-cell lung and gastrointestinal cancers, melanomas, and neuroblastomas. Using the Xenopus embryonic system, we have demonstrated that signaling mediated by the intracellular domain of ephrinB affects cell-cell adhesion, and that this activity can be modulated by interaction with an activated FGF receptor. The transmembrane ephrinB1 protein is a bi-directional signaling molecule that signals through its cytoplasmic domain to promote cellular movements into the eye field, whereas activation of the fibroblast growth factor receptor (FGFR) represses these movements and retinal fate. In Xenopus embryos, ephrinB1 plays a role in retinal progenitor cell movement into the eye field through an interaction with the scaffold protein Dishevelled (Dsh). However, the mechanism by which the FGFR may regulate this cell movement is unknown. Here we present evidence that FGFR-induced repression of retinal fate is dependent upon phosphorylation within the intracellular domain of ephrinB1. We demonstrate that phosphorylation of tyrosines 324 and 325 within ephrinB1 disrupts the ephrinB1/Dsh interaction, thus modulating retinal progenitor movement that is dependent on the planar cell polarity (PCP) pathway. These results provide mechanistic insight into how FGF signaling modulates ephrinB1 control of retinal progenitor movement within the eye field.During normal development progenitor cells of many tissues undergo progressive restriction of pluripotency, epithelial-to-mesenchymal transition, proliferation, migration, and differentiation. Most, if not all, of these events involve modifications of cell-cell and cell-matrix adhesion, and abnormal modifications of these adhesion systems are often associated with the formation of tumors. The Eph family of receptor tyrosine kinases and their ligands, the ephrins, are frequently over-expressed in a wide variety of cancers, including breast, small-cell lung and gastrointestinal cancers, melanomas, and neuroblastomas. Using the Xenopus embryonic system, we have demonstrated that signaling mediated by the intracellular domain of ephrinB affects cell-cell adhesion, and that this activity can be modulated by interaction with an activated FGF receptor. The transmembrane ephrinB1 protein is a bi-directional signaling molecule that signals through its cytoplasmic domain to promote cellular movements into the eye field, whereas activation of the fibroblast growth factor receptor (FGFR) represses these movements and retinal fate. In Xenopus embryos, ephrinB1 plays a role in retinal progenitor cell movement into the eye field through an interaction with the scaffold protein Dishevelled (Dsh). However, the mechanism by which the FGFR may regulate this cell movement is unknown. Here we present evidence that FGFR-induced repression of retinal fate is dependent upon phosphorylation within the intracellular domain of ephrinB1. We demonstrate that phosphorylation of tyrosines 324 and 325 within ephrinB1 disrupts the ephrinB1/Dsh interaction, thus modulating retinal progenitor movement that is dependent on the planar cell polarity (PCP) pathway. These results provide mechanistic insight into how FGF signaling modulates ephrinB1 control of retinal progenitor movement within the eye field.