Mechanisms of Cross-talk Between EphrinB and Alternate Signaling Pathways

EphrinB 与替代信号通路之间的串扰机制

• 批准号: 7965177
• 负责人: Ira Daar
• 金额: $ 59.32万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7965177
• 关键词: Adhesions; Affect; Axon; Benign; Biological Models; Breast; Cancer cell line; Cell Adhesion; Cell Cycle Progression; Cell Polarity; Cell-Cell Adhesion; Cell-Matrix Junction; Cells; Colon; Congenital Abnormality; Cytoplasmic Tail; Development; Embryo; Embryonic Development; Eph Family Receptors; Ephrins; Event; Eye; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Frequencies; Human; Laboratories; Ligand Binding; Ligands; Link; Lung; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Membrane; Modification; Movement; Neoplasm Metastasis; Neural Crest Cell; Neuroblastoma; Pathway interactions; Pattern; Phenotype; Phosphorylation; Play; Positioning Attribute; Process; Prostate; Protein Tyrosine Kinase; Proteins; Repression; Research; Retinal; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Stem cells; System; Tissues; Tumor Angiogenesis; Tumor Cell Invasion; Tumor Stem Cells; Tyrosine Phosphorylation; Vertebrates; Visual Fields; Xenopus; angiogenesis; cell motility; embryonic stem cell; epithelial to mesenchymal transition; hindbrain; human disease; insight; melanoma; member; migration; neoplastic cell; pluripotency; retinal progenitor cell; skeletal; stem cell fate specification; tumor; tumorigenesis

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.

在正常发育过程中，许多组织的祖细胞经历了多能性、上皮向间充质转化、增殖、迁移和分化的进行性限制。这些事件中的大多数(如果不是全部)涉及细胞-细胞和细胞-基质黏附的改变，这些黏附系统的异常改变通常与肿瘤的形成有关。Eph家族受体酪氨酸激酶及其配体--肾上腺素经常在多种癌症中过度表达，包括乳腺癌、小细胞肺癌和胃肠道肿瘤、黑色素瘤和神经母细胞瘤。利用非洲爪哇胚胎系统，我们已经证明了由eaffinB胞内结构域介导的信号影响细胞与细胞之间的黏附，并且这种活性可以通过与激活的成纤维细胞生长因子受体的相互作用来调节。跨膜的ewitinB1蛋白是一种双向信号分子，通过其细胞质结构域发出信号，促进细胞运动进入眼场，而成纤维细胞生长因子受体(FGFR)的激活抑制了这些运动和视网膜的命运。在非洲爪哇胚胎中，eparinB1通过与支架蛋白disheveled(Dsh)的相互作用，在视网膜前体细胞进入眼场中发挥作用。然而，FGFR调节这种细胞运动的机制尚不清楚。在这里，我们提出的证据表明，FGFR诱导的视网膜命运的抑制依赖于ewitinB1细胞内区域的磷酸化。我们证明了ewitinB1中324和325酪氨酸的磷酸化破坏了ewitinB1/Dsh的相互作用，从而调节了依赖于平面细胞极性(PCP)途径的视网膜前体细胞的移动。这些结果从机制上深入了解了成纤维细胞生长因子信号如何调控视网膜祖细胞在眼场内的运动。在正常发育过程中，许多组织的祖细胞经历了多能性、上皮向间充质转化、增殖、迁移和分化的进行性限制。这些事件中的大多数(如果不是全部)涉及细胞-细胞和细胞-基质黏附的改变，这些黏附系统的异常改变通常与肿瘤的形成有关。Eph家族受体酪氨酸激酶及其配体--肾上腺素经常在多种癌症中过度表达，包括乳腺癌、小细胞肺癌和胃肠道肿瘤、黑色素瘤和神经母细胞瘤。利用非洲爪哇胚胎系统，我们已经证明了由eaffinB胞内结构域介导的信号影响细胞与细胞之间的黏附，并且这种活性可以通过与激活的成纤维细胞生长因子受体的相互作用来调节。跨膜的ewitinB1蛋白是一种双向信号分子，通过其细胞质结构域发出信号，促进细胞运动进入眼场，而成纤维细胞生长因子受体(FGFR)的激活抑制了这些运动和视网膜的命运。在非洲爪哇胚胎中，eparinB1通过与支架蛋白disheveled(Dsh)的相互作用，在视网膜前体细胞进入眼场中发挥作用。然而，FGFR调节这种细胞运动的机制尚不清楚。在这里，我们提出的证据表明，FGFR诱导的视网膜命运的抑制依赖于ewitinB1细胞内区域的磷酸化。我们证明了ewitinB1中324和325酪氨酸的磷酸化破坏了ewitinB1/Dsh的相互作用，从而调节了依赖于平面细胞极性(PCP)途径的视网膜前体细胞的移动。这些结果提供了对成纤维细胞生长因子信号如何调控视网膜前体细胞在眼野内运动的控制的机械性洞察。