Eph受体家族及其配体的信号转导途径及功能

Eph受体是已知最大的酪氨酸蛋白激酶受体家族,Eph受体和其膜附着型配体（ephrin）在发育过程中呈现不同的表达模式,近来研究证明,Eph受体和其配体在包括神经网络形成,神经管和轴旁中胚层的成型（patterning）,细胞迁移导向和轴突路径导引,血管形成等许多的发育过程中起重要作用.Eph受体及其配体也与肿瘤发生有关,因此深入分析这些分子尤其在肿瘤细胞生长中的功能而应用于治疗具有重要的临床意义.     

Exogenous nitric oxide causes collapse of retinal ganglion cell axonal growth cones in vitro

We show that nitric oxide (NO) from applied NO-donating chemicals induces collapse of ganglion cell axonal growth cones extending from explants of tadpole retina in culture. Peroxynitrite, a neurotoxic product of NO and superoxide reaction, did not induce collapse, and oxyhemoglobin, which binds NO, blocked the highly effective collapsing activity of the NO donor S-nitrosocysteine. Membrane-permeable analogs of cyclic guanosine monophosphate had no collapsing activity. Inhibitors of NO synthase did not induce collapse. NO is a potential retrograde messenger through which postsynaptic neurons signal to their inputs to modify synaptic efficacy following NMDA receptor activation. Our results suggest a role for NO as such a messenger during development of the retinotectal projection. © 1996 John Wiley & Sons, Inc.     

Homotypic receptor-receptor interactions regulating Eph signaling

The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, and mediate many other cell-cell communication events. The Ephs and ephrins both localize to the plasma membrane and, upon cell-cell contact, form extensive signaling assemblies at the contact sites. Recent structural, biochemical and cell-biological studies revealed that these assemblies are generated not only via Eph-ephrin interactions, but also via homotypic interactions between neighboring receptor molecules. In addition, Eph-Eph interactions mediate receptor pre-clustering, which ensures fast and efficient activation once ligands come into contact range. Here we summarize the current knowledge about the homotypic Eph-Eph interactions and discuss how they could modulate the initiation of Eph/ephrin signaling.     

Homotypic receptor-receptor interactions regulating Eph signaling

The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, and mediate many other cell-cell communication events. The Ephs and ephrins both localize to the plasma membrane and, upon cell-cell contact, form extensive signaling assemblies at the contact sites. Recent structural, biochemical and cell-biological studies revealed that these assemblies are generated not only via Eph-ephrin interactions, but also via homotypic interactions between neighboring receptor molecules. In addition, Eph-Eph interactions mediate receptor pre-clustering, which ensures fast and efficient activation once ligands come into contact range. Here we summarize the current knowledge about the homotypic Eph-Eph interactions and discuss how they could modulate the initiation of Eph/ephrin signaling.     

Irradiation affects cellular properties and Eph receptor expression in human melanoma cells

X-ray irradiation influences metastatic properties of tumor cells and, moreover, metastasis and cellular motility can be modified by members of the Eph receptor/ephrin family of receptor tyrosine kinases. We hypothesized that irradiation-induced changes in cellular properties relevant for metastasis in melanoma cells could be mediated by Eph receptor/ephrin signaling. In this pilot study, we analyzed one pre-metastatic (Mel-Juso) and three metastatic human melanoma (Mel-Juso-L3, A375, and A2058) cells lines and predominantly found anti-metastatic effects of X-ray irradiation with impaired cell growth, clonal growth and motility. Additionally, we observed an irradiation-induced increase in adhesion paralleled by a decrease in migration in Mel-Juso and Mel-Juso-L3 cells and, in part, also in A375 cells. We further demonstrate a decrease of EphA2 both in expression and activity at 7 d after irradiation paralleled by an upregulation of EphA3. Analyzing downstream signaling after irradiation, we detected decreased Src kinase phosphorylation, but unchanged focal adhesion kinase (FAK) phosphorylation, indicating, in part, irradiation-induced downregulation of signaling via the EphA2-Src-FAK axis in melanoma cells. However, to which extent this finding contributes to the modification of metastasis-relevant cellular properties remains to be elucidated.     

Irradiation affects cellular properties and Eph receptor expression in human melanoma cells

X-ray irradiation influences metastatic properties of tumor cells and, moreover, metastasis and cellular motility can be modified by members of the Eph receptor/ephrin family of receptor tyrosine kinases. We hypothesized that irradiation-induced changes in cellular properties relevant for metastasis in melanoma cells could be mediated by Eph receptor/ephrin signaling. In this pilot study, we analyzed one pre-metastatic (Mel-Juso) and three metastatic human melanoma (Mel-Juso-L3, A375, and A2058) cells lines and predominantly found anti-metastatic effects of X-ray irradiation with impaired cell growth, clonal growth and motility. Additionally, we observed an irradiation-induced increase in adhesion paralleled by a decrease in migration in Mel-Juso and Mel-Juso-L3 cells and, in part, also in A375 cells. We further demonstrate a decrease of EphA2 both in expression and activity at 7 d after irradiation paralleled by an upregulation of EphA3. Analyzing downstream signaling after irradiation, we detected decreased Src kinase phosphorylation, but unchanged focal adhesion kinase (FAK) phosphorylation, indicating, in part, irradiation-induced downregulation of signaling via the EphA2-Src-FAK axis in melanoma cells. However, to which extent this finding contributes to the modification of metastasis-relevant cellular properties remains to be elucidated.     

CyclinD2-mediated regulation of neurogenic output from the retinal ciliary margin is perturbed in albinism

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Organization and emergence of a mixed GABA-glycine retinal circuit that provides inhibition to mouse ON-sustained alpha retinal ganglion cells

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EphrinB3 blocks EphB3 dependence receptor functions to prevent cell death following traumatic brain injury

Eph receptor tyrosine kinases and their membrane-bound ligands, ephrins, have a variety of roles in the developing and adult central nervous system that require direct cell–cell interactions; including regulating axon path finding, cell proliferation, migration and synaptic plasticity. Recently, we identified a novel pro-survival role for ephrins in the adult subventricular zone, where ephrinB3 blocks Eph-mediated cell death during adult neurogenesis. Here, we examined whether EphB3 mediates cell death in the adult forebrain following traumatic brain injury and whether ephrinB3 infusion could limit this effect. We show that EphB3 co-labels with microtubule-associated protein 2-positive neurons in the adult cortex and is closely associated with ephrinB3 ligand, which is reduced following controlled cortical impact (CCI) injury. In the complete absence of EphB3 (EphB3^−/−), we observed reduced terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL), and functional improvements in motor deficits after CCI injury as compared with wild-type and ephrinB3^−/− mice. We also demonstrated that EphB3 exhibits dependence receptor characteristics as it is cleaved by caspases and induces cell death, which is not observed in the presence of ephrinB3. Following trauma, infusion of pre-clustered ephrinB3-Fc molecules (eB3-Fc) into the contralateral ventricle reduced cortical infarct volume and TUNEL staining in the cortex, dentate gyrus and CA3 hippocampus of wild-type and ephrinB3^−/− mice, but not EphB3^−/− mice. Similarly, application of eB3-Fc improved motor functions after CCI injury. We conclude that EphB3 mediates cell death in the adult cortex through a novel dependence receptor-mediated cell death mechanism in the injured adult cortex and is attenuated following ephrinB3 stimulation.