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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Heparan sulfate regulates ephrin-A3/EphA receptor signaling
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Heparan sulfate regulates ephrin-A3/EphA receptor signaling

机译：硫酸乙酰肝素调节ephrin-A3 / EphA受体信号转导

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Increasing evidence indicates that many signaling pathways involve not only ligands and receptors but also various types of coreceptors and matrix components as additional layers of regulation. Signaling by Eph receptors and their ephrin ligands plays a key role in a variety of biological processes, such as axon guidance and topographic map formation, synaptic plasticity, angiogenesis, and cancer. Little is known about whether the ephrin-Eph receptor signaling system is subject to such additional layers of regulation. Here, we show that ephrin-A3 binds to heparan sulfate, and that the presence of cell surface heparan sulfate is required for the full biological activity of ephrin-A3. Among the ephrins tested, including ephrin-A1, -A2, -A5, -B1, and -B2, only ephrin-A3 binds heparin or heparan sulfate. Ephrin-A3-dependent EphA receptor activation is reduced in mutant cells that are defective in heparan sulfate synthesis, in wild-type cells from which cell surface heparan sulfate has been removed, and in the hippocampus of conditional knockout mice defective in heparan sulfate synthesis. Ephrin-A3-depen-dent cell rounding is impaired in CHO cells lacking heparan sulfate, and cortical neurons lacking heparan sulfate exhibit impaired growth cone collapse. In contrast, cell rounding and growth cone collapse in response to ephrin-A5, which does not bind heparan sulfate, are not affected by the absence of heparan sulfate. These results show that heparan sulfate modulates ephrin/Eph signaling and suggest a physiological role for heparan sulfate proteoglycans in the regulation of ephrin-A3-dependent biological processes.
机译：越来越多的证据表明，许多信号传导途径不仅涉及配体和受体，还涉及各种类型的共受体和基质成分，作为额外的调控层。 Eph受体及其ephrin配体发出的信号在各种生物学过程中发挥关键作用，例如轴突引导和地形图形成，突触可塑性，血管生成和癌症。关于ephrin-Eph受体信号传导系统是否受到这种额外的调节层知之甚少。在这里，我们显示了ephrin-A3与硫酸乙酰肝素结合，并且细胞表面硫酸乙酰肝素的存在是ephrin-A3的全部生物学活性所必需的。在所测试的ephrin中，包括ephrin-A1，-A2，-A5，-B1和-B2，只有ephrin-A3与肝素或硫酸乙酰肝素结合。在硫酸乙酰肝素合成有缺陷的突变细胞中，在去除了细胞表面硫酸乙酰肝素的野生型细胞中以及在硫酸乙酰肝素合成有缺陷的条件敲除小鼠海马中，Ephrin-A3依赖的EphA受体激活减少。在缺乏硫酸乙酰肝素的CHO细胞中，Ephrin-A3依赖性细胞舍入受损，而缺乏硫酸乙酰肝素的皮质神经元表现出受损的生长锥塌陷。相反，不结合硫酸乙酰肝素的ephrin-A5引起的细胞变圆和生长锥塌陷不受硫酸乙酰肝素缺乏的影响。这些结果表明硫酸乙酰肝素调节ephrin / Eph信号，并暗示硫酸乙酰肝素蛋白聚糖在调节ephrin-A3依赖性生物过程中的生理作用。

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