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首页> 外文期刊>The FASEB Journal >Epidermal growth factor-induced cellular invasion requires sphingosine-1-phosphate/sphingosine-1-phosphate 2 receptor-mediated ezrin activation
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Epidermal growth factor-induced cellular invasion requires sphingosine-1-phosphate/sphingosine-1-phosphate 2 receptor-mediated ezrin activation

机译：表皮生长因子诱导的细胞侵袭需要鞘氨醇-1-磷酸盐/鞘氨醇-1-磷酸2受体介导的Ezrin活化

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Ezrin, radixin, and moesin (ERM) proteins link cortical actin to the plasma membrane and coordinate cellular events that require cytoskeletal rearrangement, including cell division, migration, and invasion. While ERM proteins are involved in many important cellular events, the mechanisms regulating their function are not completely understood. Our laboratory previously identified reciprocal roles for the sphingolipids ceramide and sphingosine-1-phosphate (S1P) in the regulation of ERM proteins. We recently showed that ceramide-induced activation of PP1α leads to dephosphorylation and inactivation of ERM proteins, while S1P results in phosphorylation and activation of ERM proteins. Following these findings, we aimed to examine known inducers of the SK/S1P pathway and evaluate their ability to regulate ERM proteins. We examined EGF, a known inducer of the SK/S1P pathway, for its ability to regulate the ERM family of proteins. We found that EGF induces ERM c-terminal threonine phosphorylation via activation of the SK/S1P pathway, as this was prevented by siRNA knockdown or pharmacological inhibition of SK. Using pharmacological, as well as genetic, knockdown approaches, we determined that EGF induces ERM phosphorylation via activation of S1PR2. In addition, EGF led to cell polarization in the form of lamellipodia, and this occurred through a mechanism involving S1PR2-mediated phosphorylation of ezrin T567. EGF-induced cellular invasion was also found to be dependent on S1PR2-induced T567 ezrin phosphorylation, such that S1PR2 antagonist, JTE-013, and expression of a dominant-negative ezrin mutant prevented cellular invasion toward EGF. In this work, a novel mechanism of EGF-stimulated invasion is unveiled, whereby S1P-mediated activation of S1PR2 and phosphorylation of ezrin T567 is required.—Orr Gandy, K. A., Adada, M., Canals, D., Carroll, B., Roddy, P., Hannun, Y. A., Obeid, L. M. Epidermal growth factor-induced cellular invasion requires sphingosine-1-phosphate/sphingosine-1-phosphate 2 receptor-mediated ezrin activation.
机译：ezrin，radixin和moesin（ERM）蛋白（ERM）蛋白链接皮质肌动蛋白与血浆膜和坐标细胞事件，需要细胞骨骼重排，包括细胞分裂，迁移和侵袭。虽然ERM蛋白涉及许多重要的细胞事件，但不完全理解调节其功能的机制。我们的实验室先前鉴定了鞘脂素神经酰胺和鞘氨醇-1-磷酸（S1P）的互惠作用在ERM蛋白的调节中。我们最近表明神经酰胺诱导的PP1α激活导致ERM蛋白的去磷酸化和失活，而S1P导致ERM蛋白的磷酸化和活化。在这些发现之后，我们旨在研究SK / S1P途径的已知诱导剂，并评估它们调节ERM蛋白的能力。我们检查了EGF，是SK / S1P途径的已知诱导剂，以便其调节ERM蛋白质的能力。我们发现EGF通过激活SK / S1P途径诱导ERM C末端苏氨酸磷酸化，因为SiRNA敲低或SK的药理学抑制预防。使用药理学，以及遗传敲击方法，我们确定EGF通过S1PR2的活化诱导ERM磷酸化。另外，EGF导致薄层的形式的细胞偏振，并通过涉及S1PR2介导的Ezrin T567磷酸化的机制发生。还发现EGF诱导的细胞侵袭依赖于S1PR2诱导的T567 Ezrin磷酸化，使得S1PR2拮抗剂，JTE-013和显性阴性Ezrin突变体的表达阻止了对EGF的细胞侵袭。在这项工作中，推出了一种新的EGF刺激侵袭机制，由此需要S1P介导的S1PR2的激活和Ezrin T567的磷酸化。 - ORR Gandy，Ka，Adada，M.，Canals，D.，Carroll，B。 ，罗迪，P.，汉恩，ya，obeid，lm表皮生长因子诱导的细胞侵袭需要鞘氨醇-1-磷酸盐/鞘氨酸-1-磷酸2受体介导的ezrin活化。

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