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首页> 外文期刊>Molecular and Cellular Biology >Interaction of Tumor Necrosis Factor Receptor-Associated Factor Signaling Proteins with the Latent Membrane Protein 1 PXQXT Motif Is Essential for Induction of Epidermal Growth Factor Receptor Expression
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Interaction of Tumor Necrosis Factor Receptor-Associated Factor Signaling Proteins with the Latent Membrane Protein 1 PXQXT Motif Is Essential for Induction of Epidermal Growth Factor Receptor Expression

机译：肿瘤坏死因子受体相关因子信号蛋白与潜在膜蛋白1 PXQXT母题的相互作用是诱导表皮生长因子受体表达所必需的。

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The Epstein-Barr virus latent membrane protein 1 (LMP1) oncoprotein causes multiple cellular changes, including induction of epidermal growth factor receptor (EGFR) expression and activation of the NF-κB transcription factor. LMP1 and the cellular protein CD40, which also induces EGFR expression, interact with the tumor necrosis factor receptor-associated factor (TRAF) proteins. The LMP1 carboxy-terminal activation region 1 signaling domain interacts specifically with the TRAFs and is essential for EGFR induction through a mechanism independent of NF-κB alone. LMP1 and CD40 share a common TRAF binding motif, PXQXT. In this study, the PXQXT motifs in both LMP1 and CD40 were altered and mutant proteins were analyzed for induction of EGFR expression. Replacement of the T residue with A in CD40 completely blocked induction of the EGFR, while the same mutation in LMP1 did not affect EGFR induction. Replacement of both P and Q residues with A’s in LMP1 reduced EGFR induction by >75%, while deletion of PXQXT blocked EGFR induction. These results genetically link EGFR induction by LMP1 to the TRAF signaling pathway. Overexpression of TRAF2 potently activates NF-κB, although TRAF2 did not induce expression of the EGFR either alone or in combination with TRAF1 and TRAF3. In vivo analyses of the interaction of the TRAFs with LMP1 variants mutated in the PXQXT domain indicate that high-level induction of EGFR expression requires interaction with TRAF1, -2, and -3. However, exogenous expression of TRAF3 decreased EGFR induction mediated by either LMP1 or CD40. These data suggest that TRAF-mediated activation of EGFR expression requires assembly of a complex containing the appropriate stoichiometry of TRAF proteins clustered at the cell membrane with LMP1.
机译：EB病毒潜伏膜蛋白1（LMP1）癌蛋白会引起多种细胞变化，包括诱导表皮生长因子受体（EGFR）表达和激活NF-κB转录因子。 LMP1和也诱导EGFR表达的细胞蛋白CD40与肿瘤坏死因子受体相关因子（TRAF）蛋白相互作用。 LMP1羧基末端激活区1信号域与TRAF特异性相互作用，并且通过独立于NF-κB的机制对EGFR诱导至关重要。 LMP1和CD40共有一个常见的TRAF结合基序PXQXT。在这项研究中，LMP1和CD40中的PXQXT基序均被改变，并分析了突变蛋白对EGFR表达的诱导。 CD40中的A取代T残基完全阻​​断了EGFR的诱导，而LMP1中的相同突变并不影响EGFR的诱导。在LMP1中以A取代P和Q残基可将EGFR诱导降低> 75％，而删除PXQXT则可阻止EGFR诱导。这些结果将LMP1对EGFR的诱导与TRAF信号通路遗传联系起来。尽管TRAF2不能单独或与TRAF1和TRAF3组合诱导EGFR表达，但TRAF2的过表达有效激活了NF-κB。在体内对TRAF与PXQXT域中突变的LMP1变异的相互作用的分析表明，高水平诱导EGFR表达需要与TRAF1，-2和-3相互作用。但是，TRAF3的外源表达减少了LMP1或CD40介导的EGFR诱导。这些数据表明，TRAF介导的EGFR表达激活需要组装一个复合物，该复合物包含与LMP1聚集在细胞膜上的TRAF蛋白的适当化学计量。

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