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首页> 美国卫生研究院文献>The Journal of Experimental Medicine >Identification of Grb2 As a Novel Binding Partner of  Tumor Necrosis Factor (TNF) Receptor I
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Identification of Grb2 As a Novel Binding Partner of  Tumor Necrosis Factor (TNF) Receptor I

机译：Grb2作为Factor肿瘤坏死因子（TNF）受体I的新型结合伴侣的鉴定。

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Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine. Its pleiotropic biological properties are signaled through two distinct cell surface receptors: the TNF receptor type I (TNFR-I) and the TNF receptor type II. Neither of the two receptors possesses tyrosine kinase activity. A large majority of TNF-α–dependent activities can be mediated by TNFR-I. Recently, c-Raf-1 kinase was identified as an intracellular target of a signal transduction cascade initiated by binding of TNF-α to TNFR-I. However, the mechanism engaged in TNF-α–dependent activation of c-Raf-1 kinase is still enigmatic.Here we report that the cytosolic adapter protein Grb2 is a novel binding partner of TNFR-I. Grb2 binds with its COOH-terminal SH3 domain to a PLAP motif within TNFR-I and with its NH2-terminal SH3 domain to SOS (son of sevenless). A PLAP deletion mutant of TNFR-I fails to bind Grb2. The TNFR-I/Grb2 interaction is essential for the TNF-α–dependent activation of c-Raf-1 kinase; activation of c-Raf-1 kinase by TNF-α can be blocked by coexpression of Grb2 mutants harboring inactivating point mutations in the NH2- or COOH-terminal SH3 domain, cell-permeable peptides that disrupt the Grb2/TNFR-I interaction or transdominant negative Ras. Functionality of the TNFR-I/Grb2/SOS/Ras interaction is a prerequisite but not sufficient for TNF-α–dependent activation of c-Raf-1 kinase. Inhibition of the TNFR-I/FAN (factor associated with neutral sphingomyelinase) interaction, which is essential for TNF-α–dependent activation of the neutral sphingomyelinase, either by cell-permeable peptides or by deletion of the FAN binding domain, prevents activation of c-Raf-1 kinase. In conclusion, binding of the Grb2 adapter protein via its COOH-terminal SH3 domain to the nontyrosine kinase receptor TNFR-I results in activation of a signaling cascade known so far to be initiated, in the case of the tyrosine kinase receptors, by binding of the SH2 domain of Grb2 to phosphotyrosine.
机译：肿瘤坏死因子α（TNF-α）是促炎细胞因子。它的多效性生物学特性通过两种不同的细胞表面受体发出信号：I型TNF受体（TNFR-I）和II型TNF受体。两种受体均不具有酪氨酸激酶活性。绝大多数TNF-α依赖的活性可以由TNFR-1介导。最近，c-Raf-1激酶被确定为通过TNF-α与TNFR-1结合而引发的信号转导级联的细胞内靶标。然而，参与c-Raf-1激酶的TNF-α依赖性激活的机制仍然是未知的。在这里，我们报道了胞质衔接蛋白Grb2是TNFR-1的新型结合伴侣。 Grb2以其COOH末端的SH3结构域与TNFR-1中的PLAP基序结合，以其NH2末端的SH3结构域与SOS结合（sevenless的儿子）。 TNFR-1的PLAP缺失突变体无法结合Grb2。 TNFR-I / Grb2相互作用对于c-Raf-1激酶的TNF-α依赖性激活至关重要。可以通过在NH2-或COOH-末端SH3域中具有失活点突变的Grb2突变体的共表达来阻断TNF-α激活c-Raf-1激酶，破坏细胞的通透性肽破坏了Grb2 / TNFR-I的相互作用或转导负面拉斯。 TNFR-I / Grb2 / SOS / Ras相互作用的功能是先决条件，但不足以依赖于TNF-α依赖性的c-Raf-1激酶激活。 TNFR-I / FAN（与中性鞘磷脂酶相关的因子）相互作用的抑制，这对于通过细胞渗透性肽或缺失FAN结合域的TNF-α依赖性中性鞘磷脂酶的激活是必不可少的。 c-Raf-1激酶。总之，Grb2衔接蛋白通过其COOH末端SH3结构域与非酪氨酸激酶受体TNFR-1的结合导致激活迄今为止已知的信号级联，在酪氨酸激酶受体的情况下，通过结合Grb2的SH2结构域为磷酸酪氨酸。

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