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首页> 外文期刊>Oncogene >Five carboxyl-terminal residues of neuregulin2 are critical for stimulation of signaling by the ErbB4 receptor tyrosine kinase
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Five carboxyl-terminal residues of neuregulin2 are critical for stimulation of signaling by the ErbB4 receptor tyrosine kinase

机译：神经调节蛋白2的五个羧基末端残基对于ErbB4受体酪氨酸激酶刺激信号传导至关重要

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摘要

The neuregulins (NRGs) are members of the epidermal growth factor (EGF) family of peptide growth factors. These hormones are agonists for the ErbB family of receptor tyrosine kinases, a family that includes the epidermal growth factor receptor (EGFR/ErbB1), ErbB2/Neu/HER2, ErbB3/HER3, and ErbB4/HER4. We recently observed that the EGF family hormone NRG2 is a potent agonist for ErbB4. In contrast, NRG2, a splicing isoform of the same gene that encodes NRG2, is a poor ErbB4 agonist. We hypothesized that carboxyl-terminal residues of NRG2 are critical for stimulation of ErbB4 tyrosine phosphorylation and coupling to downstream signaling events. Here, we demonstrate that the substitution of a lysine residue for Phe45 in NRG2 results in reduced ligand potency. We also demonstrate that substitution of a phenylalanine for Lys45 in NRG2 results in increased ligand potency. Finally, analyses of the gain-of-function NRG2 Chg5 mutant demonstrate that Gln43, Met47, Asn49, and Phe50 regulate ligand efficacy. Thus, these data indicate that carboxyl-terminal residues of NRG2 are critical for activation of ErbB4 signaling. Moreover, these NRG2 and NRG2 mutants reveal new insights into models for ligand-induced ErbB family receptor tyrosine phosphorylation and coupling to downstream signaling events.
机译：神经调节蛋白（NRG）是肽生长因子的表皮生长因子（EGF）家族的成员。这些激素是受体酪氨酸激酶ErbB家族的激动剂，该家族包括表皮生长因子受体（EGFR / ErbB1），ErbB2 / Neu / HER2，ErbB3 / HER3和ErbB4 / HER4。我们最近观察到EGF家族激素NRG2是ErbB4的有效激动剂。相反，NRG2是编码NRG2的同一基因的剪接同工型，是差的ErbB4激动剂。我们假设，NRG2的羧基末端残基对于刺激ErbB4酪氨酸磷酸化和与下游信号传递事件耦合至关重要。在这里，我们证明了赖氨酸残基被NRG2中的Phe45取代导致配体效价降低。我们还证明了在NRG2中用苯丙氨酸替代Lys45会导致配体效价增加。最后，对功能获得的NRG2 Chg5突变体的分析表明，Gln43，Met47，Asn49和Phe50调节配体功效。因此，这些数据表明，NRG2的羧基末端残基对于激活ErbB4信号至关重要。此外，这些NRG2和NRG2突变体揭示了配体诱导的ErbB家族受体酪氨酸磷酸化和与下游信号事件耦合的模型的新见解。

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