Epidermal growth factor (EGF) receptor kinase-independent signaling by EGF
Epidermal growth factor (EGF) receptor kinase-independent signaling by EGF
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DOI：
10.1074/jbc.m100928200
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发表时间：
2001-05-04
影响因子：
4.8
通讯作者：
Johnson, GR
中科院分区：
文献类型：
--
作者：
Deb, TB;Su, L;Johnson, GR
ErbB受体家族，包括表皮生长因子受体（EGFR）、ErbB2、ErbB3和ErbB4，通过egf样多肽介导信号传导。为了更好地了解EGFR酪氨酸激酶的作用，我们分析了ErbB缺失32D细胞中激酶失活的EGFR （K721M）的信号传导。单独K721M未表现出可检测到的信号传导能力，而K721M与ErbB2共表达，而不与ErbB3或ErbB4共表达，导致egf依赖性丝裂原活化蛋白激酶（MAPK）激活。egf诱导的MAPK激活需要ErbB2的激酶活性，而不是酪氨酸磷酸化。K721M中酪氨酸磷酸化位点的存在并不是信号传导的必要条件，这表明ErbB2对K721M的转磷酸化并不是受体激活的必要机制。相反，K721M的突变激酶结构域（残基648-973）和至少一个受体的酪氨酸磷酸化是必需的。在表达K721M和ErbB2的稳定细胞系中，EGF可以激活促存活蛋白激酶Akt，但与表达野生型EGFR的细胞不同，EGF不能激活信号转导和转录激活因子（STAT）或驱动细胞增殖。这些结果表明，EGFR- erbb2低聚物是MAPK和Akt的有效激活剂，而这种信号传导不需要EGFR激酶的活性。
The ErbB family of receptors, which includes the epidermal growth factor receptor (EGFR), ErbB2, ErbB3, and ErbB4, mediate signaling by EGF-like polypeptides, To better understand the role of the EGFR tyrosine kinase, we analyzed signaling by a kinase-inactive EGFR (K721M) in ErbB-devoid 32D cells. K721M alone exhibited no detectable signaling capacity, whereas coexpression of K721M with ErbB2, but not ErbB3 or ErbB4, resulted in EGF-dependent mitogen-activated protein kinase (MAPK) activation. The kinase activity, but not tyrosine phosphorylation, of ErbB2 was required for EGF-induced MAPK activation. The presence of tyrosine phosphorylation sites in K721M was not a requisite for signaling, indicating that transphosphorylation of K721M by ErbB2 was not an essential mechanism of receptor activation. Conversely, the mutated kinase domain of K721M (residues 648-973) and tyrosine phosphorylation of at least one of the receptors were necessary. EGF was found to activate the pro-survival protein kinase Akt in stable cell lines expressing K721M and ErbB2 but, unlike cells expressing wild-type EGFR, was incapable of activating signal transducers and activators of transcription (STAT) or driving cell proliferation. These results demonstrate that EGFR-ErbB2 oligomers are potent activators of MAPK and Akt, and this signaling does not require EGFR kinase activity.