HGF-independent potentiation of EGFR action by c-Met.
HGF-independent potentiation of EGFR action by c-Met.
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DOI：
10.1038/onc.2011.84
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发表时间：
2011-08-18
期刊：
影响因子：
8
通讯作者：
Siegfried, J. M.
中科院分区：
文献类型：
--
作者：
Dulak, A. M.;Gubish, C. T.;Stabile, L. P.;Henry, C.;Siegfried, J. M.
c-Met受体是非小细胞肺癌（NSCLC）的潜在治疗靶点。c-Met和突变型表皮生长因子受体（EGFR）之间的信号相互作用已被广泛研究，但在EGFR野生型肿瘤中c-Met的侧向信号传导的信号中间体和生物学后果的了解最少。我们的观察结果表明，NSCLC细胞系中延迟的c-Met激活是由野生型EGFR启动的，野生型EGFR是NSCLC肿瘤中最常见的受体。EGFR配体诱导活化的c-Met蓄积，其在8 h开始持续48 h。这种效应伴随着c-Met表达的增加和关键c-Met酪氨酸残基的磷酸化，而不激活MAPK或Akt。延迟的c-Met激活需要基因转录;然而，EGFR对c-Met的磷酸化在不产生HGF或其他分泌因子的情况下发生，支持配体非依赖性机制。两种选择性c-Met酪氨酸激酶抑制剂（TKI）PF 2341066和SU 11274或EGFR TKI吉非替尼可阻断侧向信号传导，表明该效应需要两种受体的激酶活性。观察到延长的c-Src磷酸化，并且c-Src途径对于EGFR至c-Met通讯是必需的。用pan-SFK抑制剂PP 2和达沙替尼预处理可消除延迟的c-Met磷酸化。与对照相比，c-Src显性阴性构建体减少EGF诱导的c-Met磷酸化，进一步证实了c-Src的需要。用PF 2341066和siRNA抑制c-Met可使EGF诱导的侵袭表型降低约86%，运动性降低约81%，表明EGFR利用一种新形式的c-Met激活来最大化这些生物学效应。c-Met和EGFR的联合靶向导致异种移植物抗肿瘤活性增加，表明抑制EGFR-c-Src-c-Met轴的下游和侧向信号传导可能有效治疗NSCLC。
The c-Met receptor is a potential therapeutic target for non-small cell lung cancer (NSCLC). Signaling interactions between c-Met and the mutant Epidermal Growth Factor Receptor (EGFR) have been studied extensively, but signaling intermediates and biological consequences of lateral signaling to c-Met in EGFR wild-type tumors is minimally understood. Our observations indicate that delayed c-Met activation in NSCLC cell lines is initiated by wild-type EGFR, the receptor most often found in NSCLC tumors. EGFR ligands induce accumulation of activated c-Met which begins at 8 h continues for 48 h. This effect is accompanied by an increase in c-Met expression and phosphorylation of critical c-Met tyrosine residues without activation of MAPK or Akt. Gene transcription is required for delayed c-Met activation; however, phosphorylation of c-Met by EGFR occurs without production of HGF or another secreted factor, supporting a ligand-independent mechanism. Lateral signaling is blocked by two selective c-Met tyrosine kinase inhibitors (TKIs), PF2341066 and SU11274, or with gefitinib, an EGFR TKI, suggesting kinase activity of both receptors is required for this effect. Prolonged c-Src phosphorylation is observed, and c-Src pathway is essential for EGFR to c-Met communication. Pre-treatment with pan-SFK inhibitors, PP2 and dasatinib, abolishes delayed c-Met phosphorylation. A c-Src dominant-negative construct reduces EGF-induced c-Met phosphorylation compared to control, further, confirming a c-Src requirement. Inhibition of c-Met with PF2341066 and siRNA decreases EGF-induced phenotypes of invasion by ~86% and motility by ~81%, suggesting that a novel form of c-Met activation is utilized by EGFR to maximize these biological effects. Combined targeting of c-Met and EGFR leads to increased xenograft anti-tumor activity, demonstrating that inhibition of downstream and lateral signaling from the EGFR-c-Src-c-Met axis might be effective in treatment of NSCLC.
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影响因子：
11.4
作者：
Goi, T;Shipitsin, M;Feig, LA
通讯作者：
Feig, LA
影响因子：
11.4
作者：
Daub, H;Wallasch, C;Ullrich, A
通讯作者：
Ullrich, A
影响因子：
56.9
作者：
BOTTARO, DP;RUBIN, JS;AARONSON, SA
通讯作者：
AARONSON, SA
DOI：
10.1073/pnas.0707270105
发表时间：
2008-01-15
影响因子：
11.1
作者：
Guo, Ailan;Villen, Judit;Comb, Michael J.
通讯作者：
Comb, Michael J.
影响因子：
11.2
作者：
Ma, PC;Jagadeeswaran, R;Salgia, R
通讯作者：
Salgia, R