EGF-mediated regulation of IGFBP-3 determines esophageal epithelial cellular response to IGF-I
EGF-mediated regulation of IGFBP-3 determines esophageal epithelial cellular response to IGF-I
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DOI：
10.1152/ajpgi.00344.2005
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发表时间：
2006-02-01
影响因子：
4.5
通讯作者：
Nakagawa, H
中科院分区：
文献类型：
--
作者：
Takaoka, M;Smith, CE;Nakagawa, H
IGF和EGF调节多种生理和病理过程。胰岛素样生长因子结合蛋白（IGFBP）-3以胰岛素样生长因子依赖性和非依赖性方式调节细胞增殖。最近，我们确定IGFBP-3作为一种新的EGF受体（EGFR）的下游靶分子在原代和永生化的人食管上皮细胞，这表明EGF和IGF信号通路之间的相互作用。然而，IGFBP-3表达的调控机制及其在食管细胞增殖中的功能作用仍有待阐明。在此，我们报告，IGFBP-3的mRNA和蛋白诱导生长因子剥夺后，在原代和永生化的人食管细胞通过机制，需要p53-独立的从头mRNA转录和蛋白质合成。这发生在面对活化的磷脂酰肌醇3-OH-激酶（PI 3 K）/哺乳动物雷帕霉素靶（mTOR）途径时。分泌的IGFBP-3中和IGFs并阻止IGF-I受体（IGF-IR）活化。与此相反，EGF抑制IGFBP-3的mRNA和蛋白质的表达，通过激活MAPK的EGFR-酪氨酸激酶依赖的方式恢复细胞对IGF-I的反应。当稳定过表达时，野生型IGFBP-3而不是I56 G/L 80 G/L 81 G（GGG）突变体IGFBP-3（其对IGFs的亲和力降低）阻止IGF-I激活IGF-IR和Akt以及刺激细胞增殖。然而，与IGFBP-3发挥抗增殖作用的其他细胞类型不同，单独的野生型或GGG突变体IGFBP-3都不影响细胞增殖或EGFR活性。这些结果表明，IGF信号通过IGFBP-3受到负调节，通过EGF受到正调节，后者抑制IGFBP-3。这为理解EGF和IGF介导的途径之间的新串扰提供了一个平台。
IGF and EGF regulate various physiological and pathological processes. IGF binding protein (IGFBP)-3 regulates cell proliferation in IGF-dependent and -independent fashions. Recently, we identified IGFBP-3 as a novel EGF receptor (EGFR) downstream target molecule in primary and immortalized human esophageal epithelial cells, suggesting an interplay between the EGF and IGF signaling pathways. However, the regulatory mechanisms for IGFBP-3 expression and its functional role in esophageal cell proliferation remain to be elucidated. Herein, we report that IGFBP-3 mRNA and protein were induced upon growth factor deprivation in primary and immortalized human esophageal cells through mechanisms requiring p53-independent de novo mRNA transcription and protein synthesis. This occurred in the face of the activated phosphatidylinositol 3-OH-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. Secreted IGFBP-3 neutralized IGFs and prevented IGF-I receptor (IGF-IR) activation. In contrast, EGF suppressed IGFBP-3 mRNA and protein expression through activation of MAPK in an EGFR-tyrosine kinase-dependent manner to restore the cellular response to IGF-I. When stably overexpressed, wild-type IGFBP-3 but not I56G/L80G/L81G (GGG) mutant IGFBP-3, which has a reduced affinity to IGFs, prevented IGF-I from activating IGF-IR and Akt as well as stimulating cell proliferation. However, unlike other cell types where IGFBP-3 exerts antiproliferative effects, neither wild-type nor GGG mutant IGFBP-3 alone affected cell proliferation or EGFR activity. These results indicate that IGF signaling is subject to negative regulation through IGFBP-3 and positive regulation by EGF, the latter of which suppresses IGFBP-3. This provides a platform for understanding the novel cross talk between EGF- and IGF-mediated pathways.