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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. <\/jats:p>","DOI":"10.1152\/ajpgi.00344.2005","type":"journal-article","created":{"date-parts":[[2005,10,7]],"date-time":"2005-10-07T00:43:50Z","timestamp":1128645830000},"page":"G404-G416","source":"Crossref","is-referenced-by-count":26,"title":["EGF-mediated regulation of IGFBP-3 determines esophageal epithelial cellular response to IGF-I"],"prefix":"10.1152","volume":"290","author":[{"given":"Munenori","family":"Takaoka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin E.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael K.","family":"Mashiba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaomi","family":"Okawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia D.","family":"Andl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wafik S.","family":"El-Deiry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Nakagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M209148200"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1016\/1357-2725(96)00056-8"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-3449"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1136\/mp.54.3.145"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1994.1322"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1200804"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(01)69892-6"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1038\/377646a0"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.86.10.7936"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2003-030914"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(02)02001-6"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.14.7.4588"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1038\/ng0593-42"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(199905)179:2<201::AID-JCP10>3.0.CO;2-9"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.2004.06350.x"},{"key":"R16","unstructured":"Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, and Semenza GL. 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