+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

A raf-independent epidermal growth factor receptor autocrine loop is necessary for Ras transformation of rat intestinal epithelial cells



A raf-independent epidermal growth factor receptor autocrine loop is necessary for Ras transformation of rat intestinal epithelial cells



Journal of Biological Chemistry 272(30): 18926-18931



We recently have shown that activated Ras, but not Raf, causes transformation of intestinal (RIE-1, IEC-6) epithelial cells, whereas both activated Ras and Raf transform NIH 3T3 fibroblasts (Oldham, S. M., Clark, G. J., Gangarosa, L. M., Coffey, R. J., and Der, C. J. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 6924-6928). The observations that conditioned medium from Ras-, but not Raf-, transfected RIE-1 cells, as well as exogenous transforming growth factor alpha (TGF-alpha), promoted morphological transformation of parental RIE-1 cells prompted us to identify epidermal growth factor (EGF) receptor (EGFR) ligands produced by Ras-transformed RIE-1 cells responsible for this autocrine effect. Since studies in fibroblasts have shown that v-Src is transforming, we also determined if v-Src could transform RIE-1 cells. H- or K-Ras-transformed cells secreted significant amounts of TGF-alpha protein, and mRNA transcripts for TGF-alpha, amphiregulin (AR), and heparin-binding EGF-like growth factor (HB-EGF) were induced. Like Ras, v-Src caused morphological and growth transformation of parental RIE-1 cells. However, TGF-alpha protein was not secreted by RIE-1 cells stably expressing v-Src or activated Raf, and only minor increases in EGFR ligand mRNA expression were detected in these cells. A selective EGFR tyrosine kinase inhibitor PD153035 attenuated the Ras-, but not Src-, transformed phenotype. Taken together, these observations provide a mechanistic and biochemical basis for the ability of activated Ras, but not activated Raf, to cause transformation of RIE-1 cells. Finally, we suggest that an EGFR-dependent mechanism is necessary for Ras, but not Src, transformation of these intestinal epithelial cells.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 008021702

Download citation: RISBibTeXText

PMID: 9228072

DOI: 10.1074/jbc.272.30.18926


Related references

Autocrine growth loop of the epidermal growth factor receptor in normal and immortalized human bronchial epithelial cells. Experimental Cell Research 223(2): 268-273, 1996

Ras Oncogene triggers up-regulation of cIAP2 and XIAP in intestinal epithelial cells: epidermal growth factor receptor-dependent and -independent mechanisms of ras-induced transformation. Journal of Biological Chemistry 280(45): 37383-37392, 2005

The autocrine loop of epidermal growth factor receptor-epidermal growth factor / transforming growth factor-alpha in malignant rhabdoid tumor cell lines: heterogeneity of autocrine mechanism in TTC549. Japanese Journal of Cancer Research 92(3): 269-278, 2001

Interferon gamma induces prostaglandin G/H synthase-2 through an autocrine loop via the epidermal growth factor receptor in human bronchial epithelial cells. Journal of Clinical Investigation 99(5): 1057-1063, 1997

The Autocrine Loop of Epidermal Growth Factor Receptor-Epidermal Growth Factor/Transforming Growth Factor-α in Malignant Rhabdoid Tumor Cell Lines: Heterogeneity of Autocrine Mechanism in TTC549. Cancer Science 92(3): 269-278, 2001

Epidermal growth factor part of an autocrine loop responsible for transformation of cells. Breast Cancer Research & Treatment 16(2): 186, 1990

Cytokine epithelial interaction induction of both components of an autocrine loop tgf alpha and epidermal growth factor receptor in pancreatic cancer cells by tnf alpha. Immunobiology 183(3-4): 263, 1991

Transformation of rat intestinal epithelial cells by activated ras and src, but not raf, and the role of epidermal growth factor receptor signalling. Gastroenterology 110(4 Suppl. ): A516, 1996

Trafficking of nuclear heparin-binding epidermal growth factor-like growth factor into an epidermal growth factor receptor-dependent autocrine loop in response to oxidative stress. Cancer Research 65(18): 8242-8249, 2005

Epidermal growth factor-independent transformation of Ba/F3 cells with cancer-derived epidermal growth factor receptor mutants induces gefitinib-sensitive cell cycle progression. Cancer Research 65(19): 8968-8974, 2005

Sa1865 Helicobacter pylori Induces Phosphorylation of Epidermal Growth Factor Receptor via p38/Erk Activation in Gastric Epithelial Cells in Heparin Binding-Epidermal Growth Factor Independent Manner. Gastroenterology 144(5): S-323, 2013

Autocrine regulation of cell migration by the epidermal growth factor and its receptor in mammary epithelial cells. Molecular Biology of the Cell 9(Suppl. ): 233A, 1998

Epidermal growth factor receptor autocrine signaling is required for tumor necrosis factor alpha activity in human mammary epithelial cells. Molecular Biology of the Cell 13(Suppl.): 14a-15a, 2002

Induced autocrine signaling through the epidermal growth factor receptor contributes to the response of mammary epithelial cells to tumor necrosis factor alpha. Journal of Biological Chemistry 279(18): 18488-18496, 2004

Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells. Cancer Research 66(2): 867-874, 2006