Activation of c-fos gene expression by a kinase-deficient epidermal growth factor receptor

Emelyn R. Eldredge, Gina M. Korf, Trace A. Christensen, Denise C. Connolly, Michael J. Getz, Nita J. Maihle

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Abstract

The intrinsic tyrosine kinase activity of the epidermal growth factor receptor (EGFR) has been shown to be responsible for many of the pleiotropic intracellular effects resulting from ligand stimulation [W. S. Chen, C. S. Lazar, M. Poenie, R. Y. Tsien, G. N. Gill, and M. G. Rosenfeld, Nature (London) 328:820-823, 1987; A. M. Honegger, D. Szapary, A. Schmidt, R. Lyall, E. Van Obberghen, T. J. Dull, A. Ulrich, and J. Schlessinger, Mol. Cell. Biol. 7:4568-4571, 1987]. Recently, however, it has been shown that addition of ligand to cells expressing kinase-defective EGFR mutants can result in the phosphorylation of mitogen-activated protein kinase (R. Campos-Gonzalez and J. R. Glenney, Jr., J. Biol. Chem. 267:14535-14538, 1992; E. Selva, D. L. Raden, and R. J. Davis, J. Biol. Chem. 268:2250-2254, 1993), as well as stimulation of DNA synthesis (K. J. Coker, J. V. Staros, and C. A. Guyer, Proc. Natl. Acad. Sci. USA 91:6967-6971, 1994). Moreover, mitogen-activated protein kinase has been shown to phosphorylate the transcription factor p62(TCF) in vitro, leading to enhanced ternary complex formation between p62(TCF), p67(SRF), and the c-fos serum response element (SRE) [H. Gille, A. D. Sharrocks, and P. E. Shaw, Nature (London) 358:414-417, 1992]. On the basis of these observations, we have investigated the possibility that the intrinsic tyrosine kinase activity of the EGFR may not be necessary for transcriptional activation mediated via p62(TCF). Here, we demonstrate that a kinase-defective EGFR mutant can signal ligand-induced expression of c-fos protein and that a significant component of this induction appears to be mediated at the transcriptional level. Investigation of transcriptional activation mediated by the c-fos SRE shows that this response is impaired by mutations in the SRE which eliminate binding of p62(TCF). These data indicate that information inherent in the structure of the EGFR can be accessed by ligand stimulation independent of the receptor's catalytic kinase function.

Original languageEnglish (US)
Pages (from-to)7527-7534
Number of pages8
JournalMolecular and Cellular Biology
Volume14
Issue number11
DOIs
StatePublished - Nov 1994

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Eldredge, E. R., Korf, G. M., Christensen, T. A., Connolly, D. C., Getz, M. J., & Maihle, N. J. (1994). Activation of c-fos gene expression by a kinase-deficient epidermal growth factor receptor. Molecular and Cellular Biology, 14(11), 7527-7534. https://doi.org/10.1128/MCB.14.11.7527