Sci. Signal., 7 October 2008
EGF Signaling More Than Just Constitutively Active
Annalisa M. VanHook
Science Signaling, AAAS, Washington, DC 20005, USA
Signaling mediated by epidermal growth factor receptors (EGFRs) modulates cellular growth and migration in development and disease. EGFRvIII is a constitutively active mutant form of EGFR1 that is expressed in some human cancers and confers increased aggressiveness to tumors. Upon ligand binding, EGFR1 is endocytosed and signals from endosomes as it is trafficked through the cell for degradation or recycling. In contrast, EGFRvIII is not internalized and thus initiates signaling only from the plasma membrane. Fromm et al. determined that signaling through EGFR1 and EGFRvIII differs not only quantitatively but also qualitatively. As determined by immunoblotting and reporter assays in human glioblastoma U87 cells overexpressing EGFR1 or EGFRvIII, signaling through either receptor stimulated expression of TATA-binding protein (TBP) through mitogen-activated protein kinase (MAPK) intermediates. The MAPKs ERK1 and ERK2 were preferentially phosphorylated in response to signaling through EGFR1, and JNK1 and JNK2 were preferentially phosphorylated in response to signaling through EGFRvIII. Experiments with small interfering RNAs (siRNAs) targeting the transcription factors Elk-1, c-Jun, and c-Fos indicated that TBP promoter activity induced by signaling through EGFR1 required only Elk-1, whereas TBP promoter activity induced by signaling through EGFRvIII required both c-Fos and c-Jun, heterodimers of which constitute the AP-1 transcription factor. Chromatin immunoprecipitation (ChIP) analyses revealed that the TBP promoter, in which Elk-1 and AP-1 binding sites overlap, was occupied by Elk-1 in EGFR1-overexpressing cells stimulated with EGF and occupied by c-Fos and c-Jun in EGFRvIII-overexpressing cells. When internalization of EGFR1 was prevented with an siRNA targeting clathrin, stimulating EFGR1-overexpressing cells with EGF resulted in TBP promoter activation through the AP-1 binding site. These results suggest that signaling initiated at the plasma membrane by EGFRvIII is mediated by JNK and results in AP-1 recruitment to the TBP promoter, whereas signaling initiated in endosomes by EGFR1 is preferentially mediated by ERK and recruits Elk-1 to the TBP promoter. Given that the two receptors stimulate TBP expression through distinct mechanisms, it is possible EGFRvIII may have other unique activities that contribute to its role in tumorigenesis.
J. A. Fromm, S. A. S. Johnson, D. L. Johnson, Epidermal growth factor receptor 1 (EGFR1) and its variant EGFRvIII regulate TATA-binding protein expression through distinct pathways. Mol. Cell. Biol. 28, 6483-6495 (2008). [Abstract] [Full Text]
Citation: A. M. VanHook, More Than Just Constitutively Active. Sci. Signal. 1, ec347 (2008).
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