Epidermal growth factor receptor 1 (EGFR1) and its variant EGFRvIII regulate TATA-binding protein expression through distinct pathways.
The epidermal growth factor receptor (EGFR) family regulates essential biological processes. Various epithelial tumors are linked to EGFR overexpression or expression of variant forms, such as the EGFR1 variant, EGFRvIII. Perturbations in expression of the transcription initiation factor, TATA-binding protein (TBP), alter cellular growth properties. Here we demonstrate that EGFR1 and EGFRvIII, but not HER2, induce TBP expression at a transcriptional level through distinct mechanisms. EGFR1 enhances the phosphorylation and function of Elk-1, recruiting it to the TBP promoter. In contrast, EGFRvIII robustly induces c-jun expression, stimulating recruitment of c-fos/c-jun to an overlapping AP-1 site. Enhancing c-jun expression alone induces TBP promoter activity through the AP-1 site. To determine the underlying mechanism for differences in Elk-1 function and c-jun expression by these receptors, we inhibited the internalization of EGFR1. Persistent EGFR1 cell surface occupancy mimics EGFRvIII-mediated effects on Elk-1 and c-jun and switches the requirement of Elk-1 to AP-1 for TBP promoter induction. Together, these studies define a new molecular mechanism for the regulation of TBP expression. In addition, we identify distinct molecular targets of EGFR1 and EGFRvIII and demonstrate the importance of receptor internalization in distinguishing their specific functions.
Fromm
Jody A
JA
Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Johnson
Sandra A S
SA
Johnson
Deborah L
DL
D000818:Animals; D002460:Cell Line; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018716:Molecular Mimicry; D011401:Promoter Regions, Genetic / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D035181:TATA-Box Binding Protein / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
D002966:Clathrin; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D016755:Proto-Oncogene Proteins c-jun; D018719:Erb-b2 Receptor Tyrosine Kinases; D035181:TATA-Box Binding Protein; D018808:Transcription Factor AP-1; D050807:ets-Domain Protein Elk-1; C410723:epidermal growth factor receptor VIII