Transforming growth factor-alpha short-circuits downregulation of the epidermal growth factor receptor

✍ Scribed by Xiaomei Ouyang; Timothy Gulliford; Guocai Huang; Richard J. Epstein

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 153 KB
• Volume: 179
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/(sici)1097-4652(199904)179:1<52::aid-jcp7>3.0.co;2-m

✦ Synopsis

Transforming growth factor-alpha (TGF␣) is an epidermal growth factor receptor (EGFR) ligand which is distinguished from EGF by its acid-labile structure and potent transforming function. We recently reported that TGF␣ induces less efficient EGFR heterodimerization and downregulation than does EGF (Gulliford et al., 1997, Oncogene, 15:2219 -2223). Here we use isoform-specific EGFR and ErbB2 antibodies to show that the duration of EGFR signalling induced by a single TGF␣ exposure is less than that induced by equimolar EGF. The protein trafficking inhibitor brefeldin A (BFA) reduces the duration of EGF signalling to an extent similar to that seen with TGF␣ alone; the effects of TGF␣ and BFA on EGFR degradation are opposite, however, with TGF␣ sparing EGFR from downregulation but BFA accelerating EGF-dependent receptor loss. This suggests that BFA blocks EGFR recycling and thus shortens EGF-dependent receptor signalling, whereas TGF␣ shortens receptor signalling and thus blocks EGFR downregulation. Consistent with this, repeated application of TGF␣ is accompanied by prolonged EGFR expression and signalling, whereas similar application of EGF causes receptor downregulation and signal termination. These findings indicate that constitutive secretion of pH-labile TGF␣ may perpetuate EGFR signalling by permitting early oligomer dissociation and dephosphorylation within acidic endosomes, thereby extinguishing a phosphotyrosine-based downregulation signal and creating an irreversible autocrine growth loop.