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

Transforming growth factor-alpha (TGF alpha) is an epidermal growth factor receptor (EGFR) ligand which is distinguished from EGF by its acid-labile s tructure and potent transforming function. We recently reported that TGF al pha induces less efficient EGFR heterodimerization and downregulation than does EGF (Gulliford et al,, 1997, Oncogene, 15:2219-2223). Here we use isof orm-specific EGFR and ErbB2 antibodies to show that the duration of EGFR si gnalling induced by a single TGF alpha exposure is less than that induced b y equimolar EGF. The protein trafficking inhibitor brefeldin A (BFA) reduce s the duration of EGF signalling to an extent similar to that seen with TGF alpha alone; the effects of TGF alpha and BFA on EGFR degradation are oppo site, however, with TGF alpha sparing EGFR from downregulation but BFA acce lerating EGF-dependent receptor loss. This suggests that BFA blocks EGFR re cycling and thus shortens EGF-dependent receptor signalling, whereas TGF al pha shortens receptor signalling and thus blocks EGFR downregulation. Consi stent with this, repeated application of TGF alpha is accompanied by prolon ged EGFR expression and signalling, whereas similar application of EFF caus es receptor downregulation and signal termination. These findings indicate that constitutive secretion of pH-labile TGF alpha may perpetuate EGFR sign alling by permitting-early oligomer dissociation and dephosphorylation with in acidic endosomes, thereby extinguishing a phosphotyrasine-based downregu lation signal and creating an irreversible autocrine growth loop. J. Cell. Physiol. 179:52-57, 1999. (C) 1999 Wiley-Liss, Inc.