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Transforming growth factor‐alpha short‐circuits downregulation of the epidermal growth factor receptor
Author(s) -
Ouyang Xiaomei,
Gulliford Timothy,
Huang Guocai,
Epstein Richard J.
Publication year - 1999
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/(sici)1097-4652(199904)179:1<52::aid-jcp7>3.0.co;2-m
Subject(s) - downregulation and upregulation , autocrine signalling , tgf alpha , epidermal growth factor receptor , epidermal growth factor , microbiology and biotechnology , receptor , transforming growth factor , biology , signal transduction , chemistry , cancer research , endocrinology , biochemistry , gene
Transforming growth factor‐alpha (TGFα) 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 TGFα 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 TGFα 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 TGFα alone; the effects of TGFα and BFA on EGFR degradation are opposite, however, with TGFα 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 TGFα shortens receptor signalling and thus blocks EGFR downregulation. Consistent with this, repeated application of TGFα 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 TGFα 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. J. Cell. Physiol. 179:52–57, 1999. © 1999 Wiley‐Liss, Inc.