PMID- 10082132
OWN - NLM
STAT- MEDLINE
DCOM- 19990413
LR  - 20181201
IS  - 0021-9541 (Print)
IS  - 0021-9541 (Linking)
VI  - 179
IP  - 1
DP  - 1999 Apr
TI  - Transforming growth factor-alpha short-circuits downregulation of the epidermal 
      growth factor receptor.
PG  - 52-7
AB  - Transforming growth factor-alpha (TGFalpha) 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 TGFalpha 
      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 TGFalpha 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 TGFalpha alone; the effects of 
      TGFalpha and BFA on EGFR degradation are opposite, however, with TGFalpha 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 TGFalpha shortens receptor signalling and thus blocks EGFR 
      downregulation. Consistent with this, repeated application of TGFalpha 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 TGFalpha 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.
FAU - Ouyang, X
AU  - Ouyang X
AD  - Department of Metabolic Medicine, Imperial College School of Medicine, London, 
      United Kingdom.
FAU - Gulliford, T
AU  - Gulliford T
FAU - Huang, G
AU  - Huang G
FAU - Epstein, R J
AU  - Epstein RJ
LA  - eng
GR  - CA61953/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Cell Physiol
JT  - Journal of cellular physiology
JID - 0050222
RN  - 0 (Transforming Growth Factor alpha)
RN  - 20350-15-6 (Brefeldin A)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
SB  - IM
MH  - 3T3 Cells/drug effects
MH  - Animals
MH  - Brefeldin A/pharmacology
MH  - Down-Regulation/*drug effects
MH  - Epidermal Growth Factor/pharmacology
MH  - ErbB Receptors/*biosynthesis/drug effects/genetics
MH  - Humans
MH  - Mice
MH  - Phosphorylation/drug effects
MH  - Protein Processing, Post-Translational/drug effects
MH  - Receptor, ErbB-2/physiology
MH  - Signal Transduction
MH  - Transfection
MH  - Transforming Growth Factor alpha/*pharmacology
MH  - Tumor Cells, Cultured/drug effects
EDAT- 1999/03/19 03:03
MHDA- 2000/06/20 09:00
CRDT- 1999/03/19 03:03
PHST- 1999/03/19 03:03 [pubmed]
PHST- 2000/06/20 09:00 [medline]
PHST- 1999/03/19 03:03 [entrez]
AID - 10.1002/(SICI)1097-4652(199904)179:1<52::AID-JCP7>3.0.CO;2-M [pii]
AID - 10.1002/(SICI)1097-4652(199904)179:1<52::AID-JCP7>3.0.CO;2-M [doi]
PST - ppublish
SO  - J Cell Physiol. 1999 Apr;179(1):52-7. doi: 
      10.1002/(SICI)1097-4652(199904)179:1<52::AID-JCP7>3.0.CO;2-M.