PMID- 9872991
OWN - NLM
STAT- MEDLINE
DCOM- 19990205
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 2
DP  - 1999 Jan 8
TI  - Domain-specific interactions between the p185(neu) and epidermal growth factor 
      receptor kinases determine differential signaling outcomes.
PG  - 574-83
AB  - We expressed the epidermal growth factor receptor (EGFR) along with mutant 
      p185(neu) proteins containing the rat transmembrane point mutation. The work 
      concerned the study of the contributions made by various p185(neu) subdomains to 
      signaling induced by a heterodimeric ErbB complex. Co-expression of full-length 
      EGFR and oncogenic p185(neu) receptors resulted in an increased EGF-induced 
      phosphotyrosine content of p185(neu), increased cell proliferation to limiting 
      concentrations of EGF, and increases in both EGF-induced MAPK and 
      phosphatidylinositol 3-kinase (PI 3-kinase) activation. Intracellular 
      domain-deleted p185(neu) receptors (T691stop neu) were able to associate with 
      full-length EGFR, but induced antagonistic effects on EGF-dependent EGF receptor 
      down-regulation, cell proliferation, and activation of MAPK and PI 3-kinase 
      pathways. Ectodomain-deleted p185(neu) proteins (TDelta5) were unable to 
      physically associate with EGFR, and extracellular domain-deleted p185(neu) forms 
      failed to augment activation of MAPK and PI 3-kinase in response to EGF. 
      Association of EGFR with a carboxyl-terminally truncated p185(neu) mutant 
      (TAPstop) form did not increase transforming efficiency and phosphotyrosine 
      content of the TAPstop species, and proliferation of EGFR.TAPstop-co-expressing 
      cells in response to EGF was similar to cells containing EGFR only. Thus, neither 
      cooperative nor inhibitory effects were observed in cell lines co-expressing 
      either TDelta5 or TAPstop mutant proteins. Unlike the formation of potent 
      homodimer assemblies composed of oncogenic p185(neu), the induction of signaling 
      from p185(neu).EGFR heteroreceptor assemblies requires the ectodomain for 
      ligand-dependent physical association and intracellular domain contacts for 
      efficient intermolecular kinase activation.
FAU - Qian, X
AU  - Qian X
AD  - Department of Pathology and Laboratory Medicine, University of Pennsylvania 
      School of Medicine, Philadelphia, Pennsylvania 19104, USA.
FAU - O'Rourke, D M
AU  - O'Rourke DM
FAU - Fei, Z
AU  - Fei Z
FAU - Zhang, H T
AU  - Zhang HT
FAU - Kao, C C
AU  - Kao CC
FAU - Greene, M I
AU  - Greene MI
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
SB  - IM
MH  - Animals
MH  - COS Cells
MH  - Cell Division
MH  - Cell Membrane/metabolism
MH  - Dimerization
MH  - Down-Regulation
MH  - ErbB Receptors/*metabolism
MH  - Mice
MH  - Mutation
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Receptor, ErbB-2/genetics/*metabolism
MH  - *Signal Transduction
EDAT- 1999/01/05 00:00
MHDA- 1999/01/05 00:01
CRDT- 1999/01/05 00:00
PHST- 1999/01/05 00:00 [pubmed]
PHST- 1999/01/05 00:01 [medline]
PHST- 1999/01/05 00:00 [entrez]
AID - S0021-9258(19)88315-1 [pii]
AID - 10.1074/jbc.274.2.574 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 Jan 8;274(2):574-83. doi: 10.1074/jbc.274.2.574.