PMID- 10372802
OWN - NLM
STAT- MEDLINE
DCOM- 19990817
LR  - 20190921
IS  - 0898-6568 (Print)
IS  - 0898-6568 (Linking)
VI  - 11
IP  - 4
DP  - 1999 Apr
TI  - Intensification of growth factor receptor signalling by phorbol treatment of
      ligand-primed cells implies a dimer-stabilizing effect of protein kinase
      C-dependent juxtamembrane domain phosphorylation.
PG  - 245-52
AB  - Protein kinase C (PKC) phosphorylates the juxtamembrane domain of many growth
      factor receptors, but the physiologic effect of this modification on ligand
      signalling and desensitisation is unclear. Here we show that PKC-dependent
      transmodulation of EGFR and ErbB2 signalling is schedule-specific: prolonged
      pre-treatment of A431 cells with the PKC agonist phorbol dibutyrate potently
      inhibits subsequent ligand-induced EGFR signalling as expected, but EGF
      pre-treatment reverses the inhibitory effect of phorbol. The agonist activity of 
      PKC on receptor signalling is even more apparent when cells are treated with
      phorbol in the presence of a tyrosine phosphatase inhibitor. Because these
      findings suggested a synergistic interaction between tyrosine- and PKC-dependent 
      phosphorylation events, we sought to define the interactions of
      tyrosine-phosphorylated and PKC-modified ErbB2 subsets within EGF-inducible
      hetero-oligomers. Growth factor-dependent PKC transphosphorylation takes place
      exclusively within endocytosed tyrosine-phosphorylated receptor oligomers.
      Moreover, phorbol differentially affects two ErbB2 C-terminal autophosphorylation
      sites: whereas phosphorylation of Tyr1222 is reduced, phosphorylation of Tyr1139 
      is increased. These results suggest that PKC-dependent phosphorylation of the
      juxtamembrane domain may contribute positively to both internalisation and
      signalling of ligand-activated receptors, simultaneously accelerating termination
      of growth factor action. We propose that transient PKC-dependent signal
      amplification results from enhanced stability of liganded receptor oligomers due 
      to phosphorylation-dependent juxtamembrane domain interactions, analogous to the 
      protein-protein binding now known to be induced by serine-threonine
      phosphorylation of CREB and SMAD.
FAU - Gulliford, T
AU  - Gulliford T
AD  - Department of Oncology, Charing Cross Hospital, London, UK.
FAU - Ouyang, X
AU  - Ouyang X
FAU - Epstein, R J
AU  - Epstein RJ
LA  - eng
GR  - R01 61953/PHS 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  - England
TA  - Cell Signal
JT  - Cellular signalling
JID - 8904683
RN  - 0 (Ligands)
RN  - 0 (Phorbol Esters)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.11.13 (Protein Kinase C)
SB  - IM
MH  - Animals
MH  - Binding Sites
MH  - Cell Line
MH  - Dimerization
MH  - Epidermal Growth Factor/metabolism/pharmacology
MH  - ErbB Receptors/*metabolism
MH  - Humans
MH  - Ligands
MH  - Mice
MH  - Phorbol Esters/pharmacology
MH  - Phosphorylation
MH  - Protein Kinase C/*metabolism
MH  - Receptor, ErbB-2/*metabolism
MH  - *Signal Transduction
MH  - Tumor Cells, Cultured
EDAT- 1999/06/18 00:00
MHDA- 1999/06/18 00:01
CRDT- 1999/06/18 00:00
PHST- 1999/06/18 00:00 [pubmed]
PHST- 1999/06/18 00:01 [medline]
PHST- 1999/06/18 00:00 [entrez]
AID - S0898-6568(98)00058-8 [pii]
AID - 10.1016/s0898-6568(98)00058-8 [doi]
PST - ppublish
SO  - Cell Signal. 1999 Apr;11(4):245-52. doi: 10.1016/s0898-6568(98)00058-8.