PMID- 10347170
OWN - NLM
STAT- MEDLINE
DCOM- 19990701
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 23
DP  - 1999 Jun 4
TI  - Ca2+/calmodulin-dependent kinase II phosphorylates the epidermal growth factor
      receptor on multiple sites in the cytoplasmic tail and serine 744 within the
      kinase domain to regulate signal generation.
PG  - 16168-73
AB  - Down-regulation of receptor tyrosine kinase activity plays an essential role in
      coordinating and controlling cellular growth/differentiation.
      Ca2+/calmodulin-dependent kinase II (CaM kinase II)-mediated phosphorylation of
      threonine 1172 in the cytoplasmic tail of HER2/c-erbB2 can modulate tyrosine
      kinase activity and consensus phosphorylation sites are also found at serines
      1046/1047 in the structurally related epidermal growth factor receptor (EGFR). We
      show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although
      there is a preference for serine 1047, which resides within the consensus
      -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 
      1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of
      serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and
      tyrosine autokinase activity that was significantly potentiated by additional
      mutation of serines 1057 and 1142. A single CaM kinase II site was also
      identified at serine 744 within sub-kinase domain III, and autokinase activity
      was significantly affected by mutation of this serine to an aspartic acid making 
      this site appear constitutively phosphorylated. We have addressed the mechanism
      by which CaM kinase II phosphorylation of the EGFR might regulate receptor
      autokinase activity and show that this modification can hinder association of the
      cytoplasmic tail with the kinase domain to prevent an enzyme-substrate
      interaction. We postulate that the location and greater number of CaM kinase II
      phosphorylation sites in the EGFR compared with HER-2/c-erbB2, leading to
      differential regulation of autokinase activity, contributes to differences in the
      strength of downstream signaling events and may explain the higher relative
      transforming potential of HER-2/cerbB2.
FAU - Feinmesser, R L
AU  - Feinmesser RL
AD  - Department of Cancer Medicine, Imperial College School of Medicine, Charing Cross
      Campus, Fulham Palace Road, London W6 8RP, United Kingdom.
FAU - Wicks, S J
AU  - Wicks SJ
FAU - Taverner, C J
AU  - Taverner CJ
FAU - Chantry, A
AU  - Chantry A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Recombinant Fusion Proteins)
RN  - 452VLY9402 (Serine)
RN  - EC 2.5.1.18 (Glutathione Transferase)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
SB  - IM
MH  - Amino Acid Sequence
MH  - Binding Sites
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2
MH  - Calcium-Calmodulin-Dependent Protein Kinases/*metabolism
MH  - Cell Line
MH  - Cytoplasm/*metabolism
MH  - Down-Regulation
MH  - ErbB Receptors/genetics/*metabolism
MH  - Fibroblasts/metabolism
MH  - Glutathione Transferase/genetics/metabolism
MH  - Humans
MH  - Molecular Sequence Data
MH  - Phosphorylation
MH  - Receptor, ErbB-2/metabolism
MH  - Recombinant Fusion Proteins/metabolism
MH  - Serine/*metabolism
MH  - *Signal Transduction
EDAT- 1999/05/29 00:00
MHDA- 1999/05/29 00:01
CRDT- 1999/05/29 00:00
PHST- 1999/05/29 00:00 [pubmed]
PHST- 1999/05/29 00:01 [medline]
PHST- 1999/05/29 00:00 [entrez]
AID - 10.1074/jbc.274.23.16168 [doi]
AID - S0021-9258(19)72955-X [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Jun 4;274(23):16168-73. doi: 10.1074/jbc.274.23.16168.