PMID- 10075741
OWN - NLM
STAT- MEDLINE
DCOM- 19990415
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 12
DP  - 1999 Mar 19
TI  - c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 
      and Tyr1101 is associated with modulation of receptor function.
PG  - 8335-43
AB  - Accumulating evidence indicates that interactions between the epidermal growth
      factor receptor (EGFR) and the nonreceptor tyrosine kinase c-Src may contribute
      to an aggressive phenotype in multiple human tumors. Previous work from our
      laboratory demonstrated that murine fibroblasts which overexpress both these
      tyrosine kinases display synergistic increases in DNA synthesis, soft agar
      growth, and tumor formation in nude mice, and increased phosphorylation of the
      receptor substrates Shc and phospholipase gamma as compared with single
      overexpressors. These parameters correlated with the ability of c-Src and EGFR to
      form an EGF-dependent heterocomplex in vivo. Here we provide evidence that
      association between c-Src and EGFR can occur directly, as shown by receptor
      overlay experiments, and that it results in the appearance of two novel tyrosine 
      phosphorylations on the receptor that are seen both in vitro and in vivo
      following EGF stimulation. Edman degradation analyses and co-migration of
      synthetic peptides with EGFR-derived tryptic phosphopeptides identify these sites
      as Tyr845 and Tyr1101. Tyr1101 lies within the carboxyl-terminal region of the
      EGFR among sites of receptor autophosphorylation, while Tyr845 resides in the
      catalytic domain, in a position analogous to Tyr416 of c-Src. Phosphorylation of 
      Tyr416 and homologous residues in other tyrosine kinase receptors has been shown 
      to be required for or to increase catalytic activity, suggesting that c-Src can
      influence EGFR activity by mediating phosphorylation of Tyr845. Indeed,
      EGF-induced phosphorylation of Tyr845 was increased in MDA468 human breast cancer
      cells engineered to overexpress c-Src as compared with parental MDA 468 cells.
      Furthermore, transient expression of a Y845F variant EGFR in murine fibroblasts
      resulted in an ablation of EGF-induced DNA synthesis to nonstimulated levels.
      Together, these data support the hypothesis that c-Src-mediated phosphorylation
      of EGFR Tyr845 is involved in regulation of receptor function, as well as in
      tumor progression.
FAU - Biscardi, J S
AU  - Biscardi JS
AD  - Department of Microbiology and Cancer Center, Box 441, University of Virginia
      Health Sciences Center, Charlottesville, Virginia 22908, USA.
FAU - Maa, M C
AU  - Maa MC
FAU - Tice, D A
AU  - Tice DA
FAU - Cox, M E
AU  - Cox ME
FAU - Leu, T H
AU  - Leu TH
FAU - Parsons, S J
AU  - Parsons SJ
LA  - eng
GR  - CA3948/CA/NCI NIH HHS/United States
GR  - CA71449/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (CSK Tyrosine-Protein Kinase)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 2.7.10.23 (CSK protein, human)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - CSK Tyrosine-Protein Kinase
MH  - Cell Line
MH  - ErbB Receptors/*metabolism
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Mitosis
MH  - Molecular Sequence Data
MH  - Peptide Mapping
MH  - Phosphorylation
MH  - Protein Binding
MH  - Protein-Tyrosine Kinases/*metabolism
MH  - Structure-Activity Relationship
MH  - Tumor Cells, Cultured
MH  - Tyrosine/*metabolism
MH  - src Homology Domains
MH  - src-Family Kinases
EDAT- 1999/03/13 00:00
MHDA- 1999/03/13 00:01
CRDT- 1999/03/13 00:00
PHST- 1999/03/13 00:00 [pubmed]
PHST- 1999/03/13 00:01 [medline]
PHST- 1999/03/13 00:00 [entrez]
AID - 10.1074/jbc.274.12.8335 [doi]
AID - S0021-9258(19)87544-0 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Mar 19;274(12):8335-43. doi: 10.1074/jbc.274.12.8335.