PMID- 10358079
OWN - NLM
STAT- MEDLINE
DCOM- 19990706
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 24
DP  - 1999 Jun 11
TI  - ErbB receptor-induced activation of stat transcription factors is mediated by Src
      tyrosine kinases.
PG  - 17209-18
AB  - Epidermal growth factor (EGF) binding to its receptor, ErbB1, triggers various
      signal transduction pathways, one of which leads to the activation of signal
      transducer and activator of transcription (Stat) factors. The mechanism
      underlying ErbB1-induced Stat activation and whether Stats are downstream targets
      of other ErbB receptors have not been explored. In this report we show that
      ErbB2, ErbB3, and ErbB4 do not potentiate Stat5 phosphorylation by EGF. However, 
      neu differentiation factor-induced heterodimers of ErbB2 and ErbB4 activated
      Stat5. In A431 cells, Stat1, Stat3, and Stat5, were constitutively complexed with
      ErbB1 and rapidly phosphorylated on tyrosine in response to EGF. Neither mutation
      of the conserved tyrosine residue (Tyr694) nor inactivation of the Stat5a SH2
      domain disrupted this association. However, an intact SH2 domain was necessary
      for EGF-induced Stat5a phosphorylation. In contrast to prolactin, which induced
      only Tyr694 phosphorylation of Stat5a, EGF promoted phosphorylation on Tyr694 and
      additional tyrosine residue(s). Janus kinases (Jaks) were also constitutively
      associated with ErbB receptors and were phosphorylated in response to EGF-related
      ligands. However, we provide evidence that EGF- and neu differentiation
      factor-induced Stat activation are dependent on Src but not Jak kinases. Upon EGF
      stimulation, c-Src was rapidly recruited to Stat/ErbB receptor complexes.
      Pharmacological Src kinase inhibitors and a dominant negative c-Src ablated both 
      Stat and Jak tyrosine phosphorylation. However, dominant negative Jaks did not
      affect EGF-induced Stat phosphorylation. Taken together, the experiments
      establish two independent roles for Src kinases: (i) key molecules in ErbB
      receptor-mediated Stat signaling and (ii) potential upstream regulators of Jak
      kinases.
FAU - Olayioye, M A
AU  - Olayioye MA
AD  - Friedrich Miescher Institute, P.O. Box 2543, CH-4002 Basel, Switzerland.
FAU - Beuvink, I
AU  - Beuvink I
FAU - Horsch, K
AU  - Horsch K
FAU - Daly, J M
AU  - Daly JM
FAU - Hynes, N E
AU  - Hynes NE
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 (Proto-Oncogene Proteins)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Trans-Activators)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - 9002-62-4 (Prolactin)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.10.1 (Receptor, ErbB-3)
RN  - EC 2.7.10.1 (Receptor, ErbB-4)
RN  - EC 2.7.10.2 (src-Family Kinases)
SB  - IM
MH  - Epidermal Growth Factor/*pharmacology
MH  - ErbB Receptors/metabolism
MH  - Models, Biological
MH  - Phosphorylation
MH  - Prolactin/pharmacology
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Receptor, ErbB-2/metabolism
MH  - Receptor, ErbB-3
MH  - Receptor, ErbB-4
MH  - Receptors, Cell Surface/*metabolism
MH  - Signal Transduction
MH  - Trans-Activators/*metabolism
MH  - src-Family Kinases/*metabolism
EDAT- 1999/06/08 00:00
MHDA- 1999/06/08 00:01
CRDT- 1999/06/08 00:00
PHST- 1999/06/08 00:00 [pubmed]
PHST- 1999/06/08 00:01 [medline]
PHST- 1999/06/08 00:00 [entrez]
AID - 10.1074/jbc.274.24.17209 [doi]
AID - S0021-9258(19)72900-7 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Jun 11;274(24):17209-18. doi: 10.1074/jbc.274.24.17209.