PMID- 10473620
OWN - NLM
STAT- MEDLINE
DCOM- 19991007
LR  - 20190508
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 37
DP  - 1999 Sep 10
TI  - Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases.
      Identification and characterization of a signaling pathway to the nucleus.
PG  - 26563-71
AB  - ERK5 (also known as BMK1), a member of the mitogen-activated protein kinase
      (MAPK) superfamily, was known to be activated strongly by oxidant and osmotic
      stresses. Here we have found that ERK5 is strongly activated by epidermal growth 
      factor and nerve growth factor, whose receptors are tyrosine kinases. The
      activation of ERK5 was inhibited by expression of dominant-negative Ras and
      induced by expression of active Ras in PC12 cells, indicating a requirement for
      Ras in ERK5 activation. The epidermal growth factor-induced activation of ERK5
      was found to be inhibited by PD98059 and U0126 inhibitors, which were previously 
      thought to act specifically on classical MAPK kinase (also known as MEK1) and
      readily reversed by CL100 and MKP-3 dual-specificity phosphatases for which
      classical MAPKs were previously shown to serve as preferred substrates. The
      reporter assays demonstrated that the serum-induced enhancement of transcription 
      from serum response element was significantly inhibited by expression of a
      dominant-negative form of MEK5, which was a direct and specific activator for
      ERK5 and that transcription from serum response element mediated by the
      Ets-domain transcription factor Sap1a, but not by Elk1, was stimulated by
      coexpression of ERK5 and active MEK5. In addition, Sap1a was shown to be
      phosphorylated by ERK5 in vitro and by the activation of the ERK5 pathway in
      cells. Moreover, the serum-induced c-Fos expression was markedly inhibited by
      expression of dominant-negative MEK5. These results reveal a novel signaling
      pathway to the nucleus mediated by ERK5 that functions downstream of receptor
      tyrosine kinases to induce immediate early genes, in parallel with the classical 
      MAPK cascade.
FAU - Kamakura, S
AU  - Kamakura S
AD  - Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo-ku,
      Kyoto 606-8502, Japan. L50174@sakura.kudpc.kyoto-u.ac.jp
FAU - Moriguchi, T
AU  - Moriguchi T
FAU - Nishida, E
AU  - Nishida E
LA  - eng
SI  - GENBANK/AB019373
SI  - GENBANK/AB019374
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 (DNA Primers)
RN  - 0 (DNA, Complementary)
RN  - 0 (Enzyme Inhibitors)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 7)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.6.1.- (GTP Phosphohydrolases)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Base Sequence
MH  - Calcium-Calmodulin-Dependent Protein Kinases/antagonists &
      inhibitors/chemistry/genetics/*metabolism
MH  - Cell Membrane/metabolism
MH  - Cell Nucleus/enzymology/*metabolism
MH  - Cloning, Molecular
MH  - DNA Primers
MH  - DNA, Complementary
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - GTP Phosphohydrolases/metabolism
MH  - Humans
MH  - Mice
MH  - Mitogen-Activated Protein Kinase 7
MH  - *Mitogen-Activated Protein Kinases
MH  - Molecular Sequence Data
MH  - Receptor Protein-Tyrosine Kinases/antagonists & inhibitors/*metabolism
MH  - Sequence Homology, Amino Acid
MH  - *Signal Transduction
EDAT- 1999/09/03 00:00
MHDA- 1999/09/03 00:01
CRDT- 1999/09/03 00:00
PHST- 1999/09/03 00:00 [pubmed]
PHST- 1999/09/03 00:01 [medline]
PHST- 1999/09/03 00:00 [entrez]
AID - 10.1074/jbc.274.37.26563 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 Sep 10;274(37):26563-71. doi: 10.1074/jbc.274.37.26563.