PMID- 10347227
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  - MEK kinase 3 directly activates MKK6 and MKK7, specific activators of the p38 and
      c-Jun NH2-terminal kinases.
PG  - 16604-10
AB  - Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase
      kinase kinase 3 (MEKK3) activates the c-Jun NH2-terminal kinase (JNK) pathway,
      although no substrates for MEKK3 have been identified. We have examined the
      regulation by MEKK3 of MAPK kinase 7 (MKK7) and MKK6, two novel MAPK kinases
      specific for JNK and p38, respectively. Coexpression of MKK7 with MEKK3 in COS-7 
      cells enhanced MKK7 autophosphorylation and its ability to activate recombinant
      JNK1 in vitro. MKK6 autophosphorylation and in vitro activation of p38alpha were 
      also observed following coexpression of MKK6 with MEKK3. MEKK2, a closely related
      homologue of MEKK3, also activated MKK7 and MKK6 in COS-7 cells. Importantly,
      immunoprecipitates of either MEKK3 or MEKK2 directly activated recombinant MKK7
      and MKK6 in vitro. These data identify MEKK3 as a MAPK kinase kinase specific for
      MKK7 and MKK6 in the JNK and p38 pathways. We have also examined whether MEKK3 or
      MEKK2 activates p38 in intact cells using MAPK-activated protein kinase-2
      (MAPKAPK2) as an affinity ligand and substrate. Anisomycin, sorbitol, or the
      expression of MEKK3 in HEK293 cells enhanced MAPKAPK2 phosphorylation, whereas
      MEKK2 was less effective. Furthermore, MAPKAPK2 phosphorylation induced by MEKK3 
      or cellular stress was abolished by the p38 inhibitor SB-203580, suggesting that 
      MEKK3 is coupled to p38 activation in intact cells.
FAU - Deacon, K
AU  - Deacon K
AD  - Department of Cell Physiology and Pharmacology, University of Leicester School of
      Medicine, P. O. Box 138, Medical Sciences Building, University Road, Leicester
      LE1 9HN, United Kingdom.
FAU - Blank, J L
AU  - Blank JL
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  - 506T60A25R (Sorbitol)
RN  - 6C74YM2NGI (Anisomycin)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 3)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 6)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 7)
RN  - EC 2.7.12.2 (MAP2K3 protein, human)
RN  - EC 2.7.12.2 (MAP2K6 protein, human)
RN  - EC 2.7.12.2 (MAP2K7 protein, human)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Animals
MH  - Anisomycin/pharmacology
MH  - COS Cells
MH  - Calcium-Calmodulin-Dependent Protein Kinases/*metabolism
MH  - Cell Line
MH  - Enzyme Activation
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases
MH  - MAP Kinase Kinase 3
MH  - MAP Kinase Kinase 6
MH  - MAP Kinase Kinase 7
MH  - Mitogen-Activated Protein Kinase Kinases/*metabolism
MH  - *Mitogen-Activated Protein Kinases
MH  - Protein Kinases
MH  - Protein-Tyrosine Kinases/*metabolism
MH  - Sorbitol/pharmacology
MH  - Transfection
MH  - p38 Mitogen-Activated Protein Kinases
EDAT- 1999/05/29 10:00
MHDA- 2000/05/29 09:00
CRDT- 1999/05/29 10:00
PHST- 1999/05/29 10:00 [pubmed]
PHST- 2000/05/29 09:00 [medline]
PHST- 1999/05/29 10:00 [entrez]
AID - 10.1074/jbc.274.23.16604 [doi]
AID - S0021-9258(19)73012-9 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Jun 4;274(23):16604-10. doi: 10.1074/jbc.274.23.16604.