PMID- 10085121
OWN - NLM
STAT- MEDLINE
DCOM- 19990429
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 13
DP  - 1999 Mar 26
TI  - MEKK-1, a component of the stress (stress-activated protein kinase/c-Jun
      N-terminal kinase) pathway, can selectively activate Smad2-mediated
      transcriptional activation in endothelial cells.
PG  - 8797-805
AB  - Smad proteins are essential components of the intracellular signaling pathways
      utilized by members of the transforming growth factor-beta (TGF-beta) superfamily
      of growth factors. Certain Smad proteins (e.g. Smad1, -2, and -3) can act as
      regulated transcriptional activators, a process that involves phosphorylation of 
      these proteins by activated TGF-beta superfamily receptors. We demonstrate that
      the intracellular kinase mitogen-activated protein kinase kinase kinase-1
      (MEKK-1), an upstream activator of the stress-activated protein kinase/c-Jun
      N-terminal kinase pathway, can participate in Smad2-dependent transcriptional
      events in cultured endothelial cells. A constitutively active form of MEKK-1 but 
      not mitogen-activated protein kinase kinase-1 (MEK-1) or TGF-beta-activated
      kinase-1, two distinct intracellular kinases, can specifically activate a
      Gal4-Smad2 fusion protein, and this effect correlates with an increase in the
      phosphorylation state of the Smad2 protein. These effects do not require the
      presence of the C-terminal SSXS motif of Smad2 that is the site of TGF-beta type 
      1 receptor-mediated phosphorylation. Activation of Smad2 by active MEKK-1 results
      in enhanced Smad2-Smad4 interactions, nuclear localization of Smad2 and Smad4,
      and the stimulation of Smad protein-transcriptional coactivator interactions in
      endothelial cells. Overexpression of Smad7 can inhibit the MEKK-1-mediated
      stimulation of Smad2 transcriptional activity. A physiological level of fluid
      shear stress, a known activator of endogenous MEKK-1 activity in endothelial
      cells, can stimulate Smad2-mediated transcriptional activity. These data
      demonstrate a novel mechanism for activation of Smad protein-mediated signaling
      in endothelial cells and suggest that Smad2 may act as an integrator of diverse
      stimuli in these cells.
FAU - Brown, J D
AU  - Brown JD
AD  - Vascular Research Division, Department of Pathology, Brigham and Women's
      Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
FAU - DiChiara, M R
AU  - DiChiara MR
FAU - Anderson, K R
AU  - Anderson KR
FAU - Gimbrone, M A Jr
AU  - Gimbrone MA Jr
FAU - Topper, J N
AU  - Topper JN
LA  - eng
GR  - P50-HL56985/HL/NHLBI NIH HHS/United States
GR  - R37-HL51150/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
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  - 0 (DNA-Binding Proteins)
RN  - 0 (Smad2 Protein)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (Transforming Growth Factor beta)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Animals
MH  - Cattle
MH  - Cells, Cultured
MH  - DNA-Binding Proteins/*metabolism
MH  - Endothelium, Vascular/metabolism
MH  - Genes, Reporter/genetics
MH  - Immunohistochemistry
MH  - *JNK Mitogen-Activated Protein Kinases
MH  - MAP Kinase Kinase 1
MH  - MAP Kinase Kinase 4
MH  - *Mitogen-Activated Protein Kinase Kinases
MH  - Phosphorylation
MH  - Promoter Regions, Genetic/genetics
MH  - Protein Kinases/*metabolism
MH  - Protein-Serine-Threonine Kinases/genetics/*metabolism
MH  - Protein-Tyrosine Kinases/genetics
MH  - Signal Transduction
MH  - Smad2 Protein
MH  - Trans-Activators/*metabolism
MH  - Transcription Factors/genetics
MH  - Transcriptional Activation/*genetics
MH  - Transforming Growth Factor beta/genetics
EDAT- 1999/03/20 03:14
MHDA- 2001/03/28 10:01
CRDT- 1999/03/20 03:14
PHST- 1999/03/20 03:14 [pubmed]
PHST- 2001/03/28 10:01 [medline]
PHST- 1999/03/20 03:14 [entrez]
AID - 10.1074/jbc.274.13.8797 [doi]
AID - S0021-9258(19)87398-2 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Mar 26;274(13):8797-805. doi: 10.1074/jbc.274.13.8797.