Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.11.25 (
MEKK1
)
1,856
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Endothelial cell injury and death precede atherosclerosis development. Thus, it is important to understand the mechanisms that lead to these early changes in endothelial cells. Although members of the MAP kinase/ERK kinase (MEK) kinase 3 (
MEKK3
)-MEK5-ERK5 module play an essential role in underpinning endothelial cell survival, how they execute these actions remain poorly understood. Furthermore, there is poor understanding of death-inducing pathways in endothelial cells and it is also unclear whether there are direct interactions between the kinase module and death-inducing pathways. Using immunoprecipitation and liquid chromatography-electrospray ionisation tandem mass spectrometry approaches, we show in human umbilical vein endothelial cells that the
MEKK3
-MEK5-ERK5 ternary complex contains
glyceraldehyde-3-phosphate dehydrogenase
(
GAPDH
), a glycolytic enzyme that can trigger the death of certain cell-types.
GAPDH
binds directly to
MEKK3
. Interestingly, serum depletion, a trigger of endothelial cell death, results in a rapid loss of cytosolic
MEKK3
and
MEKK3
-
GAPDH
interaction.
MEKK3
rapidly reappears in the cytosol upon serum replenishment, accompanied by the restoration of
MEKK3
-
GAPDH
interaction. During serum starvation or exposure to cytotoxic concentrations of H
2
O
2
,
GAPDH
accumulates in the nucleus. Inhibition of the nuclear accumulation of
GAPDH
with R-(-)-deprenyl hydrochloride attenuates the degree of cell death. Serum replenishment of serum-starved cells reduces the level of nuclear
GAPDH
and prevents cell death. Cell-free assays show phosphorylation of
GAPDH
on four residues by
MEKK3
. These data not only strongly implicate nuclear
GAPDH
in causing endothelial cell death but also reveal a potential mechanism for
MEKK3
to regulate
GAPDH
function and hence promote endothelial cell survival.
...
PMID:Regulation of endothelial cell survival and death by the MAP kinase/ERK kinase kinase 3 - glyceraldehyde-3-phosphate dehydrogenase signaling axis. 3083 Nov 95
