Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/120369
Citations
Scopus Web of Science® Altmetric
?
?
Type: Journal article
Title: Regulation of endothelial cell survival and death by the MAP kinase/ERK kinase kinase 3 - glyceraldehyde-3-phosphate dehydrogenase signaling axis
Author: Li, Y.
Ngo, A.
Hoffmann, P.
Ferrante, A.
Hii, C.
Citation: Cellular Signalling, 2019; 58:20-33
Publisher: Elsevier
Issue Date: 2019
ISSN: 0898-6568
1873-3913
Statement of
Responsibility: 
Yong Q. Li, Andy Ngo, Peter Hoffmann, Antonio Ferrante, Charles S. Hii
Abstract: 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 H2O2, 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.
Keywords: Endothelial cell survival
Mitogen activated protein kinases
MAP kinase/ERK kinase kinase 3
Glyceraldehyde-3-phosphate dehydrogenase
Protein-protein interaction
Rights: © 2019 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cellsig.2019.03.002
Grant ID: NHMRC
Appears in Collections:Aurora harvest 8
Medicine publications

Files in This Item:
There are no files associated with this item.


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.