Activation of extracellular signal-regulated protein kinase 5 downregulates FasL upon osmotic stress.
Extracellular signal-regulated protein kinase (ERK) 5 is a mitogen-activated protein kinase (MAPK) that is activated by dual phosphorylation via a unique MAPK/ERK kinase 5, MEK5. The physiological importance of this signaling cascade is underscored by the early embryonic death caused by the targeted deletion of the erk5 or the mek5 genes in mice. Here, we have found that ERK5 is required for mediating the survival of fibroblasts under basal conditions and in response to sorbitol treatment. Increased Fas ligand (FasL) expression acts as a positive feedback loop to enhance apoptosis of ERK5- or MEK5-deficient cells under conditions of osmotic stress. Compared to wild-type cells, erk5-/- and mek5-/- fibroblasts treated with sorbitol display a reduced protein kinase B (PKB) activity associated with increased Forkhead box O3a (Foxo3a) activity. Based on these results, we conclude that the ERK5 signaling pathway promotes cell survival by downregulating FasL expression via a mechanism that implicates PKB-dependent inhibition of Foxo3a downstream of phosphoinositide 3 kinase.
Wang
X
X
Faculty of Life Sciences, University of Manchester, Manchester, UK.
Finegan
K G
KG
Robinson
A C
AC
Knowles
L
L
Khosravi-Far
R
R
Hinchliffe
K A
KA
Boot-Handford
R P
RP
Tournier
C
C
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology*; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D048671:MAP Kinase Kinase 5 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D009997:Osmotic Pressure; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013012:Sorbitol / Q000494:pharmacology
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D013012:Sorbitol; D051057:Proto-Oncogene Proteins c-akt; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human