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O-GlcNAc on PKCζ Inhibits the FGF4-PKCζ-MEK-ERK1/2 Pathway via Inhibition of PKCζ Phosphorylation in Mouse Embryonic Stem Cells
- Source :
- Stem Cell Reports, Vol 10, Iss 1, Pp 272-286 (2018), Stem Cell Reports
- Publication Year :
- 2018
- Publisher :
- Elsevier, 2018.
-
Abstract
- Summary Mouse embryonic stem cells (ESCs) differentiate into multiple cell types during organismal development. Fibroblast growth factor 4 (FGF4) signaling induces differentiation from ESCs via the phosphorylation of downstream molecules such as mitogen-activated protein kinase/extracellular signal-related kinase (MEK) and extracellular signal-related kinase 1/2 (ERK1/2). The FGF4-MEK-ERK1/2 pathway is inhibited to maintain ESCs in the undifferentiated state. However, the inhibitory mechanism of the FGF4-MEK-ERK1/2 pathway in ESCs is uncharacterized. O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a post-translational modification characterized by the attachment of a single N-acetylglucosamine (GlcNAc) to the serine and threonine residues of nuclear or cytoplasmic proteins. Here, we showed that the O-GlcNAc on the phosphorylation site of PKCζ inhibits PKCζ phosphorylation (activation) and, consequently, the FGF4-PKCζ-MEK-ERK1/2 pathway in ESCs. Our results demonstrate the mechanism for the maintenance of the undifferentiated state of ESCs via the inhibition of the FGF4-PKCζ-MEK-ERK1/2 pathway by O-GlcNAcylation on PKCζ.<br />Graphical Abstract<br />Highlights • PKCζ activates the MEK-ERK1/2 pathway by FGF4 stimulation • O-GlcNAc on the phosphorylation site of PKCζ inhibits PKCζ activation in ESCs • FGF4-PKCζ-MEK-ERK1/2 pathway is inhibited by O-GlcNAc on PKCζ in ESCs<br />In this article, Nishihara and colleagues show that PKCζ is modified by O-GlcNAc and that O-GlcNAc on PKCζ inhibits PKCζ phosphorylation (activation) in mouse embryonic stem cells (ESCs). Phosphorylated PKCζ phosphorylates MEK-ERK1/2 via FGF4 stimulation, and phosphorylated ERK1/2 induces ESC differentiation. Inhibition of PKCζ phosphorylation by O-GlcNAc resulted in the inhibition of the FGF4 signal in ESCs.
- Subjects :
- 0301 basic medicine
Glycosylation
MAP Kinase Signaling System
Fibroblast Growth Factor 4
Protein Kinase C-epsilon
Biology
Fibroblast growth factor
Biochemistry
Article
Acetylglucosamine
Serine
03 medical and health sciences
Mice
MEK-ERK1/2 pathway
FGF4
Genetics
Extracellular
Animals
Phosphorylation
Protein kinase A
lcsh:QH301-705.5
Mitogen-Activated Protein Kinase 1
PKCζ
lcsh:R5-920
Mitogen-Activated Protein Kinase 3
Kinase
Mouse Embryonic Stem Cells
Cell Biology
MAP Kinase Kinase Kinases
Embryonic stem cell
embryonic stem cell
Cell biology
FGF4 signaling
030104 developmental biology
lcsh:Biology (General)
embryonic structures
O-GlcNAc
lcsh:Medicine (General)
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 22136711
- Volume :
- 10
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Stem Cell Reports
- Accession number :
- edsair.doi.dedup.....3acb1d52b1fec2c026b05c1dfeb34844