Phosphorylations of Serines 21/9 in Glycogen Synthase Kinase 3α/β Are Not Required for Cell Lineage Commitment or WNT Signaling in the Normal Mouse Intestine.
The WNT signalling pathway controls many developmental processes and plays a key role in maintenance of intestine renewal and homeostasis. Glycogen Synthase Kinase 3 (GSK3) is an important component of the WNT pathway and is involved in regulating β-catenin stability and expression of WNT target genes. The mechanisms underpinning GSK3 regulation in this context are not completely understood, with some evidence suggesting this occurs through inhibitory N-terminal serine phosphorylation in a similar way to GSK3 inactivation in insulin signaling. To investigate this in a physiologically relevant context, we have analysed the intestinal phenotype of GSK3 knockin mice in which N-terminal serines 21/9 of GSK3α/β have been mutated to non-phosphorylatable alanine residues. We show that these knockin mutations have very little effect on overall intestinal integrity, cell lineage commitment, β-catenin localization or WNT target gene expression although a small increase in apoptosis at villi tips is observed. Our results provide in vivo evidence that GSK3 is regulated through mechanisms independent of N-terminal serine phosphorylation in order for β-catenin to be stabilised.
Department of Molecular Cell Biology, Henry Wellcome Building, University of Leicester, Leicester, United Kingdom.
Fiona
F
Hey
Department of Molecular Cell Biology, Henry Wellcome Building, University of Leicester, Leicester, United Kingdom.
Susan
S
Giblett
Department of Molecular Cell Biology, Henry Wellcome Building, University of Leicester, Leicester, United Kingdom.
Stephanie
S
Forrest
Department of Molecular Cell Biology, Henry Wellcome Building, University of Leicester, Leicester, United Kingdom.
Chelsea
C
Herbert
Department of Molecular Cell Biology, Henry Wellcome Building, University of Leicester, Leicester, United Kingdom.|Department of Cancer Studies, Robert Kilpatrick Clinical Sciences Building, University of Leicester, Leicester, United Kingdom.
Catrin
C
Pritchard
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000235:genetics; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
D051176:beta Catenin; D012694:Serine; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha