Beta-catenin phosphorylated at serine 45 is spatially uncoupled from beta-catenin phosphorylated in the GSK3 domain: implications for signaling.
C. elegans and Drosophila generate distinct signaling and adhesive forms of beta-catenin at the level of gene expression. Whether vertebrates, which rely on a single beta-catenin gene, generate unique adhesive and signaling forms at the level of protein modification remains unresolved. We show that beta-catenin unphosphorylated at serine 37 (S37) and threonine 41 (T41), commonly referred to as transcriptionally Active beta-Catenin (ABC), is a minor nuclear-enriched monomeric form of beta-catenin in SW480 cells, which express low levels of E-cadherin. Despite earlier indications, the superior signaling activity of ABC is not due to reduced cadherin binding, as ABC is readily incorporated into cadherin contacts in E-cadherin-restored cells. Beta-catenin phosphorylated at serine 45 (S45) or threonine 41 (T41) (T41/S45) or along the GSK3 regulatory cassette S33, S37 or T41 (S33/37/T41), however, is largely unable to associate with cadherins. Beta-catenin phosphorylated at T41/S45 and unphosphorylated at S37 and T41 is predominantly nuclear, while beta-catenin phosphorylated at S33/37/T41 is mostly cytoplasmic, suggesting that beta-catenin hypophosphorylated at S37 and T41 may be more active in transcription due to its enhanced nuclear accumulation. Evidence that phosphorylation at T41/S45 can be spatially separated from phosphorylations at S33/37/T41 suggests that these phosphorylations may not always be coupled, raising the possibility that phosphorylation at S45 serves a distinct nuclear function.
Maher
Meghan T
MT
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Mo
Rigen
R
Flozak
Annette S
AS
Peled
Ofra N
ON
Gottardi
Cara J
CJ
D015820:Cadherins; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism*
D015820:Cadherins; D051176:beta Catenin; D012694:Serine; D038362:Glycogen Synthase Kinase 3