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PMID:17318175

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Citation

Luo, W, Peterson, A, Garcia, BA, Coombs, G, Kofahl, B, Heinrich, R, Shabanowitz, J, Hunt, DF, Yost, HJ and Virshup, DM (2007) Protein phosphatase 1 regulates assembly and function of the beta-catenin degradation complex. EMBO J. 26:1511-21

Abstract

The Wnt/beta-catenin signaling pathway is critical in both cellular proliferation and organismal development. However, how the beta-catenin degradation complex is inhibited upon Wnt activation remains unclear. Using a directed RNAi screen we find that protein phosphatase 1 (PP1), a ubiquitous serine/threonine phosphatase, is a novel potent positive physiologic regulator of the Wnt/beta-catenin signaling pathway. PP1 expression synergistically activates, and inhibition of PP1 inhibits, Wnt/beta-catenin signaling in Drosophila and mammalian cells as well as in Xenopus embryos. The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin. Inhibition of PP1 leads to enhanced phosphorylation of specific sites on axin by casein kinase I. Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity. Specific inhibition of PP1 in this pathway may offer therapeutic approaches to disorders with increased beta-catenin signaling.

Links

PubMed PMC1829374 Online version:10.1038/sj.emboj.7601607

Keywords

Animals; Armadillo Domain Proteins/metabolism; Axin Protein; Casein Kinase I/metabolism; Cell Line; DNA Primers; Drosophila; Drosophila Proteins/metabolism; Glycogen Synthase Kinase 3/metabolism; Humans; Immunoblotting; Immunoprecipitation; Mass Spectrometry; Mice; Mutagenesis; Phosphoprotein Phosphatases/genetics; Phosphoprotein Phosphatases/metabolism; Phosphorylation; Protein Phosphatase 1; RNA Interference; Repressor Proteins/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction/physiology; Transcription Factors/metabolism; Wnt Proteins/metabolism; Xenopus; Xenopus Proteins

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:AXIN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49840

F

Seeded From UniProt

complete

HUMAN:AXIN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P62136

F

Seeded From UniProt

complete

DROME:PP12

involved_in

GO:0090263: positive regulation of canonical Wnt signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0000711,FB:FBgn0003134

P

Seeded From UniProt

complete

DROME:PP12

involved_in

GO:1904886: beta-catenin destruction complex disassembly

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:P62139

P

Seeded From UniProt

complete

DROME:PP11

involved_in

GO:0090263: positive regulation of canonical Wnt signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0000711,FB:FBgn0004103

P

Seeded From UniProt

complete

DROME:PP11

involved_in

GO:1904886: beta-catenin destruction complex disassembly

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:P62139

P

Seeded From UniProt

complete

DROME:PP1B

involved_in

GO:0090263: positive regulation of canonical Wnt signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0003134,FB:FBgn0004103

P

Seeded From UniProt

complete

DROME:PP1B

involved_in

GO:1904886: beta-catenin destruction complex disassembly

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:P62139

P

Seeded From UniProt

complete

HUMAN:GSK3A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O15169

F

Seeded From UniProt

complete

HUMAN:PP1A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O15169

F

Seeded From UniProt

complete

RABIT:PP1A

involved_in

GO:0032091: negative regulation of protein binding

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:G1U4F6)
  • has_input:(UniProtKB:G1T8E2)
  • part_of:(GO:1904886)

Seeded From UniProt

complete

RABIT:PP1A

enables

GO:0004721: phosphoprotein phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RABIT:PP1A

involved_in

GO:0006470: protein dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:G1U4F6)

Seeded From UniProt

complete

RABIT:PP1A

involved_in

GO:0090263: positive regulation of canonical Wnt signaling pathway

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

RABIT:PP1A

involved_in

GO:1904886: beta-catenin destruction complex disassembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PP1A

involved_in

GO:0060828: regulation of canonical Wnt signaling pathway

ECO:0000305: curator inference used in manual assertion

GO:0005515

P

Seeded From UniProt

complete

Notes

See also

References

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