Protein phosphatase 1 regulates assembly and function of the beta-catenin degradation complex.
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.
Luo
Wen
W
Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112-5550, USA.
Peterson
Annita
A
Garcia
Benjamin A
BA
Coombs
Gary
G
Kofahl
Bente
B
Heinrich
Reinhart
R
Shabanowitz
Jeffrey
J
Hunt
Donald F
DF
Yost
H Joseph
HJ
Virshup
David M
DM
D000818:Animals; D051186:Armadillo Domain Proteins / Q000378:metabolism*; D060466:Axin Protein; D047389:Casein Kinase I / Q000378:metabolism; D002460:Cell Line; D017931:DNA Primers; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D016296:Mutagenesis; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins
C495305:ARM protein, Drosophila; D051186:Armadillo Domain Proteins; D060466:Axin Protein; D017931:DNA Primers; D029721:Drosophila Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D029867:Xenopus Proteins; C555454:axin1 protein, Xenopus; D047389:Casein Kinase I; D038362:Glycogen Synthase Kinase 3; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1