A positive role for the PP2A catalytic subunit in Wnt signal transduction.
Protein phosphatase-2A (PP2A) is a multisubunit serine/threonine phosphatase involved in intracellular signaling, gene regulation, and cell cycle progression. Different subunits of PP2A bind to Axin and Adenomatous Polyposis Coli, components of the Wnt signal transduction pathway. Using early Xenopus embryos, we studied how PP2A functions in Wnt signal transduction. The catalytic subunit of PP2A (PP2A-C) potentiated secondary axis induction and Siamois reporter gene activation by Dishevelled, a component of the Wnt pathway, indicating a positive regulatory role of this enzyme in Wnt signaling. In contrast, small t antigen, an antagonist of PP2A-C, inhibited Dishevelled-mediated signal transduction, as did the regulatory PP2A-B'epsilon subunit, consistent with the requirement of PP2A function in this pathway. Although Wnt signaling is thought to occur via regulation of beta-catenin degradation, PP2A-C did not significantly affect beta-catenin stability. Moreover, the pathway activated by a stabilized form of beta-catenin was sensitive to PP2A-C and its inhibitors, suggesting that PP2A-C acts downstream of beta-catenin. Because previous work has suggested that PP2A can act upstream of beta-catenin, we propose that PP2A regulates the Wnt pathway at multiple levels.
Ratcliffe
M J
MJ
Department of Microbiology and Molecular Genetics, Harvard Medical School, Molecular Medicine Unit, Beth Israel Deaconess Medical Center, Boston, Massachessetts 02215, USA. mratclif@caregroup.harvard.edu
Itoh
K
K
Sokol
S Y
SY
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000957:Antigens, Viral, Tumor / Q000494:pharmacology; D020134:Catalytic Domain; D002417:Cattle; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology; D000072261:Dishevelled Proteins; D004622:Embryo, Mammalian / Q000378:metabolism; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D024002:HMGB Proteins; D018398:Homeodomain Proteins / Q000235:genetics; D008845:Microinjections; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000378:metabolism*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D051153:Wnt Proteins; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins; D051176:beta Catenin
D048868:Adaptor Proteins, Signal Transducing; D000957:Antigens, Viral, Tumor; C495266:CTNNB1 protein, Xenopus; D003598:Cytoskeletal Proteins; D000072261:Dishevelled Proteins; D024002:HMGB Proteins; D018398:Homeodomain Proteins; D010750:Phosphoproteins; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C093133:SIA1 protein, Xenopus; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2