Abstract
The Dishevelled (Dvl) gene family encodes cytoplasmic proteins that are necessary for Wnt signal transduction. Utilizing the yeast two-hybrid system, we identified protein phosphatase 2Calpha (PP2C) as a Dvl-PDZ domain-interacting protein. PP2C exists in a complex with Dvl, beta-catenin, and Axin, a negative regulator of Wnt signaling. In a Wnt-responsive LEF-1 reporter gene assay, expression of PP2C activates transcription and also elicits a synergistic response with beta-catenin and Wnt-1. In addition, PP2C expression relieves Axin-mediated repression of LEF-1-dependent transcription. PP2C utilizes Axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that PP2C is a positive regulator of Wnt signal transduction and mediates its effects through the dephosphorylation of Axin.
Highlights
Wnt genes are differentially regulated during development and encode secreted glycoproteins that are involved in cell signaling, cell fate determination, and oncogenesis [1, 2]
The current model of Wnt signal transduction proposes that in the absence of a Wnt signal, -catenin binds an APC1-Axin complex, where it is phosphorylated by GSK-3 and subsequently targeted for ubiquitin-mediated proteasomal degradation
Several studies demonstrated that Axin and Axil/conductin simultaneously bind to GSK-3 and -catenin [7,8,9]
Summary
Wnt genes are differentially regulated during development and encode secreted glycoproteins that are involved in cell signaling, cell fate determination, and oncogenesis [1, 2]. To understand the molecular mechanisms of Dvl function, we searched for new interacting proteins with Dvl. A yeast two-hybrid screen of a human fetal brain cDNA library conditionally expressed from the GAL1 promoter identified three positive clones that interacted with the LexA-Dvl2 PDZ domain bait construct. When lysates from COS-1 cells transiently transfected with PP2C and Myc epitope-tagged Axin were immunoprecipitated with antibodies to PP2C, MycAxin was detected in the immune complexes (Fig. 1A).
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