Nuclear-cytoplasmic shuttling of Axin regulates subcellular localization of beta-catenin.
Wnt signaling regulates many aspects of development by increasing the signaling activity of beta-catenin. Axin is a negative regulator of the Wnt signaling pathway, and it is responsible for the formation of the beta-catenin degradation complex. Genetic studies with Drosophila suggest that Axin promotes cytoplasmic localization of beta-catenin independent of Axin's known role of enhancing degradation of beta-catenin. Here, we show that Axin is a nuclear-cytoplasmic shuttling protein. Nuclear export of Axin depends on the chromosome maintenance region 1 nuclear receptor; treatment with the chromosome maintenance region 1 inhibitor leptomycin B induces nuclear accumulation of ectopically expressed or endogenous Axin. Functional nuclear localization and nuclear export signals have been mapped within Axin. Significantly, overexpression of an Axin fragment shifts coexpressed stabilized beta-catenin to the cytoplasm, and this effect requires shuttling of Axin between the cytoplasm and the nucleus. Our results suggest that Axin functions as a molecular chaperone for beta-catenin and that nuclear-cytoplasmic shuttling of Axin regulates the nuclear-cytoplasmic distribution of beta-catenin.
Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. congf@mskcc.org
Feng
F
Cong
Harold
H
Varmus
D000818:Animals; D060466:Axin Protein; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D021381:Protein Transport / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D051176:beta Catenin
D060466:Axin Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D005231:Fatty Acids, Unsaturated; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D015534:Trans-Activators; D051176:beta Catenin; C038752:leptomycin A