Adenomatous polyposis coli is down-regulated by the ubiquitin-proteasome pathway in a process facilitated by Axin.
Adenomatous polyposis coli (APC) protein and Axin form a complex that mediates the down-regulation of beta-catenin, a key effector of Wnt signaling. Truncation mutations in APC are responsible for familial and sporadic colorectal tumors due to failure in the down-regulation of beta-catenin. While the regulation of beta-catenin by APC has been extensively studied, the regulation of APC itself has received little attention. Here we show that the level of APC is down-regulated by the ubiquitin-proteasome pathway and that Wnt signaling inhibits the process. The domain responsible for the down-regulation and direct ubiquitination was identified. We also show an unexpected role for Axin in facilitating the ubiquitination-proteasome-mediated down-regulation of APC through the oligomerization of Axin. Our results suggest a new mechanism for the regulation of APC by Axin and Wnt signaling.
Choi
Jongkyu
J
Laboratory of Ophthalmology and Visual Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul, 137-701, Korea.
Park
Sun Young
SY
Costantini
Frank
F
Jho
Eek-Hoon
EH
Joo
Choun-Ki
CK
D025601:Adenomatous Polyposis Coli Protein / Q000096:biosynthesis*; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D060466:Axin Protein; D001665:Binding Sites; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015536:Down-Regulation; D000939:Epitopes; D017353:Gene Deletion; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D010957:Plasmids / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D015854:Up-Regulation; D051153:Wnt Proteins; D060508:Wnt3 Protein; D014981:Xenopus; D029867:Xenopus Proteins; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; D000596:Amino Acids; D060466:Axin Protein; C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; D017077:Culture Media, Conditioned; D003598:Cytoskeletal Proteins; D000939:Epitopes; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D025801:Ubiquitin; D051153:Wnt Proteins; D060508:Wnt3 Protein; D029867:Xenopus Proteins; C555454:axin1 protein, Xenopus; D051176:beta Catenin; D046988:Proteasome Endopeptidase Complex