title: Structural and functional characterization of the Wnt inhibitor APC membrane recruitment 1 (Amer1).
abstract: Amer1/WTX binds to the tumor suppressor adenomatous polyposis coli and acts as an inhibitor of Wnt signaling by inducing β-catenin degradation. We show here that Amer1 directly interacts with the armadillo repeats of β-catenin via a domain consisting of repeated arginine-glutamic acid-alanine (REA) motifs, and that Amer1 assembles the β-catenin destruction complex at the plasma membrane by recruiting β-catenin, adenomatous polyposis coli, and Axin/Conductin. Deletion or specific mutations of the membrane binding domain of Amer1 abolish its membrane localization and abrogate negative control of Wnt signaling, which can be restored by artificial targeting of Amer1 to the plasma membrane. In line, a natural splice variant of Amer1 lacking the plasma membrane localization domain is deficient for Wnt inhibition. Knockdown of Amer1 leads to the activation of Wnt target genes, preferentially in dense compared with sparse cell cultures, suggesting that Amer1 function is regulated by cell contacts. Amer1 stabilizes Axin and counteracts Wnt-induced degradation of Axin, which requires membrane localization of Amer1. The data suggest that Amer1 exerts its negative regulatory role in Wnt signaling by acting as a scaffold protein for the β-catenin destruction complex and promoting stabilization of Axin at the plasma membrane.
authors.affiliation: Nikolaus-Fiebiger-Center, Biology Department, University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Tanneberger
authors.forename: Astrid S
authors.initials: AS
authors.lastname: Pfister
authors.forename: Vitezslav
authors.initials: V
authors.lastname: Kriz
authors.forename: Vitezslav
authors.initials: V
authors.lastname: Bryja
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schambony
authors.forename: Jürgen
authors.initials: J
authors.lastname: Behrens
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D060466:Axin Protein; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D000091402:Prohibitins; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins; D014982:Xenopus laevis; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C517118:AMER1 protein, human; C555337:APC protein, human; D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; C000717331:PHB2 protein, human; D000091402:Prohibitins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D029867:Xenopus Proteins; C555454:axin1 protein, Xenopus; D051176:beta Catenin