Dataset Information

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 ?-catenin degradation. We show here that Amer1 directly interacts with the armadillo repeats of ?-catenin via a domain consisting of repeated arginine-glutamic acid-alanine (REA) motifs, and that Amer1 assembles the ?-catenin destruction complex at the plasma membrane by recruiting ?-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 ?-catenin destruction complex and promoting stabilization of Axin at the plasma membrane.

SUBMITTER: Tanneberger K

PROVIDER: S-EPMC3103299 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Structural and functional characterization of the Wnt inhibitor APC membrane recruitment 1 (Amer1).

Tanneberger Kristina K Pfister Astrid S AS Kriz Vitezslav V Bryja Vitezslav V Schambony Alexandra A Behrens Jürgen J

The Journal of biological chemistry 20110415 22

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 ...[more]

PMID: 21498506

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Project description:BackgroundThe abundant number of kinases that Entamoeba histolytica possesses allows us to assume that the regulation of cellular functions by phosphorylation-dephosphorylation processes is very important. However, the kinases responsible for the phosphorylation in Entamoeba spp. vary in the structure of their domains and, therefore, could be responsible for the unusual biological characteristics of this parasite. In higher eukaryotes, Src kinases share conserved structural domains and are very important in the regulation of the actin cytoskeleton. In both Entamoeba histolytica and Entamoeba invadens, the major Src kinase homologue of higher eukaryotes lacks SH3 and SH2 domains, but does have KELCH domains; the latter are part of actin cross-linking proteins in higher eukaryotic cells.MethodsThe function of the EhSrc protein kinase of Entamoeba spp. was evaluated using Src inhibitor-1, microscopy assays, Src kinase activity and western blot. In addition, to define the potential inhibitory mechanism of Src-inhibitor-1 for the amoebic EhSrc protein kinase, molecular dynamic simulations using NAnoscale Molecular Dynamics (NAMD2) program and docking studies were performed with MOE software.ResultsWe demonstrate that Src inhibitor-1 is able to prevent the activity of EhSrc protein kinase, most likely by binding to the catalytic domain, which affects cell morphology via the disruption of actin cytoskeleton remodeling and the formation of phagocytic structures without an effect on cell adhesion. Furthermore, in E. invadens, Src inhibitor-1 inhibited the encystment process by blocking RhoA GTPase activity, a small GTPase protein of Rho family.ConclusionsEven though the EhSrc molecule of Entamoeba is not a typical Src, because its divergent amino acid sequence, it is a critical factor in the biology of this parasite via the regulation of actin cytoskeleton remodeling via RhoA GTPase activation. Based on this, we conclude that EhSrc could become a target molecule for the future design of drugs that can prevent the transmission of the disease.

Dataset Information

Structural and functional characterization of the Wnt inhibitor APC membrane recruitment 1 (Amer1).

Publications

Structural and functional characterization of the Wnt inhibitor APC membrane recruitment 1 (Amer1).

Similar Datasets

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