Amer2 Protein Is a Novel Negative Regulator of Wnt/β-Catenin Signaling Involved in Neuroectodermal Patterning

Wnt/β-catenin signaling is negatively controlled by the adenomatous polyposis coli (APC) tumor suppressor, which induces proteasomal degradation of β-catenin as part of the β-catenin destruction complex. Amer2 (APC membrane recruitment 2; FAM123A) is a direct interaction partner of APC, related to t...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2012-01, Vol.287 (3), p.1734-1741
Main Authors: Pfister, Astrid S., Tanneberger, Kristina, Schambony, Alexandra, Behrens, Jürgen
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Adenomatous Polyposis Coli Protein - genetics
Adenomatous Polyposis Coli Protein - metabolism
Amer2
Animals
APC
beta Catenin - genetics
beta Catenin - metabolism
FAM123A
Gene Expression Regulation, Developmental - physiology
HEK293 Cells
Humans
Lipid-binding Protein
Neural Plate - metabolism
Neurodevelopment
Neuroectodermal Patterning
Signal Transduction
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Wnt Proteins - genetics
Wnt Proteins - metabolism
Wnt Signaling
Wnt Signaling Pathway - physiology
WTX
Xenopus
Xenopus laevis
Xenopus Proteins - genetics
Xenopus Proteins - metabolism
β-Catenin
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Wnt/β-catenin signaling is negatively controlled by the adenomatous polyposis coli (APC) tumor suppressor, which induces proteasomal degradation of β-catenin as part of the β-catenin destruction complex. Amer2 (APC membrane recruitment 2; FAM123A) is a direct interaction partner of APC, related to the tumor suppressor Amer1/WTX, but its function in Wnt signaling is not known. Here, we show that Amer2 recruits APC to the plasma membrane by binding to phosphatidylinositol 4,5-bisphosphate lipids via lysine-rich motifs and that APC links β-catenin and the destruction complex components axin and conductin to Amer2. Knockdown of Amer2 increased Wnt target gene expression and reporter activity in cell lines, and overexpression reduced reporter activity, which required membrane association of Amer2. In Xenopus embryos, Amer2 is expressed mainly in the dorsal neuroectoderm and neural tissues. Down-regulation of Amer2 by specific morpholino oligonucleotides altered neuroectodermal patterning, which could be rescued by expression of a dominant-negative mutant of Lef1 that interferes with β-catenin-dependent transcription. Our data characterize Amer2 for the first time as a negative regulator of Wnt signaling both in cell lines and in vivo and define Amer proteins as a novel family of Wnt pathway regulators. Background: Amer2 is a novel uncharacterized adenomatous polyposis coli (APC)-interacting protein. Results: Amer2 interacts with components of the β-catenin destruction complex via APC, inhibits Wnt target gene expression, and alters neuroectodermal patterning. Conclusion: Amer2 is a novel negative regulator of Wnt signaling involved in brain development. Significance: A novel class of membrane-associated Wnt pathway regulators has been characterized.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111.308650