Amer2 is a novel negative regulator of Wnt/beta-catenin signaling involved in neuroectodermal patterning

Wnt/β-catenin signaling is negatively controlled by the tumor suppressor APC (adenomatous polyposis coli), 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 PtdIns(4,5)P2 lipids via lysine rich motifs, and that APC links β-catenin and the destruction complex components axin/conductin to Amer2. Knockdown of Amer2 increases Wnt target gene expression and reporter activity in cell lines, and overexpression reduces reporter activity which requires membrane association of Amer2. In Xenopus embryos, Amer2 is mainly expressed in dorsal neuroectoderm and in neural tissues. Downregulation of Amer2 by specific morpholino oligonucleotides alters neuroectodermal patterning, which can 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.