Wnt Signaling through Inhibition of β-Catenin Degradation in an Intact Axin1 Complex

Abstract

Degradation of cytosolic β-catenin by the APC/Axin1 destruction complex represents the key regulated step of the Wnt pathway. It is incompletely understood how the Axin1 complex exerts its Wnt-regulated function. Here, we examine the mechanism of Wnt signaling under endogenous levels of the Axin1 complex. Our results demonstrate that β-catenin is not only phosphorylated inside the Axin1 complex, but also ubiquinated and degraded via the proteasome, all within an intact Axin1 complex. In disagreement with current views, we find neither a disassembly of the complex nor an inhibition of phosphorylation of Axin1-bound β-catenin upon Wnt signaling. Similar observations are made in primary intestinal epithelium and in colorectal cancer cell lines carrying activating Wnt pathway mutations. Wnt signaling suppresses β-catenin ubiquitination normally occurring within the complex, leading to complex saturation by accumulated phospho-β-catenin. Subsequently, newly synthesized β-catenin can accumulate in a free cytosolic form and engage nuclear TCF transcription factors.

Identification of TMEM131L as a Novel Regulator of Thymocyte Proliferation in Humans

“…3A), which was performed on bulk unfractionated thymocytes due to their limited cell numbers. Consistent with their hyperproliferative phenotype, these thymocytes expressed higher levels of cell-cycle regulators and Wnt target genes c-Myc, CCDN1, CCDN2,and Axin2 (22). Notably, the expression of Wnt receptors (LRP6, Fz7, Fz8) or signaling components (CTNNB, JUP, DVL) did not change (data not shown).…”

Involvement of the Wnt/β-catenin pathway in neurectoderm architecture in Platynereis dumerilii

“…S2B), which encodes a cargo protein responsible for the transport and secretion of Wnt ligands 21,22 , and Pdu-axin ( Supplementary Fig. S2C), a key protein of the b-catenin degradation complex 23,24 . At 33 hpf Pdu-wntless is weakly expressed in a few neurectodermal cells (Fig.…”

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

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