The  -Catenin Destruction Complex

Abstract

The Wnt/b-catenin pathway is highly regulated to insure the correct temporal and spatial activation of its target genes. In the absence of a Wnt stimulus, the transcriptional coactivator b-catenin is degraded by a multiprotein "destruction complex" that includes the tumor suppressors Axin and adenomatous polyposis coli (APC), the Ser/Thr kinases GSK-3 and CK1, protein phosphatase 2A (PP2A), and the E3-ubiquitin ligase b-TrCP. The complex generates a b-TrCP recognition site by phosphorylation of a conserved Ser/Thr-rich sequence near the b-catenin amino terminus, a process that requires scaffolding of the kinases and bcatenin by Axin. Ubiquitinated b-catenin is degraded by the proteasome. The molecular mechanisms that underlie several aspects of destruction complex function are poorly understood, particularly the role of APC. Here we review the molecular mechanisms of destruction complex function and discuss several potential roles of APC in b-catenin destruction.

PAWS 1 controls Wnt signalling through association with casein kinase 1α

“…PAWS1‐dependent induction of Siamois expression was blocked by C‐cadherin (Fig 4D), suggesting that PAWS1‐mediated activation of Wnt signalling requires β‐catenin. Ubiquitin‐mediated degradation of β‐catenin is regulated through the destruction complex, in which CK1, GSK‐3 and Axin1 play key roles 25, 26, 27. Overexpression of Axin1 in animal caps completely blocked xPAWS1‐induced Siamois expression, while overexpression of GSK‐3 did so partially (Fig 4D).…”

Wnt4 antagonises Wnt3a mediated increases in growth and glucose stimulated insulin secretion in the pancreatic beta-cell line, INS-1

“…Unexpectedly though for a proposed 'non-canonical' Wnt ligand Wnt4 itself lead to increased levels of 'total' β-catenin throughout the cell including the nucleus, cytoplasm and membrane. Under normal physiological conditions GSK3β phosphorylated β-catenin is rapidly degraded in the proteasome ensuring that cytoplasmic β-catenin proteins levels remain low [27]. Wnt4 treatment did not increase the expression of the β-catenin mRNA suggesting that increased β-catenin protein levels are due to reduced proteasomal degradation rather than increased gene transcription.…”

Controlled levels of canonical Wnt signaling are required for neural crest migration

“…Under unstimulated conditions cytoplasmic level of ß-catenin is kept low through the dual phosphorylation (Liu et al, 2002) by glycogen synthase kinase 3β (GSK-3β) (Hart et al, 1999;Yost et al, 1996) and casein kinase 1α (CK1α) (Price, 2006;Amit et al, 2002), which together with the adenomatous polyposis coli tumor suppressor protein (APC) (Hart et al, 1999;Ha et al, 2004), protein phosphatase 2A (PP2A) (Hsu et al, 1999;Seeling et al, 1999;Ratcliffe et al, 2000;Yamamoto et al, 2001) and Axin (Hart et al, 1999;Ikeda et al, 1998;Dajani et al, 2003) form a destruction complex (Stamos and Weis, 2013).…”