The links between axin and carcinogenesis

Abstract

The products of the two mammalian Axin genes (Axin1 and its homologue Axin2) are essential for the degradation of β catenin, a component of Wnt signalling that is frequently dysregulated in cancer cells. Axin is a multidomain scaffold protein that has many functions in biological signalling pathways. Overexpression of axin results in axis duplication in mouse embryos. Wnt signalling activity determines dorsal–ventral axis formation in vertebrates, implicating axin as a negative regulator of this signalling pathway. In addition, Wnts modulate pattern formation and the morphogenesis of most organs by influencing and controlling cell proliferation, motility, and fate. Defects in different components of the Wnt signalling pathway promote tumorigenesis and tumour progression. Recent biochemical studies of axins indicate that these molecules are the primary limiting components of this pathway. This review explores the intriguing connections between defects in axin function and human diseases.

Methylation by protein arginine methyltransferase 1 increases stability of Axin, a negative regulator of Wnt signaling

“…It has been reported that several post-translational modifications, such as phosphorylation/dephosphorylation by GSK3b/protein phosphatase1 Luo et al, 2007), SUMOlyation by SUMO-1 (small ubiquitin-related modifier) conjugating enzymes 3 (Rui et al, 2002;Kim et al, 2008), PARsylation by tankyrases (Huang et al, 2009) and ubiquitination, are involved in controlling the stability of Axin. Although it is not yet known how these modifications are related and why so many are required, cells seem to have various checkpoints that regulate the Axin concentration as Axin is a rate-limiting factor of Wnt/b-catenin signaling and is linked to other signaling pathways such transforming growth factor b and apoptosis signaling (Luo and Lin, 2004;Salahshor and Woodgett, 2005).…”

“…Axin is a key scaffold protein for the b-catenin destruction complex, and mutation of Axin leads to various cancers (Salahshor and Woodgett, 2005). The presence of mutated Axin in human colorectal cancer and hepatocellular carcinomas suggest that Axin is a tumor suppressor gene as well as a potential therapeutic target molecule for various types of cancer (Satoh et al, 2000;Shimizu et al, 2002).…”

Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin

“…For example, b-catenin can be degraded by Jade-1 (Chitalia et al, 2008), Siah-1 or other ubiquitin ligases (Dimitrova et al, 2010). Therefore, although the major mechanism of regulation of b-catenin activity is phosphorylation, the Wnt pathway may use multiple ways to regulate the concentration of b-catenin (Tolwinski and Wieschaus, 2004;Salahshor and Woodgett, 2005).…”

Differential effects of inactivated Axin1 and activated β-catenin mutations in human hepatocellular carcinomas

“…Mutations in Axin genes are more rare, and their role in tumorigenesis is less clear. Most of the described Axin1 mutations are inactivating and many are biallelic, consistent with its tumor suppressor role (Salahshor and Woodgett, 2005). Axin1 is a multidomain scaffold protein implicated in various signaling pathways, including the Wnt, JNK, transforming growth factor (TGF)b and p53 pathways (Rui et al, 2004;Salahshor and Woodgett, 2005).…”

“…Axin1 has also been implicated in several other signaling pathways (Rui et al, 2004;Salahshor and Woodgett, 2005). Axin1 is a master scaffolding protein that can be a negative regulator of the Wnt pathway, but a positive regulator of the JNK, TGFb and p53 pathways (Zhang et al, 1999(Zhang et al, , 2000Furuhashi et al, 2001;Rui et al, 2004).…”