Axin/Conductin (updated July 2005)

Axin is the product of the mouse fused locus. Mutations in this gene result in axial duplications in mouse embryos. Ectopic expression of wild type axin in dorsal blastomeres of Xenopus embryos causes ventralization (Zeng et al 1997)

Axin associates directly with b-catenin, GSK-3b and APC and is implicated in down- regulating Wnt signaling (Ikeda, 1998; Sakanaka, 1998 ; Ikeda, 1998; Itoh, 1998). A gene related to Axin, called Conductin (Behrens, 1998) or Axil (Yamamoto 1998) was cloned by virtue of interacting with b-catenin. Overexpressed Axin or Conductin destabilize b-catenin (Behrens, 1998; Ikeda, 1998; Nakamura, 1998; Hart, 1998; Kishida, 1998; Sakanaka, 1998; Yamamoto, 1998) and block the axis-duplicating activity of XWnt-8 in Xenopus embryos [Zeng, 1997; Itoh, 1998]. Phosphorylation of beta-catenin by GSK3 is promoted in the ternary complex between these two proteins and axin. (Sakanaka, 1998 ; Ikeda, 1998).

A mechanism that may explain how Wnt signaling removes Axin from the degradation complex is the recruitment of Axin to the cytoplasmic tail of the Wnt co-receptor LRP (Mao, 2001; Tolwinski 2003). Axin has been shown to bind preferentially to a phosphorylated form of the LRP tail (Tamai 2004)

Several domains on the Axin protein have been mapped. The RGS interacts with APC Ikeda, 1998.; Behrens, 1998). Separate binding domains for b-catenin and GSK have been found. The DIX domain in Axin is similar to a domain in Dishevelled, and may promote interacions between these two domains ((Hsu 1999 , Smalley 1999.) Axin also binds to the phosphatase PP2A. (Hsu 1999)

There are 2 vertebrate Axin genes. Both act as negative regulators. Axin1 is constutively expressed, but Axin2 (also called Conductin, or Axil) is induced by active Wnt signaling and acts therefore in a negative feedback loop (Yan, 2001 Lustig, 2002 Jho, 2002). See also Hughes et al, 2005. Chia and Costantini (2005)have shown that Axin and Axin2 are functionally equivalent in vivo. Germ line mutations in the human AXIN2 gene cause familial tooth agenesis and predispose to colorectal cancer (Lammli et al, 2004)

A Drosophila Axin has been cloned (Hamada, 1999, Willert, 1999), In C. elegans, Pry- 1 is a functional Axin homolog (Korswagen, 2002)

• Sequence alignment of 4 Axin like proteins
• Structure as determined by Spink 1999
• See pathway and interaction figures.

Mouse Gene	Mouse phenotype	Human Gene	human phenotype
Mouse Axin	neuroectodermal defects and axial duplications Zeng et al 1997	AXIN1	deleted in medulloblastoma
Mouse Axin2 Conductin/Axil	calvarial morphogenesis and craniosynostosis Yu, 2005	AXIN2/Conductin/axil	tooth agenesis and colon cancer Lammli et al, 2004
Other animals
Xenopus Axin
Zebrafish		Mutant, called masterblind Function in regeneration, Stoick-Cooper, 2007
C. elegans
Drosophila Axin