RanBP3 enhances nuclear export ofactive β-catenin independently of CR

M1

Hendriksen et al., JCB(2005)

Scheme of canonical Wnt signaling

Nusse et al., JBC, 2006

The Ran cycle

Fahrenkrog and Aebi et al., Nat Rev Mol Cell Biol , 2003

Import and export cycle mediated by importin and exportin

Kuersten et al., Trends cell bio, 2001

What is β-catenin?

• A key molecule which mediates cellular activities in the Wnt signaling pathway

• It was first identified as a component of the cell–cell adhesion complex

• It doesn’t have NLS and NES

N-terminus C-terminus

Putative phosphorylation

site(s), mutated in tumors

Ubiquitination sites

α-cateninAPC TCF/LEF-1 E-cadherin

ARM repeat

Nuclear-cytoplasmic shuttling of β-catenin

Fagotto et al., EMBO, 2002

Identification of RanBP3 as an interaction partner of β-catenin

p80

p90

Expression of RanBP3 inhibits β-catenin /TCF–mediated transcriptional activation

Expression of RanBP3 inhibits β-catenin /TCF–mediated transcriptional activation

Reduction of RanBP3 by RNAi results in Increasedβ-catenin / TCF–mediated transcription activation.

RanBP3 antagonizes Wnt/β-catenin transactivationin APC mutated colon carcinoma cells.

Depletion of RanBP3 results in nuclearaccumulation of active β-catenin

RanBP3 induces specific depletionof endogenous nuclear active β-catenin.

RanBP3 enhances nuclear export ofactive β-catenin independently of CRM1.

RanBP3 enhances nuclear export ofactive β-catenin independently of CRM1.

RanBP3 rescues β-catenin–induceddouble axis formation in X. laevis embryos.

RanBP3 rescues β-catenin–induceddouble axis formation in X. laevis embryos.

Loss of RanBP3 by RNAi results in a nakedcuticle phenotype in D. melanogaster.

Loss of RanBP3 by RNAi results in a nakedcuticle phenotype in D. melanogaster.

conclusion

summary

• RanBP3 is a novel inhibitor of Wnt signaling that acts on β-catenin directly by enhancing nuclear export of its active form.

• Expression of RanBP3 represses Wnt signaling both in vitro and in Xenopus embryonic Wnt signaling.

• Inhibition of RanBP3 by RNAi causes overactivation of Wnt signaling in tissue culture cell and Drosophila embryo.

Three pathway of export β-catenin

1. Interact directly with nuclear pore complex (Fagotto et al., Curr. Biol, 2001)

2. Exit via the CRM1 pathway it uses binding APC (Rosin-Arbesfeld et at., Nature, 2000)

3. RanBP3 enhance β-catenin export CRM1 and APC independently (In this paper)

Nuclear export of β-catenin

Gottardi et al., JCB, 2005