1. RanBP3 enhances nuclear export of active β-catenin independently of CRM1 Hendriksen et al., JCB(2005)

2. Scheme of canonical Wnt signaling Nusse et al., JBC, 2006

3. The Ran cycle Fahrenkrog and Aebi et al., Nat Rev Mol Cell Biol, 2003 Ran plays an essential role in the transport of macromolecules between the cytoplasm and nucleus Ran is small Ras-related GTPase.

4. Import and export cycle mediated by importin and exportin Kuersten et al., Trends cell bio, 2001

5. 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-catenin APC TCF/LEF-1 E-cadherin ARM repeat

6. Nuclear-cytoplasmic shuttling of β-catenin Fagotto et al., EMBO, 2002

7. Identification of RanBP3 as an interaction partner of β-catenin p80 p90

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

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

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

11. RanBP3 antagonizes Wnt/β-catenin transactivation in APC mutated colon carcinoma cells.

12. Depletion of RanBP3 results in nuclear accumulation of active β-catenin

13. RanBP3 induces specific depletion of endogenous nuclear active β-catenin.

14. RanBP3 enhances nuclear export of active β-catenin independently of CRM1.

15. RanBP3 enhances nuclear export of active β-catenin independently of CRM1.

16. RanBP3 rescues β-catenin–induced double axis formation in X. laevis embryos.

17. RanBP3 rescues β-catenin–induced double axis formation in X. laevis embryos.

18. Loss of RanBP3 by RNAi results in a naked cuticle phenotype in D. melanogaster.

19. Loss of RanBP3 by RNAi results in a naked cuticle phenotype in D. melanogaster.

20. 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)

21. Nuclear export of β-catenin Gottardi et al., JCB, 2005