▶Subject: Merlin and Usp14, signaling novel regulators of Wnt/b-catenin

▶Speaker: Prof. Eek-hoon Jho (Department of Life science, University of Seoul)

▶Date: 4:00PM/November/8(Fri)/2013
 

▶Place: Chem.Bldg.Room401

*Abctract

Neurofibromatosis type II (NF2) protein, Nf2/Merlin, is a tumor suppressor which modulates receptors of numerous mitogenic signalings. In Nf2 patients, genetic deletions of NF2 locus or point mutations of Merlin have been discovered. The level of Merlin is increased in a cell density dependent manner and recently, Merlin is known to be involved in Hippo signaling for contact inhibition of cell growth. Here, we show that Merlin can inhibit Wnt/b-catenin signaling by binding to LRP6. Overexpression and knockdown approaches showed that Merlin inhibited Wnt/b-catenin signaling by blocking of Wnt3a mediated phosphorylation of LRP6 by blocking the interaction between LRP6 and Axin-GSK3b. Interestingly, we found that activation of p21 activated kinase (PAK) by Wnt3a causes phosphorylation on Serine518 residue of merlin. The phosphorylated form of merlin dissociated from LRP6-Merlin complex, which allowed interaction between LRP6 and Axin. Finally, we showed that blocking of Wnt signaling by treatment of ICG-001 and IWP-2, inhibitors of Wnt/β-catenin signaling, significantly reduced the proliferation of RT4 rat schwannoma cells. Taken together, our findings suggest that sustained activation of Wnt/β-catenin signaling due to lack of merlin’s ability to inhibit LRP6 phosphorylation may be a cause Neurofibromatosis Type II disease.
Dishevelled (Dvl) is a key regulator of Wnt signaling both in the canonical and non-canonical pathways. Here we report an identification of a regulatory domain of ubiquitination (RDU) at the C-terminus of Dvl. Mutations of RDU resulted in accumulation of polyubiquitinated forms of Dvl, which were mainly K63-linked. siRNA-based screening identified Usp14 as a mediator of Dvl deubiquitination. Genetic and chemical suppression of Usp14 activity caused an increase of Dvl polyubiquitination and significantly impaired downstream Wnt signaling. These data suggest Usp14 functions as a positive regulator of the Wnt signaling pathway. Consistently, analysis of colon cancer tissue microarray revealed a strong correlation between the levels of Usp14 and b-catenin, which suggests an oncogenic role of Usp14 via enhancing Wnt/b-catenin signaling.

▶Inquiry: Prof. JinKwan Han(279-2126)