1. Merlin, tumor suppressor 박건수 2012.04.23 Cancer Genetics

2. Neurofibromatosis Type 2 Bilateral Vestibular Schwannoma MeningiomasFibroma Typical age of onset from late teen to early 20’s. Tumor don’t transform into malignant form yet shows significant morbidity.

3. ERM protein family ERM protein family members have two form : open and closed. Cell (2000) 101, 259-270

4. Different but Similar : Merlin Merlin, product of NF2 gene, is a member of ERM protein family. Merlin has unique domain configuration –No conserved F-actin binding domain. –Unique N-term domain. Merlin, like other ERM proteins, shows closed and open conformation change upon its phosphorylation. EMBOrep. (2012) 13, 204-215

5. Merlin phosphorylation Merlin phosphorylation is mediated by PAK(p21-activated kinase). Un-phosphorylated Merlin inhibits proliferation so that considered as ‘active’ form. J.Biol.Chem.(2002) 277, 10394-9 Oncogene (2004) 23, 580–587

6. Merlin dephosphorylation MYPT-1(myosin phosphatase targeting subunit 1) with PP1 subunit can dephosphorylate Merlin. CPI-17, MYPT-1 inhibitor, treatment transformed NIH-3T3 cells(non-cancer cell line). Nature (2006) 442, 576-579

7. Charted Paths : Three modes of Merlin’s tumor suppressive function. 1.Inhibition of mitogenic signaling pathways. 2.Rather direct action in nucleus 3.Participate to hippo tumor suppressive pathway. EMBOrep. (2012) 13, 204-215

8. Merlin controls surface receptors Merlin inhibit ligand- activated EGFR internalization upon cell- cell contact. Genetic models lacking Merlin shows increased level of membrane localized receptors. J.Cell Biol.(2007) 177, 893-903 1-1

9. Positive feedback Loop : Rac Fibronectin coated bead can induce RAC membrane localization. However, constitutively active- unphosphorylated- merlin inhibit such effect. As RAC can activate PAK, we can come up with positive feedback loop. 1-2 J.Cell Biol.(2005) 171, 361-371

10. Merlin on mTORC1 Loss of Merlin activate mTORC1 independently of AKT or ERK. Meningioma cell lack merlin shows resistance to rapamycin, mTOR inhibitor. 1-3 Mol.Cell.Biol.(2009) 29, 4250-4261

11. Merlin acts in cave : in Nucleus Closed form of Merlin translocates to the nucleus and binds to CRL4 DCAF1. Deregulation of CRL4 DCAF1 due to Merlin inactivation induce tumorigenesis. Many pathogenic NF2 mutation disrupts Merlin interaction with CRL4 DCAF1. 2 Cell(2010)140, 477-490

12. At The Upstream of Hippo In Drosophila, mutant of Expanded, Kibra and Merlin phenocopies Hippo mutant. 3-1 Nat.Cell Biol.(2006) 8, 27-36 Dev.Cell(2010) 18, 288-299

13. Merlin’s Role In Hippo Pathway is Conserved in Mammal Cataract is one of symptoms of neurofibromatosis type 2. Cataract phenotype induced by Nf2 mutation was rescued by half-depletion of Yap, the downstream effector of mammalian hippo pathway. 3-2 Dev.Cell(2010) 19, 27-38

14. Liver specific K/O of Merlin induce tumorigenesis Liver is thought to be the representative organ of mammal which hippo pathway acts. Liver specific knock out of Merlin induce tumorigenesis yet mechanism is not clear. 3-3 Dev.Cell(2010) 19, 27-38 Genes Dev.(2010) 24, 1718-1730

15. Genes Dev.(2010) 24, 1673-9 Liver crisis: Hippo Vs. EGFR 3-4

16. How do they do it? Introduction of Merlin into Merlin deficient mesothelioma cells induced cell cycle arrest. Mol.Cell.Biol.(2005)25, 2384-2394

17. Where do Merlin feature? EMBOrep. (2012) 13, 204-215

18. Summary Merlin, a member of ERM family, is regulated by phosphorylation and following conformational change. Tumor suppressive function of Merlin is mediated by three major pathways. –Downregulation of mitogenic signaling pathways. –Regulation of CRL4 DCAF1 in nucleus. –Act as upstream regulator of hippo pathway. Merlin also act in contact inhibition through cell junctions and polarity regulation.

19. Remaining questions… EMBOrep. (2012) 13, 204-215

20. THANK YOU.