1. NF2: A Tumor Suppressor NF2 encodes Merlin/Schwannomin, a protein that regulates cell growth and proliferation

2. NF2: A Tumor Suppressor Mutations in NF2 can cause Neurofibromatosis Type II, a cancer affecting the auditory nerve and other central nervous system tissues.

3. NF2 is located on chromosome 22 www.genome.ou.edu bioweb.wku.edu

4. Like Rb, NF2 is a Tumor Suppressor Gutmann and Giovannini

5. NF2’s protein product, merlin, serves to limit cell proliferation in several ways: 1.It regulates cytoskeletal anchorage to neighboring cells and the cell matrix.

6. NF2’s protein product, merlin, serves to limit cell proliferation in several ways: 1.It regulates cytoskeletal anchorage to neighboring cells and the cell matrix. 2. It blocks the ras pathway.

7. NF2’s protein product, merlin, serves to limit cell proliferation in several ways: 1.It regulates cytoskeletal anchorage to neighboring cells and the cell matrix. 2. It blocks the ras pathway. 3. It inhibits cyclin D and progression of the cell cycle.

8. How does merlin interact with the cytoskeleton?

9. To answer that, we need to meet a few of its relatives…

10. Merlin is related to the ERM proteins The ERM (Ezrin, Radixin, Moesin) family is a group of membrane and cytoskeleton associated proteins. McClatchey, A.I., et.al.

11. Merlin and the ERMs are fairly similar in sequence. They share a FERM domain that allows them to localize to the plasma membrane. Gutmann and Giovannini

12. Merlin is related to the ERM proteins RHOA belongs to a family of GTPases whose activation induces phosphorylation/activation of the ERM proteins McClatchey et.al.

13. RAC1 is another member of the RHO-GTPase family, but its activation leads to the phosphorylation/inactivation of merlin. McClatchey, A.I. OnOff Merlin is related to the ERM proteins

14. Mutant NF2 allows cell over-proliferation and possibly cell motility by de-polarizing cells and releasing cell-cell and cell-matrix junctions McClatchey, A.I. Loss of Merlin Normal function of ERM Proteins

15. Remember that Adherens junctions glue cells together and also connect their actin cytoskeletons. Plasma membrane Intracellular Extracellular DE-cadherin Armadillo  -catenin F-actin Intracellular Plasma membrane Merlin

16. Plasma membrane Intracellular Extracellular DE-cadherin Armadillo  -catenin F-actin Intracellular Plasma membrane In addition to regulating actin polymerization, merlin and other proteins stabilize adherens junctions. Merlin

17. Cells that are mutant in both copies of NF2 do not form functional cell-cell or cell-matrix junctions… Lallemand, D., et.al. Bright green is ß-catenin

18. In normal cells, Merlin also blocks the Ras pathway. Alfthan, K., et. al. Merlin

19. What is the normal biological role of merlin?

20. That mouse is a knockout!

21. What happens when you knock out NF2? Gutmann and Giovannini

22. What happens when you knock out NF2? Gutmann and Giovannini X No Gastrulation

23. What happens when you knock out NF2? Gutmann and Giovannini/McClatchey X No Gastrulation DEAD

24. What role does merlin play in causing cancer?

25. Neurofibromatosis Type II The gene NF2 gets its name from the type of cancer it causes: Neurofibromatosis Type II

26. Neurofibromatosis Type II NF2 can be inherited or spontaneous. R. Weinberg, Cancer Biology

27. Neurofibromatosis Type II The penetrance of NF2 is over 95% Zucman-Rossi, J., et.al. R. Weinberg, Cancer Biology

28. Neurofibromatosis Type II: A cancer occurring in about 1/40,000 people Baser, M.E., et.al.

29. DNA screens can identify patients who have no symptoms NF2 mutations in tumor cells are usually deletions; the mutant gene will be smaller than wild type. Warren, C., et.al.www.stanford.edu

30. Schwann cells insulate neurons. www.octc.kctcs.edu

31. Schwann cells are a type of glial cell. medinfo.ufl.edu

32. Vestibular Schwannomas (Acoustic Neuromas) are unequivocal indicators of NF2 www.nfinc.org These tumors often lead to deafness.

33. Benign, but still problematic http://www.neuroendoscopy.info/brain_tumors.htmwww.patients-baha.com

34. A Schwannoma: cclcm.ccf.org

35. Works Cited: McClatchey, A.I., et.al. “The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation”. Genes and Development. 10. (1997): 1253-65. Gutmann, D.H., and Giovannini, M. “Mouse Models of Neurofibromatosis 1 and 2”. Neoplasia. 4(2002): 279-90. Zucman-Rossi, J., et.al. “ Exhaustive characterization of the NF2 gene in neurofibromatosis type 2 patients ”. Human Molecular Genetics. 7 (1998): 2095-2101. Baser, M.E., et.al. “Predictors of the Risk of Mortality in Neurofibromatosis Type II”. American Journal of Human Genetics. 71 (2002): 715-723 McClatchey, A.I., “Merlin and ERM Proteins: Unappreciated Roles in Cancer Development?”. Nature Reviews, Cancer. 3 (2003): 877-84. Lallemand, D., et.al., “NF2 Deficiency Promotes Tumorigenesis and Metastasis by Destabilizing Adherens Junctions”. Genes and Development. 17 (2003): 1090-1100. Warren, C., et.al., “Identification of Recurrent Regions of Chromosome Loss and Gain in Vestibular Schwannomas Using Comparative Genomic Hybridization”. Journal of Medical Genetics. 40 (2003): 802-6.