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NF2/Merlin: THE MAGIC OF MERLIN Sarah Speed BIOL 445 Spring 2015 NF2 encodes Merlin, a structural cytoskeleton-membrane linker NF2 Locus Merlin JCS November 1, 2002 vol. 115 no. 21 3991-4000 Merlin localizes to membrane ruffles and cellular junctions Merlin inhibits the Ras pathway at cell-ECM junctions JCS November 1, 2002 vol. 115 no. 21 3991-4000 Merlin controls the stabilization of adherens junctions Merlin and β-catenin colocalize at the plasma membrane Nf2 mutants show disturbed actin organization and diffuse β-catenin Genes & development, 2003 vol. 17 no. 9 1090-1100. In flies, Merlin regulates cell proliferation and apoptosis through the Hippo signaling pathway Wild-type Mer;Ex double mutant Antenna Thorax Nature Reviews Cancer 2007 vol. 7 no. 3 182-191. Nature cell biology 2006 vol. 8 no. 1 27-36. In mammals, Merlin inhibits the E3 ubiquitin ligase CRL4 in the nucleus . Cancer cell 2014 vol. 26 no. 1 48-60 Summary of Merlin Function Contact Inhibition Nuclear regulation Integrins ECM Cell-ECM Communication Clin Cancer Res 2012 vol. 18 no. 17 4485-4490 NF2-knockout mice are embryonic lethal Wild-type Nf2 -/Most homozygous mutant mice embryos are misshaped and lack a distinct extraembryonicembryonic boundary Mutants exhibit underdeveloped ectoplacental cones and unorganized extraembryonic ectoderm Wild-type Nf2 -/- Genes & development 1997 vol. 11 no. 10 1253-1265. Nf2 -/- NF2/Merlin is a bona fide tumor-suppressor whose loss-of-function leads to Neurofibromatosis type 2 Inactivation of NF2 occurs through Knudson’s “two-hit hypothesis”: Sporadic Cancer: 2 acquired mutations Hereditary Cancer: 1 inherited and 1 acquired mutation Neurofibromatosis Type 2 manifests as benign tumors of the nervous system Meningioma Schwannoma References Ammoun, Sylwia, et al. "Dissecting and targeting the growth factor–dependent and growth factor–independent extracellular signal-regulated kinase pathway in human schwannoma." Cancer research 68.13 (2008): 5236-5245. Benhamouche, Samira, et al. "Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver." Genes & development 24.16 (2010): 1718-1730. Bretscher, Anthony, Kevin Edwards, and Richard G. Fehon. "ERM proteins and merlin: integrators at the cell cortex." Nature reviews Molecular cell biology 3.8 (2002): 586-599. Gutmann, David H., et al. "The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2." Jama 278.1 (1997): 51-57. Hamaratoglu, Fisun, et al. "The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis." Nature cell biology 8.1 (2006): 27-36. Harvey, Kieran, and Nicolas Tapon. "The Salvador–Warts–Hippo pathway—an emerging tumour-suppressor network." Nature Reviews Cancer 7.3 (2007): 182-191. Kissil, Joseph L., et al. "Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization." Journal of Biological Chemistry 277.12 (2002): 10394-10399. Lallemand, Dominique, et al. "NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions." Genes & development 17.9 (2003): 1090-1100. Li, Wei, et al. "Merlin/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4 DCAF1 in the nucleus." Cell 140.4 (2010): 477-490. Li, Wei, et al. "Merlin/NF2 Loss-Driven Tumorigenesis Linked to CRL4 DCAF1-Mediated Inhibition of the Hippo Pathway Kinases Lats1 and 2 in the Nucleus."Cancer cell 26.1 (2014): 48-60. McClatchey, Andrea I., et al. "The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation."Genes & development 11.10 (1997): 1253-1265. McClatchey, Andrea I., et al. "Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors." Genes & development 12.8 (1998): 1121-1133. McClatchey, Andrea I. "Merlin and ERM proteins: unappreciated roles in cancer development?." Nature Reviews Cancer 3.11 (2003): 877-883. Rong, et al. "Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits phosphatidylinositol 3-kinase through binding to PIKE-L." Proceedings of the National Academy of Sciences 101.52 (2004): 18200-18205. Schmucker, B., W. G. Ballhausen, and M. Kressel. "Subcellular localization and expression pattern of the neurofibromatosis type 2 protein merlin/schwannomin." European journal of cell biology 72.1 (1997): 46-53. Sun, Chun-Xiao, Victoria A. Robb, and David H. Gutmann. "Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation." Journal of cell science115.21 (2002): 39914000. Xiao, Guang‐Hui, Jonathan Chernoff, and Joseph R. Testa. "NF2: the wizardry of merlin." Genes, Chromosomes and Cancer 38.4 (2003): 389-399.