Transcript NF2/Merlin: THE MAGIC OF MERLIN

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.