Download 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
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Benhamouche, Samira, et al. "Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver." Genes & development 24.16 (2010): 1718-1730.
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Gutmann, David H., et al. "The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2." Jama 278.1 (1997): 51-57.
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biology 8.1 (2006): 27-36.
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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.
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