Transcript Document 247354

NF2/Merlin
Michael Anderson
Diseases
Neurofibromatosis 2
Mesotheliomas
• Schwannomas are hallmark trait
• Rare
• NF2 encoded tumor suppressor Merlin
• NF2 mutations found in sporadic mesotheliomas associated
with asbestos exposure
Thyroid carcinomas
Hepatocellular carcinomas
Perineurial tumors
• NF2 mutations discovered more recently
• Help reveal additional cell types affected by NF2 loss
Neurofibromatosis 2
Hallmark of disease are
schwann cell tumors
(schwannomas)
1/25,000 individuals
Tumors are benign and
slow growing,
responding poorly to
chemotherapy
Schwannomas most
often found on
vestibular branch of
both 8th cranial nerves
Rare Occurrence
Autosomal dominant
genetic disease
Highly Penetrant
>95%
Loss of Merlin leads to SC hyperproliferation and tumorigenesis in
animal models
Stained section of schwannoma emanating from the
trigeminal nerve of a NF2 mutant mouse
Schwann cell hyperplasia in the sciatic nerve of a
NF2 mutant mouse
Malignant peripheral nerve sheath tumor (MPNST)
in NF2 mutant zebrafish.
McClatchey A. I., Giovannini M. Genes Dev. 2005;19:22652277
NF2
• NF2 is located on
Chromosome 22
• Tumor suppressor
• First tumor suppressor
gene to encode more of
a structure protein than
an inhibitor
• Encodes Protein Merlin
Genetics Home Reference, 2007.
Merlin
• Amino Acid similar to Ezrin, Radixin, Moesin
(ERM) proteins
• Blocks cell proliferation
• Located near membrane
• Regulates linkage between membrane
associated proteins and cytoskeleton
• Responsible for receiving and interpreting
signals from extracellular milieu
Merlin
• Serine Residue 518 (S518)
phosphorylation weakens selfassociation inactivating the
growth suppressing Merlin
•Activation of the small GTPase
Rac1 is most common method of
phosphorylation of S518
•In folded conformation it is the
N-terminal and C-terminal that
associate
Fagan T., Conjuring with Merlin, 2001
Merlin-organized complexes prevent mitogenic signaling and
contact-dependent inhibition of proliferation
McClatchey A. I., Giovannini M. Genes Dev. 2005;19:22652277
Curto M., et al., Contact Dependent Inhibition, 2007.
Mutations of NF2
Rare
Often
Type of Mutation
Number of people
Number of Families
Nonsense
293
232
Frameshift deletion
159
128
Frameshift insertion
47
41
Indel
10
10
Splice donor site
174
88
Splice acceptor site
150
86
Missense
88
35
In-frame deletion
18
18
In-frame insertion
13
4
Large deletion
141
80
Large insertion
4
3
Chromosomal
translocation
15
13
TotalBaser M. E., NF2 Mutation1,112
Databases, 2004.
738
Oncogenic Properties
Blocks cell
proliferation
• Inactivated merlin
leads to
hyperproliferation
Contact Inhibition
• Merlin regulates
contact-dependent
inhibition of
proliferation
• Phosphorylation
regulated by cellular
density
Interaction with
Epidermal Growth
Factor Receptor
• Merlin can inhibit
EGFR upon cell to cell
contact
Summary
NF2 encodes protein
Merlin
Merlin acts as a tumor
suppressor by regulating
proliferation
First tumor suppressor
to act as more of a
structural protein
Merlin located near cell
membrane and
regulates contactdependent inhibition of
proliferation
Absence of Merlin
causes over proliferation
and most often
Neurofibromatosis
Neurofibromatosis is
autosomal dominant
most often resulting in
schwannomas