Transcript NF2 or Merlin

NF2 and Merlin
Julie Grondin
March 10th, 2005
Bio 169
Neurofibromatosis Type 2 (NF2)
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Characterized by bilateral vestibular
schwannomas
Schwannomas of other cranial,
spinal, and cutaneous nerves and
cranial and spinal meningiomas are
also occur.
NF2 mutations also found in many
cancers like with abestos exposure.
Schwannoma
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Schwannoma is the cancer of Schwann
cells.
Schwann cells are cells that wrap
themselves around the axon of neurons
thus forming sheeths of myelin.
www.biosci.uga.edu
Inheritance Pattern
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NF2 is inherited in a dominant
pattern.
Hetrozygous individuals will most
likely get the disease
But recessive at the cellular level
It behaves as you typical tumor
suppressor gene.
Mutation of the First Allele
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Majority are caused by a truncated
protein due to the insertion of a
stop codon, splicing alternation, or
a frameshift.
Changes in the function domain
through in-frame deletions and
missense mutations have also been
found.
Biochemical and Cellular Roles
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Gene of NF2 called Merlin or
schwannomin
Binds to 4 proteins with the exon 2
domain…but they are not well
understood.
Pathway Investigation
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Merlin has about ten serine/threonine
residues, eight of which have kinase
recognition sites.
The N and C terminus are both
phosphorylated in serum-starved cells.
Rac phosphorylates the C-terminus end
only.
What does phosphorylation do: it
weakens both its head to tail interaction
and association with the cytoskeleton.
Pathway Investigation Cont.
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Phosphorylation inactivates merlin.
Inactived merlin is associated with
growth arrest by serum deprivation,
increased cell density, and loss of
adhesion.
Cdc 42 also seems also induced
merlin phosphorylation.
Possible Pathway?
McClatchey, A. Merlin and ERM Proteins
Location, Location, Location
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Found at the plasma membrane
Does this make sense with its function?
Yes, it’s a cytoskeleton associated protein
that links membrane proteins to the
cytoskeleteon.
It associates with the membrane proteins
with an N terminus domain and the
cytoskeleton components with its C
terminus domain.
Relatives
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Belongs to family of cytoskeleton
associated proteins and most
specifically to the ERM proteins
ERMs
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Ezrin, radixin, and moesin
How similar is Merlin?
The domain of homology is the one that
localizes the protein at the plasma
membrane.
They link transmembrane proteins to the
actin cytoskeleton and are found in
signaling pathways.
Unlike Merlin they can directly interact
with actin
Possible ERM Pathway
McClatchey, Andrea I. Merlin
and ERM proteins
What does it do for the body
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Still not well understood at this
point
Essential for embryonic
development
Extraembryonic membranes and
gastrulation cannot occur without it
in mice.
Homozygous Mice for NF2 Mutants
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Homozygous mice for NF2 mutants
are not viable
They dies between 6.5-7 days
embryonic days
They exhibit collapsed
extraembryonic region and absence
of extraembryonic ectoderm.
Embryo continues to live but fails to
gastrulate at which point is dies.
Dead Homozygous Mice, What about
Hetrozygous Mice?
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Hetrozygous mice mainly develop
osteosarcomas, but also fibrosarcoma and
hepatocellular carcinoma at an increased
but low frequency.
They do not show the same cancers as in
humans due to insufficient rates of
second allele inactivation.
Conclusion: Mice aren’t a good model for
study of human NF2.
Model Organism Revisted
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Conditional homozygous mice
achieved by making them
homozygous only in certain cells.
Developed human
neurofibromatosis.
So now possible to use them as a
model organism.
What do Merlin and NF2 have to do
with cancer?
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Merlin associates with the
cytoskelton and plays a role in cell
adhesion which may explain why
NF2 loss faciliates tumor metasis.
Merlin plays a role in control of cell
proliferation, but the mechanism is
not understood.
Link to Cancer
McClatchey, Andrea I. Merlin and
ERM proteins
Sources
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Giovannini M, Robanus-Maandag E, van der Valk M, Niwa-Kawakita M,
Abramowski V, Goutebroze L, Woodruff JM, Berns A, Thomas G.
Conditional biallelic Nf2 mutation in the mouse promotes
manifestations of human neurofibromatosis type 2. Genes Dev. 2000
Jul 1;14(13):1617-30.
AI McClatchey, I Saotome, V Ramesh, JF Gusella and T Jacks The Nf2
tumor suppressor gene product is essential for extraembryonic
development immediately prior to gastrulation Genes & Development,
Vol 11, 1253-1265
Shaw RJ, Paez JG, Curto M, Yaktine A, Pruitt WM, Saotome I, O'Bryan
JP, Gupta V, Ratner N, Der CJ, Jacks T, McClatchey AI.
The Nf2
tumor suppressor, merlin, functions in Rac-dependent signaling. Dev
Cell. 2001 Jul;1(1):63-72
McClatchey, Andrea I. Merlin and ERM proteins: unappreciated roles
in cancer devlopment. Nature Reviews. 2003 Nov (3): 877-883
Honor Code
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This presentation
was completed in
accordance with
the honor code.