NF2/Merlin and Neurofibromatosis 2 March 25, 2003 By: Caroline Clendenin.
NF2 and Merlin
description
Transcript of NF2 and Merlin
NF2 and Merlin
Victoria BeasleyMarch 20, 2007
Glossary
• Neurofibromatosis 2 (NF2) – dominantly inherited disease characterized by nervous tissue tumors
• Merlin –moesin, ezrin, radixin-like protein• ERMs – ezrin, radixin, and moesin
– Membrane-cytoskeleton-associated proteins
What we’ll go over today
• Elements of the disease, Neurofibromatosis 2
• NF2/Merlin’s gene family and its normal function
• Merlin’s role in cancer
• Summary of important points
►DISEASE Normal gene function
Role in cancer
Summary
Neurofibromatosis 2
http://www.tinnitusformula.com/qtimes/neuroma.jpg
SchwannomaAcoustic neuroma
►DISEASE Normal gene function
Role in cancer
Summary
Facts and figures
• 1 in 33,000 to 40,000 people affected
• Typically presents as a hearing problem
• Current treatment options– Surgery– Radiation and chemotherapy– Genetic screening
SummaryDisease ►NORMAL GENE FUNCTION
Role in cancer
Normal function of Merlin in Humans
• Cytoskeletal association
• Cell-cell communication– Located at adherens junctions– Monitors cell-cell contact → growth inhibition
• Cell-ECM communication
• Embryonic development
Growth Growth Inhibition
Growth Growth Inhibition
SummaryDisease ►NORMAL GENE FUNCTION
Role in cancer
Homology: FERM Domain
SummaryDisease ►NORMAL GENE FUNCTION
Role in cancer
ERMs Merlin
Phosphorylation
Hyper-
phosphorylation
yields activity.
Hypo-
phosphorylation
yields activity.
Interaction with actin Direct
Indirect (perhaps even through ERM
interaction)
Gas pedal or Brakes?
Positive function in cell transformation.
Gas pedal (?)
Tumor suppressor -- at junctions and
cell-matrix interface
►ROLE IN CANCER
SummaryDisease Normal gene function
Merlin deficiency and human cancer
• Loss of contact inhibition → Proliferation
• Irregular cell-ECM interaction → Possible link to metastasis
►ROLE IN CANCER
SummaryDisease Normal gene function
Murine NF2 and Merlin
• Nf2+/- mice:– no schwannomas– osteosarcomas
• not a phenotypically accurate model for the human NF2 disease
►ROLE IN CANCER
SummaryDisease Normal gene function
Murine NF2 and Merlin
• Nf2 -/- mice: lethal at day 6.5– Collapsed extraembryonic region just before
gastrulation– Absence of organized ectoderm
Murine NF2 and Merlin:Lethal at Day 6.5
http://www.nature.com/ng/journal/v27/n4/images/ng0401_351_I1.gif
Disease ►SUMMARYNormal gene
functionRole
in cancer
Key questions remain…
• What happens locally to the actin cytoskeleton at the site of concentrated active or defective Merlin?
• How do ERMs and Merlin interact?
• Are there other Merlin-like proteins instrumental in other cancers?
Disease ►SUMMARYNormal gene
functionRole
in cancer
Take-home points
• NF2 is a tumor suppressor gene
• Mutations in NF2 eliminate Merlin expression
• Merlin deficiency affects cell motility and proliferation
• Merlin plays a key role in embryonic development
Bibliography
Xiao GH, Chernoff J, and Testa JR, 2003. NF2: The Wizardry of Merlin. Genes, Chromosomes, & Cancer 38:389-399.
Sun CX, Robb VA, Gutmann DH, 2002. Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation. Journal of Cell Science 115, 3991-4000. The Company of Biologists Ltd doi:10.1242/jcs.0094.
McClatchey, Andrea I, 2003.. Merlin and ERM proteins: unappreciated roles in cancer development? Nature Reviews: Cancer. Vol. 3: 877-884.
http://focus.hms.harvard.edu/2001/Jul13_2001/research_briefs.html Crystal structure of FERM.
http://www.cytoskeletons.com/structure.php?start=200. http://www.cellsignal.com/products/9168.htmlhttp://www.masstechportal.org/IP575.aspxhttp://www.pnas.org/cgi/content/full/101/52/18200http://mcb.asm.org/cgi/content/full/25/6/2384?ck=nck
Questions?