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?