nf2/merlin and neurofibromatosis

NF2/Merlin and NF2/Merlin and NeurofibromatosisNeurofibromatosis

Maciej S. TobolaMaciej S. TobolaBiol 169 Cancer BiologyBiol 169 Cancer Biology

March 30, 2004March 30, 2004

Type II NeurofibromatosisType II Neurofibromatosis

Autosomal dominantAutosomal dominant Nervous SystemNervous System RareRare Two-HitTwo-Hit

Merlin in Adherens JunctionsMerlin in Adherens Junctions

No Adherens=No Contact InhibitionNo Adherens=No Contact Inhibition

McClatchey et al., 2003

Various KO’sVarious KO’s

NF2NF2-/--/- Mouse Mouse• Dies QuicklyDies Quickly

Conditional NF2Conditional NF2-/--/- Mouse Mouse• Many SchwannomasMany Schwannomas

Drosophila Bluebox MutantDrosophila Bluebox Mutant• Overproliferation in wingOverproliferation in wing

NF2NF2

Chromosome 22Chromosome 22

Nonsense & Frameshift mutationsNonsense & Frameshift mutations DeletionsDeletions

http://www.rzpd.de/cgi-bin/cards/carddisp?NF2

MerlinMerlin

Protein 4.1 SuperfamilyProtein 4.1 Superfamily

Gutmann et al., 2002

Merlin StructureMerlin Structure

Blue BoxBlue Box A-C Salt BridgeA-C Salt Bridge

Gutmann et al., 2002

Activity in the CellActivity in the Cell

Open=InactiveOpen=Inactive Closed=Active Tumor SuppressorClosed=Active Tumor Suppressor

OpenClosed

Gutmann et al., 2002

Activity in the CellActivity in the Cell

McClatchey et al., 2003

NeurofibromatosisNeurofibromatosis

No Rac1 InhibitionNo Rac1 InhibitionMerlin PhoshorylationMerlin PhoshorylationIncreased ProliferationIncreased Proliferation

McClatchey et al., 2003

Remember This?Remember This?

No Adherens=No Contact InhibitionNo Adherens=No Contact Inhibition

McClatchey et al., 2003

Cancer RecipeCancer Recipe

Increased Proliferation +Increased Proliferation +

Loss of Contact Inhibition =Loss of Contact Inhibition =

Neurofibromatosis Type II

http://www.neurofibromatosis.org/what_is_nf/nf2_technical.htm

Treatment OptionsTreatment Options

SurgerySurgery• Location complicationsLocation complications

Focused Radiation TherapyFocused Radiation Therapy

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