Julie Grondin March 10th, 2005 Bio 169 NF2 and Merlin Julie Grondin March 10th, 2005 Bio 169

Neurofibromatosis Type 2 (NF2) 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 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 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 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 Gene of NF2 called Merlin or schwannomin Binds to 4 proteins with the exon 2 domain…but they are not well understood.

Pathway Investigation 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. 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 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 Belongs to family of cytoskeleton associated proteins and most specifically to the ERM proteins

ERMs 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 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 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? 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 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? 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 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

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