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NF2 Encodes Merlin, a Tumor Suppressor I. What is the protein merlin’s normal biochemical and cell biological role in the cell? NF2 encodes a protein called merlin which acts as a tumor suppressor. As we know, tumor suppressors are the “breaks” on cell proliferation. How does merlin achieve this? o It helps anchor the actin cytoskeleton to other cells and the matrix. o It blocks the Ras signaling pathway. o It inhibits cyclin D, which controls s-phase entry. There are several other players that act to anchor the cytoskeleton: o The ERM proteins (ezrin, radixin and moesin) o RHOA, a GTPase relative of Ras activates the ERMs. o RAC1, another GTPase Ras relative inactivates Merlin. o The activity of the ERMs and merlin is controlled by phosphorylation and GTPase feedback loops in opposite ways. In addition to interacting with the cytoskeleton, merlin helps form adherens junctions. o NF2-/- cells fail to form adherens junctions as shown by lack of β-catenin at the plasma membrane. II. What is the normal biological role of the protein, merlin? Mice that are homozygous NF2 knockouts die between day 6.5 and day 7 of development because they cannot gastrulate. o This sheds little light on the normal cellular role of merlin but does fit well with the theory that the protein acts in cell-cell junctions. This type of cellular interaction would be crucial for gastrulation. III. What is merlin’s relationship to cancer? Homozygous loss-of-function NF2 mutations cause Neurofibromatosis Type II o Like Rb, this cancer can be inherited or spontaneous and follows Knudson’s two-hit model. o NF2 can occur throughout life and does in about 1 out of 40,000 people. o Typically, numerous benign tumors develop in the tissues of the CNS, especially schwann cells. Schwann cells are a type of glial cell that insulates the axons of neurons to allow action potentials to propagate more rapidly. o Unlike most neurons, these cells retain the capacity to divide and so can accumulate mutations and develop tumors. o The most common tumor caused by NF2 is a Vestibular schwannoma (or acuoustic neuroma) which is a tumor of the vestibular or auditory nerve. o Although the tumors are benign, the location makes surgical removal difficult and can cause deafness in one or both ears.