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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.