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J. Cell Biol.,
Volume 141, Number 7, June 29, 1998 1589-1599
Developmental, Cell and Molecular Biology Group, Department of Zoology, Duke University, Durham, North Carolina
27708-1000
Merlin, the product of the Neurofibromatosis
type 2 (NF2) tumor-suppressor gene, is a member of the
protein 4.1 superfamily that is most closely related to
ezrin, radixin, and moesin (ERM). NF2 is a dominantly
inherited disease characterized by the formation of bilateral acoustic schwannomas and other benign tumors
associated with the central nervous system. To understand its cellular functions, we are studying a Merlin homologue in Drosophila. As is the case for NF2 tumors,
Drosophila cells lacking Merlin function overproliferate relative to their neighbors. Using in vitro mutagenesis, we define functional domains within Merlin required for proper subcellular localization and for
genetic rescue of lethal Merlin alleles. Remarkably, the
results of these experiments demonstrate that all essential genetic functions reside in the plasma membrane- associated NH2-terminal 350 amino acids of Merlin.
Removal of a seven-amino acid conserved sequence
within this domain results in a dominant-negative form
of Merlin that is stably associated with the plasma
membrane and causes overproliferation when expressed ectopically in the wing. In addition, we provide
evidence that the COOH-terminal region of Merlin has
a negative regulatory role, as has been shown for ERM
proteins. These results provide insights into the functions and functional organization of a novel tumor suppressor gene.
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