Merlin (protein)

Merlin (also called Neurofibromin 2 or schwannomin) is a cytoskeletal protein. In humans, it is a tumor suppressor protein involved in Neurofibromatosis type II. Sequence data reveal its similarity to the ERM proteins family.

The name "merlin" is an acronym for "Moesin-Ezrin-Radixin-Like Protein", and has nothing to do with its namesake Merlin (wizard).

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Genes

Human merlin is coded by the gene NF2 in Chromosome 22. Mouse merlin gene is located on the chromosome 11 and rat merlin gene on the chromosome 17. Fruit fly merlin gene (symbol Mer) is located on chromosome 1 and shares 58% similarity to its human homologue. Other merlin-like genes are known from a wide range of animals, and the derivation of merlin is thought to be in early metazoa. Merlin is a member of the ERM family of proteins including ezrin, moesin, and radixin, which are in the protein 4.1 superfamily of proteins. Merlin is also known as schwannomin, a name derived from the most common type of tumor in the NF2 patient phenotype, the schwannoma.

Structure

Vertebrate merlin is a 70 kDa protein. There are 10 known isoforms of human merlin molecule (the full molecule being 595 amino acids in length). The two most common these are also found in the mouse and are called type 1 and type 2, differing by the absence or presence of exon 16 or 17, respectively). All the known varieties have a conserved N-terminal part, which contains a FERM domain (a domain found in most cytoskeletal-membrane organizing proteins). The FERM domain is followed by a alpha-helical domain and a hydrophilic tail. Merlin can dimerize with itself and heterodimerize with other ERM family proteins.

Function

Merlin is a membrane-cytoskeleton scaffolding protein, i.e. linking actin filaments to cell membrane or membrane glycoproteins. Human merlin is predominantly found in nervous tissue, but also in several other fetal tissues, and is mainly located in adherens junctions. Its tumor suppressor properties are probably associated with contact-mediated growth inhibition. Drosophila merlin is expressed in embryonic hindgut, salivary gland and imaginal discs and has apparently a slightly different role than in vertebrates.

The phosphorylation of serine 518 is known to alter the functional state of merlin.The signaling pathway of merlin is proposed to include several salient cell growth controlling molecules, including eIF3c, CD44, protein kinase A and p21 activated kinases.

Mutations of the NF2 gene cause a human autosomal dominant disease called neurofibromatosis type 2. It is characterized by the development of tumors of the nervous system, most commonly of bilateral vestibular schwannomas (also called acoustic neuromas). NF2 belongs to the tumor suppressor group of genes.

References

• Rouleau et al.Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2.Nature. 1993 Jun 10;363(6429):495-6[1]
• Haase et al.The murine NF2 homologue encodes a highly conserved merlin protein with alternative forms.Hum Mol Genet 1994 3:407-411[2]
• Golovnina et al. Evolution and origin of merlin, the product of the Neurofibromatosis type 2 (NF2) tumor-suppressor gene. BMC Evolutionary Biology 2005, 5:69[3]
• Alfthan et al.Cyclic AMP-dependent Protein Kinase Phosphorylates Merlin at Serine 518 Independently of p21-activated Kinase and Promotes Merlin-Ezrin HeterodimerizationJ. Biol. Chem., Vol. 279, Issue 18, 18559-18566[4]
• Shimizu et al. Structural Basis for Neurofibromatosis Type 2.J. Biol. Chem., Vol. 277, Issue 12, 10332-10336, March 22, 2002[5]
• A.McClatchey,M.Giovannini,Membrane organization and tumorigenesis—the NF2 tumor suppressor, Merlin. Genes Dev. 2005 Oct 1;19(19):2265-77[6]
• den Bakker et al. Expression of the Neurofibromatosis Type 2 Gene in Human Tissues. J. of Histochemistry and Cytochemistry, Vol. 47, 1471-1480, November 1999[7]
• LaJeunesse et al.Structural Analysis of Drosophila Merlin Reveals Functional Domains Important for Growth Control and Subcellular Localization. J. Cell Biol., Volume 141, Number 7, June 29, 1998[8]
• Scoles et al. Schwannomin inhibits tumorigenesis through direct interaction with the eukaryotic initiation factor 3 subunit c (eIF3c). Hum. Mol. Genet. 2006 Apr 1;15(7):1059-70. [9]