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Merlin (also called Neurofibromin 2 or schwannomin) is a cytoskeletal protein. In humans, it is a tumor suppressor protein involved in Neurofibromatosis type II.^[1]^[2] Sequence data reveal its similarity to the ERM protein family.

The name "merlin" is an acronym for "Moesin-Ezrin-Radixin-Like Protein".

Gene[edit]

Human merlin is coded by the gene NF2 in Chromosome 22. Mouse merlin gene is located on the chromosome 11^[3] 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[edit]

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 an alpha-helical domain and a hydrophilic tail.^[4] Merlin can dimerize with itself and heterodimerize with other ERM family proteins.

Function[edit]

Merlin is a membrane-cytoskeleton scaffolding protein, i.e. linking actin filaments to cell membrane or membrane glycoproteins.^[5] Human merlin is predominantly found in nervous tissue, but also in several other fetal tissues, and is mainly located in adherens junctions.^[6] 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.^[7]

The phosphorylation of serine 518 is known to alter the functional state of merlin.^[8] 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.^[9]

Interactions[edit]

Merlin (protein) has been shown to interact with HGS,^[10]^[11] CUL4A,^[12] EZR,^[13] SDCBP,^[14] VPRBP,^[12] RIT1,^[12] SPTBN1,^[15] MED28^[16] and DDB1.^[12]

External links[edit]

GeneReviews/NCBI/NIH/UW entry on Neurofibromatosis 2
FlyBase synopsis of gene Mer
UMich Orientation of Proteins in Membranes protein/pdbid-1gc6 - Calculated spatial position of Radixin in membrane

References[edit]

^ Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B (1993). "Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2". Nature 363 (6429): 515–21. doi:10.1038/363515a0. PMID 8379998.
^ Golovnina K, Blinov A, Akhmametyeva EM, Omelyanchuk LV, Chang LS (2005). "Evolution and origin of merlin, the product of the Neurofibromatosis type 2 (NF2) tumor-suppressor gene". BMC Evol. Biol. 5: 69. doi:10.1186/1471-2148-5-69. PMC 1315344. PMID 16324214.
^ Haase VH, Trofatter JA, MacCollin M, Tarttelin E, Gusella JF, Ramesh V (1994). "The murine NF2 homologue encodes a highly conserved merlin protein with alternative forms". Hum. Mol. Genet. 3 (3): 407–11. doi:10.1093/hmg/3.3.407. PMID 8012352.
^ Shimizu T, Seto A, Maita N, Hamada K, Tsukita S, Tsukita S, Hakoshima T (2002). "Structural basis for neurofibromatosis type 2. Crystal structure of the merlin FERM domain". J. Biol. Chem. 277 (12): 10332–6. doi:10.1074/jbc.M109979200. PMID 11756419.
^ McClatchey AI, Giovannini M (2005). "Membrane organization and tumorigenesis--the NF2 tumor suppressor, Merlin". Genes Dev. 19 (19): 2265–77. doi:10.1101/gad.1335605. PMID 16204178.
^ den Bakker MA, Vissers KJ, Molijn AC, Kros JM, Zwarthoff EC, van der Kwast TH (1999). "Expression of the neurofibromatosis type 2 gene in human tissues". J. Histochem. Cytochem. 47 (11): 1471–80. doi:10.1177/002215549904701113. PMID 10544220.
^ LaJeunesse DR, McCartney BM, Fehon RG (1998). "Structural Analysis of Drosophila Merlin Reveals Functional Domains Important for Growth Control and Subcellular Localization". J. Cell Biol. 141 (7): 1589–99. doi:10.1083/jcb.141.7.1589. PMC 2133006. PMID 9647651.
^ Alfthan K, Heiska L, Grönholm M, Renkema GH, Carpén O (2004). "Cyclic AMP-dependent protein kinase phosphorylates merlin at serine 518 independently of p21-activated kinase and promotes merlin-ezrin heterodimerization". J. Biol. Chem. 279 (18): 18559–66. doi:10.1074/jbc.M313916200. PMID 14981079.
^ Scoles DR, Yong WH, Qin Y, Wawrowsky K, Pulst SM (2006). "Schwannomin inhibits tumorigenesis through direct interaction with the eukaryotic initiation factor subunit c (eIF3c)". Hum. Mol. Genet. 15 (7): 1059–70. doi:10.1093/hmg/ddl021. PMID 16497727.
^ Gutmann, D H; Haipek C A, Burke S P, Sun C X, Scoles D R, Pulst S M (April 2001). "The NF2 interactor, hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), associates with merlin in the "open" conformation and suppresses cell growth and motility". Hum. Mol. Genet. (England) 10 (8): 825–34. doi:10.1093/hmg/10.8.825. ISSN 0964-6906. PMID 11285248. Cite uses deprecated parameters (help)
^ Scoles, D R; Huynh D P, Chen M S, Burke S P, Gutmann D H, Pulst S M (July 2000). "The neurofibromatosis 2 tumor suppressor protein interacts with hepatocyte growth factor-regulated tyrosine kinase substrate". Hum. Mol. Genet. (ENGLAND) 9 (11): 1567–74. doi:10.1093/hmg/9.11.1567. ISSN 0964-6906. PMID 10861283. Cite uses deprecated parameters (help)
^ ^a ^b ^c ^d Huang, J; Chen J (July 2008). "VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation". Oncogene (England) 27 (29): 4056–64. doi:10.1038/onc.2008.44. PMID 18332868. Cite uses deprecated parameters (help)
^ Grönholm, M; Sainio M, Zhao F, Heiska L, Vaheri A, Carpén O (March 1999). "Homotypic and heterotypic interaction of the neurofibromatosis 2 tumor suppressor protein merlin and the ERM protein ezrin". J. Cell. Sci. (ENGLAND) 112 (6): 895–904. ISSN 0021-9533. PMID 10036239. Cite uses deprecated parameters (help)
^ Jannatipour, M; Dion P, Khan S, Jindal H, Fan X, Laganière J, Chishti A H, Rouleau G A (August 2001). "Schwannomin isoform-1 interacts with syntenin via PDZ domains". J. Biol. Chem. (United States) 276 (35): 33093–100. doi:10.1074/jbc.M105792200. ISSN 0021-9258. PMID 11432873. Cite uses deprecated parameters (help)
^ Neill, G W; Crompton M R (September 2001). "Binding of the merlin-I product of the neurofibromatosis type 2 tumour suppressor gene to a novel site in beta-fodrin is regulated by association between merlin domains". Biochem. J. (England) 358 (Pt 3): 727–35. doi:10.1042/0264-6021:3580727. ISSN 0264-6021. PMC 1222106. PMID 11535133. Cite uses deprecated parameters (help)
^ Wiederhold, Thorsten; Lee Ming-Fen, James Marianne, Neujahr Ralph, Smith Nicole, Murthy Anita, Hartwig John, Gusella James F, Ramesh Vijaya (November 2004). "Magicin, a novel cytoskeletal protein associates with the NF2 tumor suppressor merlin and Grb2". Oncogene (England) 23 (54): 8815–25. doi:10.1038/sj.onc.1208110. ISSN 0950-9232. PMID 15467741. Cite uses deprecated parameters (help)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 神経線維腫症2型 neurofibromatosis type 2
2. 髄膜腫：疫学、危険因子と病理 meningioma epidemiology risk factors and pathology
3. 狭心症の新しい治療法 new therapies for angina pectoris
4. ST上昇型心筋梗塞における血栓溶解療法の失敗または切迫再梗塞のマネージメント management of failed fibrinolysis thrombolysis or threatened reocclusion in acute st elevation myocardial infarction
5. 脳腫瘍の危険因子 risk factors for brain tumors

English Journal

NHERF1/EBP50 and NF2 as diagnostic markers for choroid plexus tumors.

Georgescu MM1,2, Mobley BC3, Orr BA4, Shang P5, Lehman NL6, Zhu X7, O'Neill TJ8, Rajaram V5, Hatanpaa KJ5, Timmons CF5, Raisanen JM9.
Acta neuropathologica communications.Acta Neuropathol Commun.2016 May 27;4(1):55. doi: 10.1186/s40478-016-0329-0.
The adaptor protein NHERF1 (Na/H exchanger-3 regulatory factor-1) and its associated ezrin-radixin-moesin-merlin/neurofibromin-2 (ERM-NF2) family proteins are required for epithelial morphogenesis and have been implicated in cancer progression. NHERF1 is expressed in ependymal cells and constitutes
PMID 27229317

Clinical impact of targeted amplicon sequencing for meningioma as a practical clinical-sequencing system.

Yuzawa S1, Nishihara H2,3, Yamaguchi S4, Mohri H1, Wang L2, Kimura T2,3, Tsuda M1, Tanino M1, Kobayashi H4, Terasaka S4, Houkin K3,4, Sato N3, Tanaka S1,2.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.Mod Pathol.2016 Apr 22. doi: 10.1038/modpathol.2016.81. [Epub ahead of print]
Recent genetic analyses using next-generation sequencers have revealed numerous genetic alterations in various tumors including meningioma, which is the most common primary brain tumor. However, their use as routine laboratory examinations in clinical applications for tumor genotyping is not cost ef
PMID 27102344

Drosophila Schip1 Links Expanded and Tao-1 to Regulate Hippo Signaling.

Chung HL1, Augustine GJ2, Choi KW3.
Developmental cell.Dev Cell.2016 Mar 7;36(5):511-24. doi: 10.1016/j.devcel.2016.02.004.
Regulation of organ size is essential in animal development, and Hippo (Hpo) signaling is a major conserved mechanism for controlling organ growth. In Drosophila, Hpo and Warts kinases are core components of this pathway and function as tumor suppressors by inhibiting Yorkie (Yki). Expanded (Ex) is
PMID 26954546

Japanese Journal

Association of Caspr/paranodin with tumour suppressor schwannomin/merlin and beta1 integrin in the central nervous system

J Neurochem 84, 209-221, 2003
NAID 80015797548

Neuro-fibromatosis 2 tumour suppressor schwannomin interacts with betaII-spectrin

Nat Genet 18(4), 354-359, 1998
NAID 80010248858

Immunohistochemical detection of schwannomin and neurofibromin in vestibular schwannomas, ependymomas and meningiomas

J Neuropathol Exp Neurol 56, 382-390, 1997
NAID 30037202395

Related Pictures

Figure 5. Schwannomin inhibits IGF-I mediated activation of the SIE promoter element NCS NF2/Merlin and Neurofibromatosis 2 - ppt video online download 人 SCHIP1 ELISA Kit | ABIN2640855 Product No. Human Schwannomin Interacting Protein 1 (SCHIP1) Protein (GST tag), Recombinant Neural tumors Neurofibromin 2; Neurofibromatosis Type 2 Protein; Schwannomin anti-SCHIP1 antibody | Product No. ABIN1500821

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Neurofibromin 2 (merlin)
	; PDB rendering based on 1h4r.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1H4R, 3U8Z
Identifiers
Symbols	NF2; ACN; BANF; SCH
External IDs	OMIM: 607379 MGI: 97307 HomoloGene: 2180 GeneCards: NF2 Gene
Gene Ontology
Molecular function	• protein binding; • cytoskeletal protein binding;
Cellular component	• nucleus; • nucleolus; • cytoplasm; • early endosome; • cytoskeleton; • plasma membrane; • adherens junction; • extrinsic to membrane; • lamellipodium; • cortical actin cytoskeleton; • filopodium membrane; • cleavage furrow; • ruffle membrane; • perinuclear region of cytoplasm;
Biological process	• mesoderm formation; • negative regulation of cell-matrix adhesion; • negative regulation of protein kinase activity; • ectoderm development; • negative regulation of DNA replication; • negative regulation of cell proliferation; • Schwann cell proliferation; • negative regulation of cell-cell adhesion; • actin cytoskeleton organization; • negative regulation of cell migration; • regulation of hippo signaling cascade; • odontogenesis of dentin-containing tooth; • negative regulation of tyrosine phosphorylation of Stat3 protein; • negative regulation of tyrosine phosphorylation of Stat5 protein; • negative regulation of MAPK cascade; • cell-cell junction organization; • negative regulation of JAK-STAT cascade; • positive regulation of stress fiber assembly; • lens fiber cell differentiation;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	This box: view; talk; edit;

　　[★]

英: merlin
同: シュワノミン schwannomin, moesin-ezrin-radxin like protein
関: ニューロフィブロミン2 NF2、神経線維腫症2型、神経線維腫症

22q12.2に座乗する遺伝子であり、神経線維腫症2型の原因遺伝子とされている。(参考1)

参考

1. NEUROFIBROMATOSIS, TYPE II; NF2 - OMIM

http://omim.org/entry/101000

[pmid8379998-1] Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B (1993). "Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2". Nature 363 (6429): 515–21. doi:10.1038/363515a0. PMID 8379998.

[pmid16324214-2] Golovnina K, Blinov A, Akhmametyeva EM, Omelyanchuk LV, Chang LS (2005). "Evolution and origin of merlin, the product of the Neurofibromatosis type 2 (NF2) tumor-suppressor gene". BMC Evol. Biol. 5: 69. doi:10.1186/1471-2148-5-69. PMC 1315344. PMID 16324214.

[pmid8012352-3] Haase VH, Trofatter JA, MacCollin M, Tarttelin E, Gusella JF, Ramesh V (1994). "The murine NF2 homologue encodes a highly conserved merlin protein with alternative forms". Hum. Mol. Genet. 3 (3): 407–11. doi:10.1093/hmg/3.3.407. PMID 8012352.

[pmid11756419-4] Shimizu T, Seto A, Maita N, Hamada K, Tsukita S, Tsukita S, Hakoshima T (2002). "Structural basis for neurofibromatosis type 2. Crystal structure of the merlin FERM domain". J. Biol. Chem. 277 (12): 10332–6. doi:10.1074/jbc.M109979200. PMID 11756419.

[pmid16204178-5] McClatchey AI, Giovannini M (2005). "Membrane organization and tumorigenesis--the NF2 tumor suppressor, Merlin". Genes Dev. 19 (19): 2265–77. doi:10.1101/gad.1335605. PMID 16204178.

[pmid10544220-6] Bakker MA, Vissers KJ, Molijn AC, Kros JM, Zwarthoff EC, van der Kwast TH (1999). "Expression of the neurofibromatosis type 2 gene in human tissues". J. Histochem. Cytochem. 47 (11): 1471–80. doi:10.1177/002215549904701113. PMID 10544220.

[pmid9647651-7] LaJeunesse DR, McCartney BM, Fehon RG (1998). "Structural Analysis of Drosophila Merlin Reveals Functional Domains Important for Growth Control and Subcellular Localization". J. Cell Biol. 141 (7): 1589–99. doi:10.1083/jcb.141.7.1589. PMC 2133006. PMID 9647651.

[pmid14981079-8] Alfthan K, Heiska L, Grönholm M, Renkema GH, Carpén O (2004). "Cyclic AMP-dependent protein kinase phosphorylates merlin at serine 518 independently of p21-activated kinase and promotes merlin-ezrin heterodimerization". J. Biol. Chem. 279 (18): 18559–66. doi:10.1074/jbc.M313916200. PMID 14981079.

[pmid16497727-9] Scoles DR, Yong WH, Qin Y, Wawrowsky K, Pulst SM (2006). "Schwannomin inhibits tumorigenesis through direct interaction with the eukaryotic initiation factor subunit c (eIF3c)". Hum. Mol. Genet. 15 (7): 1059–70. doi:10.1093/hmg/ddl021. PMID 16497727.

[pmid11285248-10] Gutmann, D H; Haipek C A, Burke S P, Sun C X, Scoles D R, Pulst S M (April 2001). "The NF2 interactor, hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), associates with merlin in the "open" conformation and suppresses cell growth and motility". Hum. Mol. Genet. (England) 10 (8): 825–34. doi:10.1093/hmg/10.8.825. ISSN 0964-6906. PMID 11285248. Cite uses deprecated parameters (help)

[pmid10861283-11] Scoles, D R; Huynh D P, Chen M S, Burke S P, Gutmann D H, Pulst S M (July 2000). "The neurofibromatosis 2 tumor suppressor protein interacts with hepatocyte growth factor-regulated tyrosine kinase substrate". Hum. Mol. Genet. (ENGLAND) 9 (11): 1567–74. doi:10.1093/hmg/9.11.1567. ISSN 0964-6906. PMID 10861283. Cite uses deprecated parameters (help)

[pmid18332868-12] Huang, J; Chen J (July 2008). "VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation". Oncogene (England) 27 (29): 4056–64. doi:10.1038/onc.2008.44. PMID 18332868. Cite uses deprecated parameters (help)

[pmid10036239-13] Grönholm, M; Sainio M, Zhao F, Heiska L, Vaheri A, Carpén O (March 1999). "Homotypic and heterotypic interaction of the neurofibromatosis 2 tumor suppressor protein merlin and the ERM protein ezrin". J. Cell. Sci. (ENGLAND) 112 (6): 895–904. ISSN 0021-9533. PMID 10036239. Cite uses deprecated parameters (help)

[pmid11432873-14] Jannatipour, M; Dion P, Khan S, Jindal H, Fan X, Laganière J, Chishti A H, Rouleau G A (August 2001). "Schwannomin isoform-1 interacts with syntenin via PDZ domains". J. Biol. Chem. (United States) 276 (35): 33093–100. doi:10.1074/jbc.M105792200. ISSN 0021-9258. PMID 11432873. Cite uses deprecated parameters (help)

[pmid11535133-15] Neill, G W; Crompton M R (September 2001). "Binding of the merlin-I product of the neurofibromatosis type 2 tumour suppressor gene to a novel site in beta-fodrin is regulated by association between merlin domains". Biochem. J. (England) 358 (Pt 3): 727–35. doi:10.1042/0264-6021:3580727. ISSN 0264-6021. PMC 1222106. PMID 11535133. Cite uses deprecated parameters (help)

[pmid15467741-16] Wiederhold, Thorsten; Lee Ming-Fen, James Marianne, Neujahr Ralph, Smith Nicole, Murthy Anita, Hartwig John, Gusella James F, Ramesh Vijaya (November 2004). "Magicin, a novel cytoskeletal protein associates with the NF2 tumor suppressor merlin and Grb2". Oncogene (England) 23 (54): 8815–25. doi:10.1038/sj.onc.1208110. ISSN 0950-9232. PMID 15467741. Cite uses deprecated parameters (help)

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schwannomin