関: merlin

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/06/14 20:25:15」(JST)

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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

Human merlin is coded by the gene NF2 in Chromosome 22. Mouse merlin gene is located on chromosome 11^[3] and rat merlin gene on 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 an alpha-helical domain and a hydrophilic tail.^[4] 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.^[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 glands, 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

Merlin (protein) has been shown to interact with:

CUL4A,^[10]
DDB1,^[10]
EZR,^[11]
HGS,^[12]^[13]
MED28,^[14]
RIT1,^[10]
SDCBP,^[15]
SPTBN1,^[16] and
VPRBP.^[10]

References

^ 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.
^ ^a ^b ^c ^d Huang J, Chen J (July 2008). "VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation". Oncogene 27 (29): 4056–64. doi:10.1038/onc.2008.44. PMID 18332868.
^ 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. 112 ( Pt 6): 895–904. PMID 10036239.
^ Gutmann DH, Haipek CA, Burke SP, Sun CX, Scoles DR, Pulst SM (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. 10 (8): 825–34. doi:10.1093/hmg/10.8.825. PMID 11285248.
^ Scoles DR, Huynh DP, Chen MS, Burke SP, Gutmann DH, Pulst SM (July 2000). "The neurofibromatosis 2 tumor suppressor protein interacts with hepatocyte growth factor-regulated tyrosine kinase substrate". Hum. Mol. Genet. 9 (11): 1567–74. doi:10.1093/hmg/9.11.1567. PMID 10861283.
^ Wiederhold T, Lee MF, James M, Neujahr R, Smith N, Murthy A, Hartwig J, Gusella JF, Ramesh V (November 2004). "Magicin, a novel cytoskeletal protein associates with the NF2 tumor suppressor merlin and Grb2". Oncogene 23 (54): 8815–25. doi:10.1038/sj.onc.1208110. PMID 15467741.
^ Jannatipour M, Dion P, Khan S, Jindal H, Fan X, Laganière J, Chishti AH, Rouleau GA (August 2001). "Schwannomin isoform-1 interacts with syntenin via PDZ domains". J. Biol. Chem. 276 (35): 33093–100. doi:10.1074/jbc.M105792200. PMID 11432873.
^ Neill GW, Crompton MR (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. 358 (Pt 3): 727–35. doi:10.1042/0264-6021:3580727. PMC 1222106. PMID 11535133.

External links

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

UpToDate Contents

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1. 遺伝性皮膚症 the genodermatoses
2. 前庭神経鞘腫（聴神経腫） vestibular schwannoma acoustic neuroma
3. 神経線維腫症I型（NF1）：病因、臨床的特徴、および診断 neurofibromatosis type 1 nf1 pathogenesis clinical features and diagnosis
4. 脳腫瘍の危険因子 risk factors for brain tumors
5. 視神経膠腫 optic pathway glioma

English Journal

Merlin's wizardry guides cohesive migration.

Zoch A1, Morrison H1.
Nature cell biology.Nat Cell Biol.2015 Mar;17(3):212-3. doi: 10.1038/ncb3126.
Cells often migrate in tightly connected groups with coordinated movement and polarity. The collective migration of epithelial cell sheets is now shown to be mediated by a signalling axis that involves the merlin tumour-suppressor protein, the tight-junction-associated angiomotin-Rich1 complex and t
PMID 25720961

A molecular mechanotransduction pathway regulates collective migration of epithelial cells.

Das T1, Safferling K2, Rausch S1, Grabe N2, Boehm H1, Spatz JP1.
Nature cell biology.Nat Cell Biol.2015 Mar;17(3):276-87. doi: 10.1038/ncb3115. Epub 2015 Feb 23.
Collective movement of epithelial cells drives essential multicellular organization during various fundamental physiological processes encompassing embryonic morphogenesis, cancer and wound healing. Yet the molecular mechanism that ensures the coordinated movement of many cells remains elusive. Here
PMID 25706233

Nf2-Yap signaling controls the expansion of DRG progenitors and glia during DRG development.

Serinagaoglu Y1, Paré J1, Giovannini M2, Cao X3.
Developmental biology.Dev Biol.2015 Feb 1;398(1):97-109. doi: 10.1016/j.ydbio.2014.11.017. Epub 2014 Nov 26.
Molecular mechanisms governing the maintenance and proliferation of dorsal root ganglia (DRG) progenitors are largely unknown. Here we reveal that the Hippo pathway regulates the expansion of DRG progenitors and glia during mammalian DRG development. The key effectors of this pathway, transcriptiona
PMID 25433207

Japanese Journal

神経線維腫症I型（neurofibromatosis 1：NF1）に合併した胆管内乳頭状腫瘍（Intraductal papillary neoplasm of the bile duct：IPNB）の1例

胆道 29(4), 782-789, 2015
NAID 130005108696

教育講演 NF 1に随伴する褐色細胞腫

日本レックリングハウゼン病学会雑誌 5(1), 7-11, 2014-04
NAID 40020239050

Solitary Epicranial Neurofibroma With NF1-Related Germline Mutation: Case Report

Neurologia medico-chirurgica 54(4), 310-313, 2014
NAID 130003383228

「ニューロフィブロミン2」

NF2
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	4ZRJ, 1H4R, 3U8Z, 4ZRI
Identifiers
Aliases	NF2, ACN, BANF, SCH, neurofibromin 2 (merlin)
External IDs	OMIM: 607379 MGI: 97307 HomoloGene: 2180 GeneCards: 4771
Gene ontology
Molecular function	• beta-catenin binding; • protein domain specific binding; • cytoskeletal protein binding; • integrin binding; • protein binding; • actin binding;
Cellular component	• cytoplasm; • cell body; • cell projection; • membrane; • filopodium; • ruffle; • adherens junction; • plasma membrane; • apical part of cell; • synapse; • protein complex; • ruffle membrane; • early endosome; • nucleolus; • cortical actin cytoskeleton; • perinuclear region of cytoplasm; • membrane raft; • neuron projection; • cleavage furrow; • cytoskeleton; • nucleus; • lamellipodium; • extrinsic component of membrane; • filopodium membrane;
Biological process	• negative regulation of tyrosine phosphorylation of Stat3 protein; • negative regulation of JAK-STAT cascade; • regulation of gliogenesis; • cell-cell junction organization; • regulation of protein stability; • negative regulation of cell-cell adhesion; • negative regulation of protein kinase activity; • negative regulation of tyrosine phosphorylation of Stat5 protein; • small GTPase mediated signal transduction; • mesoderm formation; • ectoderm development; • negative regulation of DNA replication; • Schwann cell proliferation; • regulation of neural precursor cell proliferation; • regulation of protein localization to nucleus; • negative regulation of cell-matrix adhesion; • odontogenesis of dentin-containing tooth; • brain development; • negative regulation of cell migration; • lens fiber cell differentiation; • regulation of cell proliferation; • negative regulation of cell growth; • positive regulation of cell differentiation; • negative regulation of MAPK cascade; • regulation of hippo signaling; • hippocampus development; • regulation of stem cell proliferation; • regulation of neurogenesis; • actin cytoskeleton organization; • positive regulation of stress fiber assembly; • negative regulation of cell proliferation;
	Sources:Amigo / QuickGO
RNA expression pattern
	; ; ; ;
	More reference expression data
Orthologs
	4771
	18016
	ENSG00000186575
	ENSMUSG00000009073
	P35240
	P46662
NM_181835; NM_000268; NM_016418; NM_181825; NM_181826;
	NM_181827; NM_181828; NM_181829; NM_181830; NM_181831; NM_181832; NM_181833; NM_181834
	NM_001252250; NM_001252251; NM_001252252; NM_001252253; NM_010898
NP_000259.1; NP_057502.2; NP_861546.1; NP_861966.1; NP_861967.1;
	NP_861968.1; NP_861969.1; NP_861970.1; NP_861971.1
	NP_001239179.1; NP_001239180.1; NP_001239181.1; NP_001239182.1; NP_035028.2
	Wikidata
View/Edit Human	View/Edit Mouse

　　[★]

英: neurofibromin 2
関: マーリン

「neurofibromin」

　　[★] ニューロフィブロミン

[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.

[pmid18332868-10] Huang J, Chen J (July 2008). "VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation". Oncogene 27 (29): 4056–64. doi:10.1038/onc.2008.44. PMID 18332868.

[pmid10036239-11] 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. 112 ( Pt 6): 895–904. PMID 10036239.

[pmid11285248-12] Gutmann DH, Haipek CA, Burke SP, Sun CX, Scoles DR, Pulst SM (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. 10 (8): 825–34. doi:10.1093/hmg/10.8.825. PMID 11285248.

[pmid10861283-13] Scoles DR, Huynh DP, Chen MS, Burke SP, Gutmann DH, Pulst SM (July 2000). "The neurofibromatosis 2 tumor suppressor protein interacts with hepatocyte growth factor-regulated tyrosine kinase substrate". Hum. Mol. Genet. 9 (11): 1567–74. doi:10.1093/hmg/9.11.1567. PMID 10861283.

[pmid15467741-14] Wiederhold T, Lee MF, James M, Neujahr R, Smith N, Murthy A, Hartwig J, Gusella JF, Ramesh V (November 2004). "Magicin, a novel cytoskeletal protein associates with the NF2 tumor suppressor merlin and Grb2". Oncogene 23 (54): 8815–25. doi:10.1038/sj.onc.1208110. PMID 15467741.

[pmid11432873-15] Jannatipour M, Dion P, Khan S, Jindal H, Fan X, Laganière J, Chishti AH, Rouleau GA (August 2001). "Schwannomin isoform-1 interacts with syntenin via PDZ domains". J. Biol. Chem. 276 (35): 33093–100. doi:10.1074/jbc.M105792200. PMID 11432873.

[pmid11535133-16] Neill GW, Crompton MR (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. 358 (Pt 3): 727–35. doi:10.1042/0264-6021:3580727. PMC 1222106. PMID 11535133.

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neurofibromin 2