Description: Homo sapiens neurofibromin 2 (merlin) (NF2), transcript variant 1, mRNA. RefSeq Summary (NM_000268): This gene encodes a protein that is similar to some members of the ERM (ezrin, radixin, moesin) family of proteins that are thought to link cytoskeletal components with proteins in the cell membrane. This gene product has been shown to interact with cell-surface proteins, proteins involved in cytoskeletal dynamics and proteins involved in regulating ion transport. This gene is expressed at high levels during embryonic development; in adults, significant expression is found in Schwann cells, meningeal cells, lens and nerve. Mutations in this gene are associated with neurofibromatosis type II which is characterized by nervous system and skin tumors and ocular abnormalities. Two predominant isoforms and a number of minor isoforms are produced by alternatively spliced transcripts. [provided by RefSeq, Jul 2008]. Transcript (Including UTRs) Position: hg19 chr22:29,999,545-30,094,589 Size: 95,045 Total Exon Count: 16 Strand: + Coding Region Position: hg19 chr22:29,999,988-30,090,791 Size: 90,804 Coding Exon Count: 16
ID:MERL_HUMAN DESCRIPTION: RecName: Full=Merlin; AltName: Full=Moesin-ezrin-radixin-like protein; AltName: Full=Neurofibromin-2; AltName: Full=Schwannomerlin; AltName: Full=Schwannomin; FUNCTION: Probable regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in tumor suppression by restricting proliferation and promoting apoptosis. Along with WWC1 can synergistically induce the phosphorylation of LATS1 and LATS2 and can probably function in the regulation of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway. May act as a membrane stabilizing protein. May inhibit PI3 kinase by binding to AGAP2 and impairing its stimulating activity. Suppresses cell proliferation and tumorigenesis by inhibiting the CUL4A-RBX1-DDB1-VprBP/DCAF1 E3 ubiquitin-protein ligase complex. SUBUNIT: Interacts with SLC9A3R1, HGS and AGAP2. Interacts with LAYN (By similarity). Interacts with SGSM3. Interacts (via FERM domain) with MPP1. Interacts with WWC1. Interacts with the CUL4A- RBX1-DDB1-VprBP/DCAF1 E3 ubiquitin-protein ligase complex. The unphosphorylated form interacts (via FERM domain) with VPRBP/DCAF1. INTERACTION: Q4VCS5:AMOT; NbExp=7; IntAct=EBI-1014472, EBI-2511319; Q4VCS5-1:AMOT; NbExp=2; IntAct=EBI-1014472, EBI-3903812; Q4VCS5-2:AMOT; NbExp=6; IntAct=EBI-1014472, EBI-3891843; Q9BZE4:GTPBP4; NbExp=9; IntAct=EBI-1014472, EBI-1056249; Q8NI35:INADL; NbExp=2; IntAct=EBI-1014472, EBI-724390; Q16584:MAP3K11; NbExp=4; IntAct=EBI-1014472, EBI-49961; Q9H204:MED28; NbExp=4; IntAct=EBI-1014472, EBI-514199; Q10728:Ppp1r12a (xeno); NbExp=2; IntAct=EBI-1014472, EBI-918263; Q3TI53:Schip1 (xeno); NbExp=2; IntAct=EBI-1014472, EBI-1397475; O14745:SLC9A3R1; NbExp=4; IntAct=EBI-1014500, EBI-349787; SUBCELLULAR LOCATION: Isoform 1: Cell projection, filopodium membrane; Peripheral membrane protein; Cytoplasmic side. Cell projection, ruffle membrane; Peripheral membrane protein; Cytoplasmic side. Nucleus. Note=In a fibroblastic cell line, isoform 1 is found homogeneously distributed over the entire cell, with a particularly strong staining in ruffling membranes and filopodia. Colocalizes with MPP1 in non-myelin-forming Schwann cells. Binds with VPRBP in the nucleus. The intramolecular association of the FERM domain with the C-terminal tail promotes nuclear accumulation. The unphosphorylated form accumulates predominantly in the nucleus while the phosphorylated form is largely confined to the non-nuclear fractions. SUBCELLULAR LOCATION: Isoform 7: Cytoplasm, perinuclear region. Cytoplasmic granule. Note=Observed in cytoplasmic granules concentrated in a perinuclear location. Isoform 7 is absent from ruffling membranes and filopodia. SUBCELLULAR LOCATION: Isoform 9: Cytoplasm, perinuclear region. Cytoplasmic granule. Note=Observed in cytoplasmic granules concentrated in a perinuclear location. Isoform 9 is absent from ruffling membranes and filopodia. SUBCELLULAR LOCATION: Isoform 10: Nucleus. Cell projection, filopodium membrane; Peripheral membrane protein; Cytoplasmic side. Cell projection, ruffle membrane; Peripheral membrane protein; Cytoplasmic side. Cytoplasm, perinuclear region. Cytoplasmic granule. Cytoplasm, cytoskeleton. Note=In a fibroblastic cell line, isoform 10 is found homogeneously distributed over the entire cell, with a particularly strong staining in ruffling membranes and filopodia. TISSUE SPECIFICITY: Widely expressed. Isoform 1 and isoform 3 are predominant. Isoform 4, isoform 5 and isoform 6 are expressed moderately. Isoform 8 is found at low frequency. Isoform 7, isoform 9 and isoform 10 are not expressed in adult tissues, with the exception of adult retina expressing isoform 10. Isoform 9 is faintly expressed in fetal brain, heart, lung, skeletal muscle and spleen. Fetal thymus expresses isoforms 1, 7, 9 and 10 at similar levels. PTM: Phosphorylation of Ser-518 inhibits nuclear localization by disrupting the intramolecular association of the FERM domain with the C-terminal tail. PTM: Ubiquitinated by the CUL4A-RBX1-DDB1-DCAF1/VprBP E3 ubiquitin-protein ligase complex for ubiquitination and subsequent proteasome-dependent degradation. DISEASE: Defects in NF2 are the cause of neurofibromatosis 2 (NF2) [MIM:101000]; also known as central neurofibromatosis. NF2 is a genetic disorder characterized by bilateral vestibular schwannomas (formerly called acoustic neuromas), schwannomas of other cranial and peripheral nerves, meningiomas, and ependymomas. It is inherited in an autosomal dominant fashion with full penetrance. Affected individuals generally develop symptoms of eighth-nerve dysfunction in early adulthood, including deafness and balance disorder. Although the tumors of NF2 are histologically benign, their anatomic location makes management difficult, and patients suffer great morbidity and mortality. DISEASE: Defects in NF2 are a cause of schwannomatosis (SCHWA) [MIM:162091]; also known as congenital cutaneous neurilemmomatosis. Schwannomas are benign tumors of the peripheral nerve sheath that usually occur singly in otherwise normal individuals. Multiple schwannomas in the same individual suggest an underlying tumor-predisposition syndrome. The most common such syndrome is NF2. The hallmark of NF2 is the development of bilateral vestibular-nerve schwannomas; but two-thirds or more of all NF2-affected individuals develop schwannomas in other locations, and dermal schwannomas may precede vestibular tumors in NF2-affected children. There have been several reports of individuals with multiple schwannomas who do not show evidence of vestibular schwannoma. Clinical report suggests that schwannomatosis is a clinical entity distinct from other forms of neurofibromatosis. DISEASE: Defects in NF2 may be a cause of mesothelioma malignant (MESOM) [MIM:156240]. An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos. SIMILARITY: Contains 1 FERM domain. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/NF2117.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/NF2";
Carotid atherosclerosis in HIV infection Shrestha ,et al. 2010, A genome-wide association study of carotid atherosclerosis in HIV-infected men, AIDS (London, England) 2009 .
[PubMed 20009918]
These results suggest that in the context of HIV infection and HAART, a functional SNP in a biologically plausible candidate gene, RYR3, is associated with increased common carotid IMT, which is a surrogate for atherosclerosis.
Neurofibromatosis type 2 Kluwe L et al. 1998, Phenotypic variability associated with 14 splice-site mutations in the NF2 gene., American journal of medical genetics. 1998 May;77(3):228-33.
[PubMed 9605590]
neurofibromatosis2 Baser, M. E. et al. 2004, Genotype-phenotype correlations for nervous system tumors in neurofibromatosis 2: a population-basedstudy., American journal of human genetics. 2004 Aug;75(2):231-9.
[PubMed 15190457]
We found statistically significant genotype-phenotype correlations for intracranial meningiomas, spinal tumors, and peripheral nerve tumors. People with constitutional NF2 missense mutations, splice-site mutations, large deletions, or somatic mosaicism had significantly fewer tumors than did people with constitutional nonsense or frameshift NF2 mutations. In addition, there were significant intrafamilial correlations for intracranial meningiomas and spinal tumors, after adjustment for the type of constitutional NF2 mutation. The type of constitutional NF2 mutation is an important determinant of the number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF00373 - FERM central domain PF00769 - Ezrin/radixin/moesin family PF09379 - FERM N-terminal domain PF09380 - FERM C-terminal PH-like domain
SCOP Domains: 47031 - Second domain of FERM 48678 - Moesin tail domain 50729 - PH domain-like 54236 - Ubiquitin-like
ModBase Predicted Comparative 3D Structure on P35240
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0001707 mesoderm formation GO:0001953 negative regulation of cell-matrix adhesion GO:0006469 negative regulation of protein kinase activity GO:0007398 ectoderm development GO:0007420 brain development GO:0008285 negative regulation of cell proliferation GO:0014010 Schwann cell proliferation GO:0014013 regulation of gliogenesis GO:0021766 hippocampus development GO:0022408 negative regulation of cell-cell adhesion GO:0030036 actin cytoskeleton organization GO:0030336 negative regulation of cell migration GO:0031647 regulation of protein stability GO:0035330 regulation of hippo signaling GO:0042127 regulation of cell proliferation GO:0042475 odontogenesis of dentin-containing tooth GO:0042532 negative regulation of tyrosine phosphorylation of STAT protein GO:0042981 regulation of apoptotic process GO:0043409 negative regulation of MAPK cascade GO:0045216 cell-cell junction organization GO:0045597 positive regulation of cell differentiation GO:0046426 negative regulation of JAK-STAT cascade GO:0050767 regulation of neurogenesis GO:0051496 positive regulation of stress fiber assembly GO:0051726 regulation of cell cycle GO:0070306 lens fiber cell differentiation GO:0072091 regulation of stem cell proliferation GO:1900180 regulation of protein localization to nucleus GO:2000177 regulation of neural precursor cell proliferation
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