MME (membrane metallo-endopeptidase)

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MME (membrane metallo-endopeptidase)

Written	2007-05	Emina E Torlakovic
		Department of Pathology, The Norwegian Radium Hospital, University of Oslo Montebello, Oslo 0310 Norway

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)	CALLA
	CD10
	NEP
Other alias	common acute lymphocytic leukemia antigen (CALLA)
	DKFZp686O16152
	MGC126681
	MGC126707
	Kidney-brush-border neutral proteinase
	Neprilysin (NEP)
	Enkephalinase
	Atriopeptidase
	Endopeptidase-2
	Neutral endopeptidase
HGNC (Hugo)	MME
LocusID (NCBI)	4311
Atlas_Id	41386
Location	3q25.2 [Link to chromosome band 3q25]
Location_base_pair	Starts at 155080011 and ends at 155183729 bp from pter ( according to hg19-Feb_2009) [Mapping MME.png]

Fusion genes
(updated 2017)

Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

FAM172A (5q15) / MME (3q25.2)

MME (3q25.2) / MME (3q25.2)

Note

Membrane metallo-endopeptidase (MME) is a 100-kD type II transmembrane glycoprotein originally described on human acute lymphoblastic leukemia cell lines and therefore it was originally designated as common acute lymphocytic leukemia antigen (CALLA). MME is a neutral endopeptidase that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including atrial natriuretic factor, glucagon, enkephalin, substance P, neurotensin, oxytocin, and bradykinin. It is also a major enzyme for degradation of beta-amyloid.

DNA/RNA

Note	Gene:on chromosome 3 at location: 156284651-156384186 ; length: 99536 ; type: protein coding
Description	MME gene spans a region of 99536 bases and has 24 exons. Exons 1 and 2 encode 5' untranslated sequences. Initiation codon and transmembrane and cytoplasmic domain are encoded by exon 3, which has 170 bp. 20 short exons (exons 4-23) range in size from 36 to 162 bp. They encode large part of the extracellular portion of the enzyme. Exon 24 which has about 3400 bp encodes the COOH-terminal 32 amino acids and contains the entire 3' untranslated region (UTR). Exon 19 encodes the pentapeptide sequence associated with metalloproteinase zinc binding and substrate catalysis (His-Glu-Ile-Thr-His). The sequence is nearly identical to rat and rabbit NEP. Transcriptional regulation : MME is constitutively expressed in some tissues (kidney, adipose tissue, brain) and at some developmental stages in other (T- and B-lymphocytes, neutrophils). Its gene transcription is regulated by at least two alternative regulation regions including type 1 and type 2 promoter. Both regulatory regions are characterized by the presence of multiple transcription initiation sites and the absence of classic TATA boxes and consensus initiator elements. The purine-rich type 1 regulatory region, which includes 5' UTR exon 1 sequence, is characterized by multiple putative PU. l-binding sites and consensus ets-binding motifs. In marked contrast, the GC-rich type 2 regulatory region contains multiple putative Sp-l-binding sites, a potential consensus retinoblastoma control element (RCE); and an inverted CCAAT box. Type 2 promoter has a wide tissue distribution, a low constitutive level of expression, and multiple transcription initiation sites. However, normal and malignant lymphoid progenitors (fetal thymocytes and pre-B ALL) as well as fetal kidney and glioblastoma cell line A172 showed significantly higher levels of type 1 transcripts.
Transcription	The 5' untranslated region of this gene is alternatively spliced, resulting in four separate mRNA transcripts. The coding region is not affected by alternative splicing. The transcript variants 1, 1bis, and 2a contain an alternate 5' UTR exon, compared to variant 2b. The 2b variant is the longest transcript and includes alternate exon 2b. Variants 2b, 2a, 1bis and 1 all encode the same protein. Transcript variant 1 mRNA has 5643 bp. Transcript variant 1bis mRNA has 5619 bp. Transcript variant 2a mRNA has 5665 bp. Transcript variant 2b mRNA has 5710 bp. In normal human tissues, the highest mRNA levels were found in kidney, prostate, liver, and lung. Other tissues with high levels include whole blood, bone marrow, thymus, skeletal muscle, brain, ovary, testis, and placenta. Levels in lymph nodes and other secondary lymphoid tissues are dependent on the content of CD10+ B-cells in secondary germinal centers.

Protein

Note	MME belongs to peptidase family M13, which belongs to a peptidase superfamily known as the metzincins. These are zinc-dependent metallopeptidases. Family M13 also includes endothelin-converting enzyme 1 (ECE-1), Kell blood group glycoprotein, and peptidase O from Lactococcus lactis (gene pepO).

Description	MME protein contains 750 amino acids, and is a type-II membrane anchored enzyme known to inactivate oligopeptides. It has a single 24-amino acid hydrophobic segment that could function as both a transmembrane region and a signal peptide. The COOH-terminal 700 amino acids compose the extracellular protein segment, whereas the 25 NH2-terminal amino acids remaining after cleavage of the initiation methionine form the cytoplasmic tail.
Function	Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids. Biologically important in the destruction of opioid peptides by cleavage of a Gly-Phe bond. Involved in the degradation of atrial natriuretic factor. Preferential cleavage of polypeptides between hydrophobic residues, particularly with Phe or Tyr at P1'. Inhibited in a dose dependent manner by opiorphin. Inhibited by phosphoramidon and thiorphan.

Mutations

Note

Truncating mutations in the MME gene in mothers are the cause of alloimmunisation during pregnancy (1342 C to T nonsense mutation and 446delC). The absence of the MMP protein in pregnant women induces an alloimmunisation against MMP presented by fetus. Maternal antibodies attack fetal podocytes ensuing nephron loss, which could lead to chronic renal failure in early adulthood. This is the first model of idiopathic renal failure in early adulthood, which appears to be caused by immune-mediated fetal nephron loss.

Note

Entity	Alzheimer disease and normal aging
Note	Decreased MME expression in cerebral cortex correlates with amyloid-beta deposition but not with degeneration and dementia.


Entity	Enkephalin metabolism in anxiety
Note	A dinucleotide polymorphism in the 5' region of the MME gene was linked to type of anxiety.


Entity	T-cell apoptosis
Note	Both, CD8+ and CD4+ T-cells express MME upon induction of apoptosis in vitro as well as in apoptotic T-cells in vivo.


Entity	Low amplitude of the P300 evoked potential waves (linked to substance abuse)
Note	Based on the association of MME gene polymorphisms with P300 wave amplitudes of the parietal and coronal leads, it is suggested that MME plays a significant role in the regulation of the amplitude of the P300 wave. It is presumed that lower molecular weight alleles of the MME polymorphism are associated with increased levels of NEP and thus lower CNS enkephalin levels.


Entity	Recessive dystrophic epidermolysis bullosa
Note	In recessive dystrophic epidermolysis bullose, MME activities were considerably increased in the skin and blister fluid samples compared with values found in normal control skin and in blister fluid from a patient with a burn.


Entity	Acute lymphoblastic leukemia
Note	MME is expressed in majority acute lymphoblastic leukemias, in which MME was originally described as common acute lymphocytic leukemia antigen (CALLA). The role of MME in acute leukemia is not clear.


Entity	Burkitt lymphoma
Note	Burkitt lymphoma/leukemia was originally misclassified with acute lymphoblastic leukemia due to its expression of CD10 and blastic cytologic appearance. However, now it is correctly classified as mature B-cell neoplasm and expression of MME (referred as to CD10 in this context) is secondary to its germinal center stage of development. In normal B-cell development MME transitory reappears on B-cells in germinal centers.


Entity	Follicular lymphoma and other malignant lymphomas
Note	Follicular lymphomas originate from mature B-cells with germinal center stage of differentiation. Majority of follicular lymphomas typically express MME (referred to in this context as CD10) and its expression positively correlates with survival and negatively with the grade of follicular lymphoma. Other B-cell malignant lymphomas that typically express MME (CD10) are some diffuse large B-cell lymphomas (DLBCL) which are than subtyped as so-called germinal center type (GC-type DLBCL). Of T-cell lymphomas, angioimmunoblastic T-cell lymphoma typically shows expression of CD10.


Entity	Carcinoma
Note	MME is expressed in some carcinomas that originate in organs, which normally express high levels of MME, which is best illustrated in renal cell carcinoma. MME detection is important for identification of bile canaliculi, which appear by neogenesis in hepatocellular carcinoma. This feature is diagnostically useful in hepatocellular carcinoma. It is also expressed in many other carcinomas including prostate carcinoma, urothelial carcinoma, colorectal carcinoma, and others in which expression of higher levels of MME were associated with more aggressive tumors.


Entity	Melanoma
Note	Higher expression levels were associated with more aggressive disease.


Entity	Stromal cells
Note	Various benign stromal cells express MME. In particular, adipose tissue, endometrial stroma, and dendritic stromal cells in the bone marrow are know to express significant levels of MME. The role of MME in these tissue is not know. However, it possibly contributes to functional changes of the endometrial stromal in the secretory phase when its levels are highest in this tissue. It is also known that dendritic MME+ stromal cells of the bone marrow provide maturational niche for development of B-cells. Other MME+ benign stromal cells are induced by invasion of malignant tumors like melanoma, breast carcinoma, and others. In malignant stromal lesions MME has been found expressed in rhabdomyosarcoma, leiomyosarcoma and other sarcomas.


Entity	Juvenile idiopathic arthritis (JIA) and rheumatoid arthritis (RA)
Note	Circulating MME levels were lower in JIA patients than in controls, while synovial fluid values were higher than those found in circulation, which might reflect a reactive effort to control synovial proliferation. RA patients have higher levels of MME in plasma and synovial fluid than patients with osteoarthritis.


Entity	Acne
Note	Sebaceous glands in acne patients express high levels of MME. In addition, in vitro experiments using an organ culture system demonstrated that substance P induced expression MME in sebaceous glands in a dose dependent manner.


Entity	Idiopathic diffuse hyperplasia of pulmonary neuroendorine cells (IDHPNC)
Note	MME expression in patients with IDHPNC was compared with MME expression in patients with idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, and normal lung by using immunohistochemistry, ELISA, activity assay, and Western blot analysis. MME expression was highest in IDHPNC. Increased MME expression in lung tissue from patients with IDHPNC may reflect a compensatory increase that partly counteracts abundant neuropeptides, including BLP, present in this disorder.


Entity	Pathophysiology of ischemia/reperfusion myocardial injury
Note	MME expression was increased in the neutrophils from patients with early phase of acute myocardial infarction (AMI) by 5.2- and by 4.2-fold of the neutrophils from patients with late phase of AMI, respectively. ANP and BNP, which increase in AMI, modulate the neutrophil functions and exert protective effects against the neutrophils-induced endothelial cytotoxity at the physiological concentrations. But the effects are suppressed due to their degradation by the neutrophil own MME. Thus, neutrophil MME, which also increases in AMI, may play a role in the pathophysiology of ischemia/reperfusion myocardial injury.

	Nomenclature
HGNC (Hugo)	MME 7154
	Cards
Atlas	MMEID41386ch3q25
Entrez_Gene (NCBI)	MME 4311 membrane metalloendopeptidase
Aliases	CALLA; CD10; CMT2T; NEP;
	SCA43; SFE
GeneCards (Weizmann)	MME
Ensembl hg19 (Hinxton)	ENSG00000196549 [Gene_View]
Ensembl hg38 (Hinxton)	ENSG00000196549 [Gene_View] ENSG00000196549 [Sequence] chr3:155080011-155183729 [Contig_View] MME [Vega]
ICGC DataPortal	ENSG00000196549
TCGA cBioPortal	MME
AceView (NCBI)	MME
Genatlas (Paris)	MME
WikiGenes	4311
SOURCE (Princeton)	MME
Genetics Home Reference (NIH)	MME
	Genomic and cartography
GoldenPath hg38 (UCSC)	MME - chr3:155080011-155183729 + 3q25.2 [Description] (hg38-Dec_2013)
GoldenPath hg19 (UCSC)	MME - 3q25.2 [Description] (hg19-Feb_2009)
GoldenPath	MME - 3q25.2 [CytoView hg19] MME - 3q25.2 [CytoView hg38]
ImmunoBase	ENSG00000196549
Mapping of homologs : NCBI	MME [Mapview hg19] MME [Mapview hg38]
OMIM	120520 617017 617018
	Gene and transcription
Genbank (Entrez)	AK291761 AK310664 AL833459 BC101632 BC101658
RefSeq transcript (Entrez)	NM_000902 NM_001354642 NM_001354643 NM_001354644 NM_007287 NM_007288 NM_007289
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)	MME
Cluster EST : Unigene	Hs.307734 [ NCBI ]
CGAP (NCI)	Hs.307734
Alternative Splicing Gallery	ENSG00000196549
Gene Expression	MME [ NCBI-GEO ] MME [ EBI - ARRAY_EXPRESS ] MME [ SEEK ] MME [ MEM ]
Gene Expression Viewer (FireBrowse)	MME [ Firebrowse - Broad ]
SOURCE (Princeton)	Expression in : [Datasets] [Normal Tissue Atlas] [carcinoma Classsification] [NCI60]
Genevestigator	Expression in : [tissues] [cell-lines] [cancer] [perturbations]
BioGPS (Tissue expression)	4311
GTEX Portal (Tissue expression)	MME
Human Protein Atlas	ENSG00000196549-MME [pathology] [cell] [tissue]
	Protein : pattern, domain, 3D structure
UniProt/SwissProt	P08473 [function] [subcellular_location] [family_and_domains] [pathology_and_biotech] [ptm_processing] [expression] [interaction]
NextProt	P08473 [Sequence] [Exons] [Medical] [Publications]
With graphics : InterPro	P08473
Splice isoforms : SwissVar	P08473
PhosPhoSitePlus	P08473
Domaine pattern : Prosite (Expaxy)	ZINC_PROTEASE (PS00142)
Domains : Interpro (EBI)	MetalloPept_cat_dom_sf MME/CD10/NEP Peptidase_M13 Peptidase_M13_C Peptidase_M13_N
Domain families : Pfam (Sanger)	Peptidase_M13 (PF01431) Peptidase_M13_N (PF05649)
Domain families : Pfam (NCBI)	pfam01431 pfam05649
Conserved Domain (NCBI)	MME
DMDM Disease mutations	4311
Blocks (Seattle)	MME
PDB (RSDB)	1DL9 1DMT 1QVD 1R1H 1R1I 1R1J 1Y8J 2QPJ 2YB9 4CTH 5JMY
PDB Europe	1DL9 1DMT 1QVD 1R1H 1R1I 1R1J 1Y8J 2QPJ 2YB9 4CTH 5JMY
PDB (PDBSum)	1DL9 1DMT 1QVD 1R1H 1R1I 1R1J 1Y8J 2QPJ 2YB9 4CTH 5JMY
PDB (IMB)	1DL9 1DMT 1QVD 1R1H 1R1I 1R1J 1Y8J 2QPJ 2YB9 4CTH 5JMY
Structural Biology KnowledgeBase	1DL9 1DMT 1QVD 1R1H 1R1I 1R1J 1Y8J 2QPJ 2YB9 4CTH 5JMY
SCOP (Structural Classification of Proteins)	1DL9 1DMT 1QVD 1R1H 1R1I 1R1J 1Y8J 2QPJ 2YB9 4CTH 5JMY
CATH (Classification of proteins structures)	1DL9 1DMT 1QVD 1R1H 1R1I 1R1J 1Y8J 2QPJ 2YB9 4CTH 5JMY
Superfamily	P08473
Human Protein Atlas [tissue]	ENSG00000196549-MME [tissue]
Peptide Atlas	P08473
HPRD	00392
IPI	IPI00247063 IPI00654862 IPI00946548 IPI00945510 IPI00946944 IPI00945178 IPI00947417
	Protein Interaction databases
DIP (DOE-UCLA)	P08473
IntAct (EBI)	P08473
FunCoup	ENSG00000196549
BioGRID	MME
STRING (EMBL)	MME
ZODIAC	MME
	Ontologies - Pathways
QuickGO	P08473
Ontology : AmiGO	kidney development angiotensin maturation endopeptidase activity endopeptidase activity metalloendopeptidase activity metalloendopeptidase activity protein binding cytoplasm plasma membrane plasma membrane integral component of plasma membrane brush border focal adhesion proteolysis peptide metabolic process synaptic vesicle metallopeptidase activity exopeptidase activity zinc ion binding integral component of membrane sensory perception of pain axon dendrite secretory granule membrane peptide binding neutrophil degranulation neuron projection terminus synapse creatinine metabolic process amyloid-beta metabolic process extracellular exosome cellular response to cytokine stimulus cellular response to UV-A cellular response to UV-B replicative senescence amyloid-beta clearance
Ontology : EGO-EBI	kidney development angiotensin maturation endopeptidase activity endopeptidase activity metalloendopeptidase activity metalloendopeptidase activity protein binding cytoplasm plasma membrane plasma membrane integral component of plasma membrane brush border focal adhesion proteolysis peptide metabolic process synaptic vesicle metallopeptidase activity exopeptidase activity zinc ion binding integral component of membrane sensory perception of pain axon dendrite secretory granule membrane peptide binding neutrophil degranulation neuron projection terminus synapse creatinine metabolic process amyloid-beta metabolic process extracellular exosome cellular response to cytokine stimulus cellular response to UV-A cellular response to UV-B replicative senescence amyloid-beta clearance
Pathways : KEGG	Renin-angiotensin system Hematopoietic cell lineage Protein digestion and absorption Alzheimer's disease
REACTOME	P08473 [protein]
REACTOME Pathways	R-HSA-6798695 [pathway]
NDEx Network	MME
Atlas of Cancer Signalling Network	MME
Wikipedia pathways	MME
	Orthology - Evolution
OrthoDB	4311
GeneTree (enSembl)	ENSG00000196549
Phylogenetic Trees/Animal Genes : TreeFam	MME
HOGENOM	P08473
Homologs : HomoloGene	MME
Homology/Alignments : Family Browser (UCSC)	MME
	Gene fusions - Rearrangements
Fusion : FusionGDB	12655 22207 39272
Fusion : Fusion_Hub	ALMS1--MME COL6A3--MME FAM172A--MME LPIN2--MME MED15--MME MME--AMOTL2 MME--BCL6 MME--DLG2 MME--FN1 MME--KDSR MME--MET MME--MGMT MME--MME MME--TNS1 PLAGL1--MME
	SILV--MME SYCP2L--MME TPT1--MME
Fusion : Quiver	MME
	Polymorphisms : SNP and Copy number variants
NCBI Variation Viewer	MME [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)	MME
dbVar	MME
ClinVar	MME
1000_Genomes	MME
Exome Variant Server	MME
ExAC (Exome Aggregation Consortium)	ENSG00000196549
GNOMAD Browser	ENSG00000196549
Varsome Browser	MME
Genetic variants : HAPMAP	4311
Genomic Variants (DGV)	MME [DGVbeta]
DECIPHER	MME [patients] [syndromes] [variants] [genes]
CONAN: Copy Number Analysis	MME
	Mutations
ICGC Data Portal	MME
TCGA Data Portal	MME
Broad Tumor Portal	MME
OASIS Portal	MME [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMIC	MME [overview] [genome browser] [tissue] [distribution]
Mutations and Diseases : HGMD	MME
LOVD (Leiden Open Variation Database)	Whole genome datasets
LOVD (Leiden Open Variation Database)	LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)	LOVD 3.0 shared installation
BioMuta	search MME
DgiDB (Drug Gene Interaction Database)	MME
DoCM (Curated mutations)	MME (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)	MME (select a term)
intoGen	MME
NCG5 (London)	MME
Cancer3D	MME(select the gene name)
Impact of mutations	[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
	Diseases
OMIM	120520 617017 617018
Orphanet	23470
DisGeNET	MME
Medgen	MME
Genetic Testing Registry	MME
NextProt	P08473 [Medical]
TSGene	4311
GENETests	MME
Target Validation	MME
Huge Navigator	MME [HugePedia]
snp3D : Map Gene to Disease	4311
BioCentury BCIQ	MME
ClinGen	MME
	Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD	4311
Chemical/Pharm GKB Gene	PA30864
Clinical trial	MME
	Miscellaneous
canSAR (ICR)	MME (select the gene name)
DataMed Index	MME
	Probes
	Litterature
PubMed	293 Pubmed reference(s) in Entrez
GeneRIFs	Gene References Into Functions (Entrez)
CoreMine	MME
EVEX	MME
GoPubMed	MME
iHOP	MME

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed