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Gene Section
Review
MME (membrane metallo-endopeptidase)
Emina E Torlakovic
Department of Pathology, The Norwegian Radium Hospital, University of Oslo Montebello, Oslo 0310,
Norway
Published in Atlas Database: May 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/MMEID41386ch3q25.html
DOI: 10.4267/2042/16960
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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 (Tand 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 etsbinding motifs. In marked contrast, the GC-rich type 2
regulatory region contains multiple putative Sp-lbinding 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.
Identity
Hugo: MME
Other names: common acute lymphocytic leukemia
antigen (CALLA); CD10; DKFZp686O16152;
MGC126681; MGC126707; Kidney-brush-border
neutral proteinase; Neprilysin (NEP); Enkephalinase;
Atriopeptidase; Endopeptidase-2;Neutral endopeptidase
Location: 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 betaamyloid.
DNA/RNA
Note: Gene: on chromosome 3 at location: 156284651156384186; length: 99536; type: protein coding.
Transcription
Description
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
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
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4)
304
MME (membrane metallo-endopeptidase)
Torlakovic EE
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.
Implicated in
Protein
T-cell apoptosis
Alzheimer disease and normal aging
Note: Decreased MME expression in cerebral cortex
correlates with amyloid-beta deposition but not with
degeneration and dementia.
Enkephalin metabolism in anxiety
Note: A dinucleotide polymorphism in the 5' region of
the MME gene was linked to type of anxiety.
Note: Both, CD8+ and CD4+ T-cells express MME
upon induction of apoptosis in vitro as well as in
apoptotic T-cells in vivo.
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).
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.
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 NH2terminal amino acids remaining after cleavage of the
initiation methionine form the cytoplasmic tail.
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.
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.
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.
Mutations
Burkitt lymphoma
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: 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.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4)
305
MME (membrane metallo-endopeptidase)
Torlakovic EE
in plasma and synovial fluid than patients with
osteoarthritis.
Follicular lymphoma and other
malignant lymphomas
Acne
Note: Follicular lymphomas originate from mature Bcells 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 socalled germinal center type (GC-type DLBCL). Of Tcell lymphomas, angioimmunoblastic T-cell lymphoma
typically shows expression of CD10.
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.
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.
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.
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.
Melanoma
Note: Higher expression levels were associated with
more aggressive disease.
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.
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This article should be referenced as such:
Torlakovic EE. MME (membrane metallo-endopeptidase). Atlas
Genet Cytogenet Oncol Haematol.2007;11(4):304-307.
Bilalovic N, Blystad AK, Golouh R, Nesland JM, Selak I, Trinh
D, Torlakovic E. Expression of bcl-6 and CD10 protein is
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307