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FLASH GENE

Symbol

MME

contributors: mct - updated : 11-10-2016

HGNC name	membrane metallo-endopeptidase
HGNC id	7154

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a single 24-amino acid hydrophobic segment that could function as both a transmembrane region and a signal peptide
	a conserved pentapeptide zinc binding motif (HEXXH)
	a second zinc binding motif and 10 cysteine residues
	C-terminal 700 amino acids, including six potential N-linked glycosylation sites composing the extracellular protein segment

conjugated

GlycoP , MetalloP

HOMOLOGY

Homologene

FAMILY

peptidase M13 family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm
	intracellular,nucleus
text	transmembrane glycoprotein type II
	only the mature form of MME, which has been glycosylated in the Golgi, exists in lipid rafts, where it is directly associated with phosphatidylserine

basic FUNCTION	playing a role in regulating cerebral amyloid deposition
	has proteolytic activity toward beta-amyloid, suggesting a possible association with Alzheimer disease
	involved in lowering of brain APP due to plasma MME which altered blood-brain APP transport dynamics
	fibroblastic MME expression may down-regulate skin inflammation by degrading TAC1 or reducing its level in the dermal microenvironment
	neutral endopeptidase, that is one of the major APP-degrading enzymes in the brain
	plays potentially a relevant role in renal embryogenesis
	contributes to free fatty acid (FFA)-induced cellular dysfunction in nonislet tissues in type 2 diabetes
	MME activity in the skin was elevated at early anagen, and decreased during catagen to telogen
	plays likely an important role in regulating the hair cycle by its increased expression and activity in the follicular epithelium during early anagen
	might be involved in the development of endometriosis due to its influence on CD44-dependent cell adhesion
	important, previously neglected, role of MME for regulation of luminal factors in the epididymis

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

protein constituent of transmembrane

INTERACTION

DNA

RNA

small molecule

protein	cleaves and inactivates various neuropeptides and peptide hormones, including glucagon, enkephalins, TAC1, neurotensin, oxytocin, and bradykinin
	APP-degrading protease neprilysin (MME) is down-regulated in normal aging and late-onset form of Alzheimer disease (LOAD)
	estrogen stimulates degradation of APP by up-regulating MME, reducing risk for Alzheimer
	TAC1 in pulmonary and synovial cells is degraded by MME
	MME protected against beta cell cytotoxicity induced by exogenously added or endogenously produced human IAPP
	major regulator of bioactivity of natriuretic peptides
	MME up-regulation might be an adaptive response to hypoxia, which was mediated by HIF1A binding to HDAC1 at the early stage of hypoxia

cell & other

REGULATION

induced by

PRKCE; specific PRKCE activation directly stimulated MME activity, leading to degradation of a monomeric form of APP peptide and decreased APP neuronal toxicity

inhibited by

PROL1

Other

developmentally regulated in other cell types, i.e. lymphocytes

ASSOCIATED DISORDERS

corresponding disease(s)

CMT2T , SCA43

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in acute lymphoblastic leukemias constitutional germinal mutation       truncating mutations causing alloimmunisation during pregnancy and diopathic renal failure in early adulthood (might be caused by immune-mediated fetal nephron loss) constitutional       gain of function per se mediates insulin secretory dysfunction tumoral       loss of function hypoxia negatively regulates the tumor suppressor function of MME in prostate cancer tumoral     --low   in prostate cancer constitutional       loss of function reduction in MME and IDE activity is not the primary cause of APP accumulation in Alzheimer disease, but rather a late-stage phenomenon secondary to neurodegeneration

Susceptibility

to late-onset Alzheimer's disease

Variant & Polymorphism

Candidate gene	for the development of alternative therapies for Alzheimer's disease
Marker	tumoral MME expression correlated with aggressive histologic types and higher mitotic activity and is an independent prognostic factor for patients with malignant pleural mesothelioma
Therapy target
	System Type Disorder Pubmed neurology neurodegenerative alzheimer recombinant brain-targeted neprilysin, ASN12, may be an effective treatment for AD and warrant further investigation in clinical trials diabete     interventions to inhibit neprilysin may improve beta-cell function in obese humans with type 2 diabetes cancer reproductive prostate upregulation of MME may provide a novel therapeutic strategy in prostate cancer

ANIMAL & CELL MODELS

mice deficient in neprilysin showed no obvious degenerative changes in peripheral nerves