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FLASH GENE

Symbol

ADAM12

contributors: mct/ - updated : 04-01-2017

HGNC name	ADAM metallopeptidase domain 12
HGNC id	190

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	10q26.2      Physical location : 127.702.901 - 128.077.127
Synonym name	a disintegrin and metalloproteinase domain 12 (meltrin alpha)
	meltrin alpha
Synonym symbol(s)	MLTN, MCMP, RP11-295J3.5, MLTNA, MCMPMltna, ADAM12-OT1, CAR10
EC.number	3.4.24.-

DNA

TYPE	functioning gene
STRUCTURE	376.17 kb     23 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

Map	cen - D10S1398E - D10S1602 - ADAM12 - D10S575 - D10S214 - qter

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003474 23 splicing 6093 NP_003465 - 909 membrane protein 2008 18621736 also called ADAM12L membrane-anchored long form having a cytoplasmic tail that interacts with several SH3 domain containing proteins including the Src-kinase SRC and YES1 contains extracellular prodomain (P), catalytic (C), disintegrin (D), cysteine-rich (CR), and epidermal growth factor-like (EGF) domains; a class I transmembrane region; and a cytoplasmic tail new role for ADAM12L in mediating the functional association of ILK with ITGB1 to regulate cell adhesion/survival through a PI3K/Akt signaling pathway is associated with EMT and contributes to TGFB1-dependent EMT by favoring both SMAD-dependent and SMAD-independent pathways NM_021641 19 splicing 3433 NP_067673 - 738 secreted form 2008 18621736 also called ADAM12S lacking the C-terminal transmembrane and cytoplasmic domains of ADAM12L (PMID: 20533908) the non-catalytic C-terminal domains of ADAM12-S regulate the catalytic activity (PMID: 20533908) active metalloprotease that cleaves IGFBP3 and -5 five extracellular domains and a unique stretch of 33 AAs at the C terminus proteolytic activity of trophoblast-derived ADAM12S, and likely ADAM12S exerts its pro-migratory function in trophoblasts by inducing ITGB1-mediated cellular spreading NM_001288973 23 - 8041 NP_001275902 - 906 - 2008 18621736 NM_001288975 19 - 3411 NP_001275904 - 735 - 2008 18621736 NM_001288974 19 - 3417 NP_001275903 - 737 - 2008 18621736

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular vessel         Homo sapiens Hearing/Equilibrium ear       highly Nervous brain       moderately Reproductive female system placenta     highly Homo sapiens   male system prostate     moderately Respiratory respiratory tract larynx     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective bone     highly Muscular smooth       Muscular striatum cardiac     Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial cell Homo sapiens Nervous oligodendrocyte

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

pregnancy

Text	term placenta

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a catalytic domain
	three zinc-binding histidines
	a catalytic glutamic acid in the conserved HEXXHXXGXXH motif
	a prodomain/catalytic domain cationic molecular switch, regulated by exogenous heparan sulfate and heparin but also endogenous cell surface proteoglycans and the polyanion, calcium pentosan polysulfate
	a Zn-binding site metalloproteinase
	a disintegrin-like domain
	a cysteine rich domains
	an EGF-like repeat
	a transmembrane domain
	a cytoplasmic tail, proteolytic activity (after cleavage of the prodomain at a site for a furin-like endopeptidase)
	a c-Src interaction site in the cytoplasmic domain required for the induction of invadopodia clusters

conjugated

GlycoP , MetalloP

HOMOLOGY

interspecies

homolog to murine maltrin alpha

Homologene

FAMILY

ADAM (a disintegrin and metalloprotease domain) family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,nucleus,nucleoplasm

basic FUNCTION	involved in tumor cell adhesion
	contribution to protease activity in pregnancy serum
	required for myotube formation and in osteoblast differentiation
	involved in the development of white adipose tissue, and in obesity induced by high- fat diet
	membrane-anchored metalloprotease, which has been implicated in activation-inactivation of growth factors that play an important role in wound healing
	increased expression of ADAM12 in chronic wounds impairs wound healing through the inhibition of keratinocyte migration
	would be functional in a highly chondroitin sulfate-rich environment
	multifunctional zinc-dependent enzyme, regulating
	the availability of bioreactive molecules, such as cell-surface receptors, growth factors and cytokines
	in normal tissue, may inhibit cell migration by mediating cell adhesion via integrin interactions, whereas, in tumor cells, higher levels of ADAM12-S proteolytic function stimulate cell migration and invasion
	constitutively internalized primarily via the clathrin-dependent pathway and is subsequently detected in both early and recycling endosomes
	ADAM12 internalization involves the clathrin-dependent pathway and GRB2
	can activate membrane-anchored proteins, such as SHH, DLL1 and certain epidermal growth factor receptor ligands, through a process called ectodomain shedding
	role for ADAM12 in ectodomain shedding of several membrane-anchored endothelial proteins and likely this process may have importance in tumour neovascularization or/and tumour cell extravasation
	function for ADAM12 in trophoblast biology, where ADAM12 may play a central role regulating the behavior of invasive trophoblast subsets in early pregnancy
	BSG and ADAM12 play a major role in cancer invasion and metastasis owing to the fact that they are directly related to the cell microenvironment and extracellular matrix (ECM) degradation
	function for ADAM12 in regulating trophoblast fusion
	novel role for ADAM12 in placental development, specifically important role in controlling the differentiation of villous cytotrophoblasts into multinucleated cellular structures
	ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function

CELLULAR PROCESS

protein, degradation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule	metal binding,
	Zn2+

protein	IGFBP3 and ACTN2, ACTN1 (acting on cell-cell adhesion or cell signaling during myoblast differentiatino and fusion)
	interacting with ITGB1 and ITGB3 (ADAM12-mediated focal adhesion formation is differently regulated by beta1 and beta3 integrins)
	may modulate cell adhesion and spreading through interaction with alpha1-integrin
	SKIL plays likely a role in regulating ADAM12 expression in response to TGFB1
	positive activation loop between ADAM12 and ERBB2 that may contribute to head and neck squamous cell carcinoma (HNSCC) progression
	ADAM12 enhanced EPHA1 cleavage in response to TGFB1 in primary tumors
	CDH1 is a novel ADAM12 substrate

cell & other

REGULATION

inhibited by	TIMP2 (TIMP2 exhibits high inhibitory
		activity against ADAM12)

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --other   aberrantly expressed in breast cancer patient urine, and increased urinary levels correlate with breast cancer progression tumoral     --over   in gastric carcinoma constitutional     --over   in osteoarthritic cartilage and enhances IGF1-mediated chondrocyte proliferation by degradation of insulin-like growth factor-binding protein IGFBP5 constitutional     --over   fivefold upregulated in the nonhealing edge of chronic ulcers compared to healthy skin tumoral     --low   hypomethylated in Triple-negative breast cancer (TNBC)

Susceptibility

to late-onset Alzheimer disease

Variant & Polymorphism other	interaction between the ADAM12 and SH3PXD2A genes may confer susceptibility to late-onset Alzheimer disease

Candidate gene	for rapid diagnostic of cancer (detection of urinary ADAM 12 may prove useful in the development of noninvasive diagnostic and prognostic tests for breast and perhaps other cancers)
	can be detected in the urine of breast and bladder cancer patients, and its levels have been shown to correlate with disease status, stage, and cancer risk
Marker	urinary MMP9/LCN2 and ADAM12 are potential noninvasive biomarkers for gastric cancer, including early-stage disease
	serum BSG and ADAM12 values and urine ADAM12 values may be useful markers in prostate cancer
	is a promising marker for the diagnosis of complete spontaneous abortion and ectopic pregnancy in symptomatic women, and under certain conditions, ADAM12 can diagnose ectopic pregnancy and spontaneous abortion before an ultrasonographic detection of the conditions
	ADAM12L may serve as a novel marker and/or a novel therapeutic target in breast tumor-initiating cells (BTICs)
	ADAM12 hypomethylation could be a poor outcome biomarker in Triple-negative breast cancer (TNBC)
Therapy target
	System Type Disorder Pubmed cancer reproductive breast may represent a potential therapeutic target in breast cancer immunology autoimmune articular treatment of patients with the heparin analog CaPPS may promote ADAM12 degradation of IGFBP 3 and stimulate chondrocyte proliferation in osteoarthritic cartilage cancer digestive oesophagus ADAM12L might be potential targets of esophageal carcinoma for anti-metastasis therapy miscelleaneous dermatology   topical ADAM12 inhibitors may therefore prove useful for the treatment of chronic wounds cancer reproductive breast potential therapeutic target in Triple-negative breast cancer (TNBC

ANIMAL & CELL MODELS