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FLASH GENE

Symbol

MMP14

contributors: mct - updated : 22-10-2016

HGNC name	matrix metalloproteinase 14 (membrane-inserted)
HGNC id	7160

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
SPECIAL FEATURE
text	member of the MMP cluster
STRUCTURE	11.01 kb     10 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
text structure	at the 5' putative regulatory elements including one SP1 site and four CCAAT boxes, promoter with distinctive structure

MAPPING

cloned

Y

linked

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004995 10 - 3558 NP_004986 - 582 - 2005 16219679

EXPRESSION

Type	ubiquitous

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 Digestive mouth tongue     highly   pharynx       highly Endocrine thyroid       highly Reproductive male system testis       Rattus norvegicus Fetal Respiratory respiratory tract larynx     highly Skeleton   breast       Mus musculus

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective bone

cells

System Cell Pubmed Species Stage Rna symbol Reproductive germ cell Rattus norvegicus Fetal Skeleton osteoblast Mus musculus

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

pregnancy

Text

placenta

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	four hemoplexin-like domains
	an extracellular domain connected to extracellular matrix, while its intracellular domain is a strong modulator of cell signaling

conjugated

MetalloP

isoforms

Precursor

cleaved by a furin endopeptidase

HOMOLOGY

interspecies	homolog to murine Mmp14 (96.2pc)
	homolog to rattus Mmp14 (96.7pc)

Homologene

FAMILY

peptidase M10A family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION

plasma membrane

basic FUNCTION	regulator of matrix remodeling
	initiating pro-MMP2 activation by a process tightly regulated by TIMP2
	activating MMP13
	participates in kidney tubulogenesis and epithelial cells migration
	having a role in reduced cell adhesion and spreading
	catalyzing the cleavage of APP
	mediating MUC1 shedding independent of ADAM17
	degrades the extracellular matrix, initiates the activation pathway of soluble MMPs and regulates the functionality of cell adhesion signaling receptors, thus playing an important role in many cell functions
	cleaving MMP14, directly, rather than indirectly
	with TIMP2, control cell proliferation and migration through a non-proteolytic mechanism
	role for MMP14/TIMP-2 interaction, in controling cell functions by a mechanism independent of extracellular matrix degradation
	activating MMP2 on the tumor cell surface and thus may be involved in tumor invasion
	involved in endothelial cell tubulogenesis during vascular morphogenesis
	master regulator of the pathologic extracellular matrix remodeling that characterizes rheumatoid arthritis as well as the coupled angiogenic response that maintains the aggressive phenotype of the advancing pannus
	cleaving BCAM (Lu protein)
	plays a required role in mesenchymal stem cell-mediated collagenolysis, 3D invasion and intravasation
	plays a role in both inflammation and the onset of multiple sclerosis and, potentially, other neuroimmune diseases
	membrane-anchored metalloproteinase that mediates pericellular proteolysis of a wide range of extracellular matrix proteins including type-I collagen
	zinc-dependent type-I transmembrane metalloproteinase involved in pericellular proteolysis, migration and invasion
	regulates KDR cell surface localisation and forms a complex with KDR and SRC that is dependent on the MMP14 hemopexin domain and independent of its catalytic activity
	promotes macrophage migration in a non-proteolytic manner
	having APBA3-dependent and APBA3-independent activities (APBA3-dependent mechanism represents the effect of MMP14 on ATP production in macrophages)
	MMP14 and MMP19 are proteolytic enzymes potentially involved in aneurysm formation in the ascending aorta of patients with tricuspid aortic valves
	crucial regulator of fibronectin turnover
	regulates ECM fibronectin remodeling by promoting extracellular cleavage of fibronectin and by regulating ITGA5/B1-integrin endocytosis
	plays a role in osteocyte mechanosensing by affecting the osteocyte response to mechanical loading
	regulating HIF-mediated chemokine/cytokine gene transcription within niche cells
	its expression in keratinocytes is dispensable for skin homeostasis and repair, but plays a crucial role in the epidermal-dermal crosstalk leading to modulation of vessel density
	membrane-tethered metalloproteinase MMP14, capable of remodeling the extracellular matrix and modulating receptors on the cell surface
	MMP14 and MMP19 have been demonstrated to play an important role in the development of human gliomas
	functions in part as a pericellular activator of MMP2
	is the only MT-MMP that contributes to soluble endoglin production in pre-eclampsia
	play an important role in invasion and metastasis of human solid tumor
	prevents growth inhibition by three dimensional fibronectin matrix
	may play role in regulating angiogenesis in human endothelial cells

CELLULAR PROCESS

cell migration & motility

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

central pathway involving MMP14 and TGFbeta that mediates vessel stability and vascular response to tissue injury

a component

forms a complex with FGFR2 and ADAM9 in osteoblasts

INTERACTION

DNA

RNA

small molecule	metal binding,
	Ca2+
	Zn2+

protein	interacting with BSGN
	CLDN5
	MMP2
	CSF2
	NANOS1, by regulating MMP14 expression, plays an important role in the acquisition of invasive properties by epithelial tumor cells
	binding TIMPs in a 1:1 stoechiometry, stimulating invasion-promoting MEK/ERK signaling in cancer cells
	binds tissue inhibitor of metalloproteinases-2 (TIMP2), activates matrix metalloproteinase-2 (MMP2), and stimulates cell migration in various cell types
	MMP14 and FURIN were found to co-localize with Golgi reassembly stacking protein 55 (GORASP2)
	interacting with CD9 (CD9 appears to, at least in part, contribute to the delocalization of integrins and MMP14, disruption of which may prevent angiogenesis)
	activates HIF1A via APBA3 in many types of cell so as to stimulate glycolysis
	inactivates ADAM9, hence protecting FGFR2 from ADAM9-mediated ectodomain shedding on the cell surface
	in actively invading cells, WASL promoted trafficking of MMP14 into invasive pseudopodia, primarily from late endosomes, from which it was delivered to the plasma membrane
	direct interactions between cellular MMP14 and PTK7 that constitute an evolutionary conserved master switch in directional cell motility
	TACR1 was a potential regulator of human glioma cell migration by the up-regulation of MMP2 and MMP14
	MMP14 cleaved EPHA2 at its Fibronectin type-III domain 1
	MMP14 is an up-stream regulator for MMP2 and TIMP2 expression
	WASH1 and exocyst are required for matrix degradation by an exocytic mechanism that involves tubular connections between MMP14–positive late endosomes and the plasma membrane in contact with the matrix
	MMP14 proteolysis of BRCA2 regulates the abundance of BRCA2 on centrosomes
	CD81 stimulates melanoma cell motility by inducing MMP14 expression through the AKT1-dependent Sp1 activation signaling pathway, leading to increased melanoma invasion and metastasis
	TGFB1I1 appears to enhance complex formation between MMP14 and PTK2 in activated endothelial cells, which likely coordinates matrix proteolysis and cell motility
	MMP14 inhibits the tetherin activity of BST2 by interacting with BST2, and the cytoplasmic domains of both BST2 and MMP14 play critical roles within this interaction

cell & other

REGULATION

activated by

furin (intracellularly) and proteinases

inhibited by	prolonged or reduced hypoxia
	TFPI2
	RECK

Other	TIMP2,promoting the availability of active MMP14 and active pericellular proteolysis,inhibiting MMP14 autocatalysis to the 44kDa form
	regulated by claudin
	regulated on the cell surface through a vacuolar H(+)-ATPase-dependent degradation process

ASSOCIATED DISORDERS

corresponding disease(s)

WINCH2

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in oral squamous cell carcinoma (OSCC) with lymph node metastasis constitutional     --over   in keratoconus cornea tumoral       gain of function in head and neck cancer (by CSF2)and in melanoma in progression tumoral     --over   in glioma-associated microglia constitutional     --over   reduced corneal opacity and expression of the major genes involved in corneal scarring, especially type III collagen and alpha-smooth muscle actin tumoral     --over   in human gastric cancer and its association with tumor progression

Susceptibility

to chronic obstructive pulmonary

Variant & Polymorphism other	haplotype -165 T : +221 T : +6727 C : +7096 C, might be involved in the pathogenesis of chronic obstructive pulmonary disease

Candidate gene	tyrosine-phosphorylated MMP14 plays an important role in neuroblastoma progression and its expression is preferentially observed in tumor specimens from neuroblastoma patients showing poor clinical outcome
Marker
Therapy target
	System Type Disorder Pubmed cancer brain   targeted inhibition of MMP14 or SLC37A4 may lead to reduced infiltrative and invasive properties of brain tumor cells

ANIMAL & CELL MODELS

Mt1-Mmp-/- mice had a lower number of empty lacunae and a higher osteocyte density