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FLASH GENE

Symbol

MMP9

contributors: mct/pgu - updated : 24-04-2019

HGNC name	matrix metalloproteinase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase)
HGNC id	7176

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	MAND1 metaphyseal anadysplasia 1
Location	20q13.12      Physical location : 44.637.546 - 44.645.199
Synonym name	92 kDa gelatinase
	gelatinase B
	type V collagenase
Synonym symbol(s)	CLG4B, MMP-9, GELB, MANDP2
EC.number	3.4.24.35

DNA

TYPE	functioning gene
STRUCTURE	7.65 kb     13 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Binding site   transcription factor
text structure	consensus binding sequence for NFKB and the activation of NFKB is prerequisite for the expression of MMP9 in response to various catabolic stimuli
	FOSL1 occupy regions of the MMP9 promoter in trophoblast cells critical for the regulation of MMP9 gene expression
	a potential Stat3 binding site, just juxtaposed AP-1 consensus sequence (activation of MMP9 promoter is dependent upon interactions of FOSL1/c-Jun with STAT3)
	KLF8 directly bound and activated the human MMP9 gene promoter

MAPPING

cloned

Y

linked

Y

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004994 13 - 2387 NP_004985 78.3 707 - 1992 1281792 variant 2 - - - isoform 2 82 - expressed on the surface of malignant cells 2007 17489740 also called 82 pro-MMP9 may escape inhibition by natural TIMP1, thereby facilitating cellular invasion

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 Digestive esophagus       highly   mouth tongue     highly Lymphoid/Immune spleen       highly   thymus       highly   tonsils       highly Nervous brain limbic system hippocampus   highly Homo sapiens Adult

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Connective

cells

System Cell Pubmed Species Stage Rna symbol   mast cell Blood/Hematopoietic granulocyte Cardiovascular endothelial cell Lymphoid/Immune macrophage not specific chondrocyte Skeleton osteoclast

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a signal sequence
	a unique CBD (collagen-binding domain) containing three fibronectin type II-like modules
	a prodomain with cysteine residue, essential for latency
	a hinge region
	a C terminal hemopexin-like domain with integrin binding activity, that is a prerequisite for enhanced cell migration

conjugated

HemoP , MetalloP

mono polymer

homomer , dimer

HOMOLOGY

Homologene

FAMILY

MMP family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	extracellular
text	extracellular matrix
	is secreted as a latent pro-enzyme that requires activation in the extracellular space

basic FUNCTION	regulator of matrix remodeling
	playing a significant role in tumour invasion and angiogenesis
	highly involved in early embryo implantation
	codes for an enzyme engaged in the regulation of neuronal plasticity and can also contribute to neuronal cell death in pathological conditions
	MMP9 and MMP12 promote intimal thickening by independent cleavage of N-cadherin, which elevates vascular smooth muscle cell proliferation via beta-catenin signalling
	associated with neovascularization
	generating angiostatin fragments by hydrolyzing plasminogen
	also involved in the migratory process (acute and chronic inflammation of tumoral metastatic process and in injury processus of myofibers)
	playing a control role of keratinocyte growth
	involved in enhanced collagen affinity, reduced IL-2 response
	pro/antiinflammatory roles
	may act not only as a solubilizer of bone matrix but also as a regulator of initiation of bone resorption and coupling to bone formation
	with MMP13 play a role in endochondral ossification
	involved in a wide range of normal and pathologic conditions, including inflammation, tissue repair, tumor invasion, and metastasis
	initiates cross-talk between CD44 and EGFR, which in turn activates downstream effectors for cell migration
	NEU1 and MMP9 in complex with TLR receptors at the ectodomain form a molecular organizational signaling platform on the cell surface that is essential for ligand activation of TLR receptors and cellular signaling
	extracellularly acting, Zn(2+)-dependent endopeptidase, that is important not only for pathologies of the central nervous system but also for neuronal plasticity
	is functionally involved in synaptic remodelling
	novel effector which is required for Neural Crest Cells delamination and migration
	regulates survival of neurons by regulating laminin-integrin beta1 signaling during developmental neuronal death
	role for MMP9 in regulating neuronal survival through the developmental process that establishes the functional brain
	plays a major role in regulating laminin levels in neonatal hippocampus
	extracellular matrix proteolytic protease, playing an important role in epileptogenesis
	converts proBDNF to mature BDNF and may play a role in the pathophysiology of major depressive disorder
	plays a critical role in regulation of spine morphology and synaptic plasticity
	key enzyme for the degradation of extracellular matrix in aneurysm walls

CELLULAR PROCESS	cell life, proliferation/growth
	cell migration & motility

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

among secreted MMPs, only MMP9 is capable of forming a homodimer

INTERACTION

DNA

RNA

small molecule	metal binding,
	Zn2+

protein	binding TIMPs in a 1:1 stoechiometry
	interacting with PGF (PGF/MMP9 expressing cells restore microcirculation and efficacy of cell therapy in aged dystrophic muscle)
	interacting with KLF5 (causes cartilage matrix degradation through transcriptional induction of MMP9, providing the first evidence that transcriptional regulation of a proteinase contributes to endochondral ossification and skeletal development)
	interacting with EGR1 (directly binds to the MMP9 promoter and plays an essential role for TNF1 induction of MMP9 transcription)
	bind to several cell surface receptors including CD44, LRP1, LRP2
	MMP9 expression induced by TGFA is a valid target of PPARD ligands in keratinocytes
	ITGB4 associates with MMP9 and its ectodomain is a target for cleavage by MMP9
	PLG regulates MMP9-dependent CXCR4 expression to facilitate hematopoietic progenitor and stem cell (HPSC) mobilization in response to CSF3
	CREB3 plays a critical role in MMP9 expression and is probably involved in invasion and metastasis of cervical cancer
	SMYD3 is an important new regulator of MMP9 transcription, providing a molecular link between SMYD3 overexpression and metastatic cancer progression
	MMP9 is a gene tightly regulated by the MXI1 gene
	induce the expression of MMP9 in macrophages, and MMP9 is known to be essential for tumor cell migration and invasion
	TNF promotes human RPE cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression
	ADAM10 and/or MMP9 are playing important roles in constitutive and PACAP-induced RAGE shedding
	regulator of ERBB2 expression on human mammary epithelial cells
	PIWIL2 modulates the proliferation and metastasis of colon cancer via regulation of MMP9 transcriptional activity
	MMP9 cleaved NINJ1 in between Leu56 and Leu57 on its N-terminal ectodomain
	MMP9 constitutes an endogenous islet protease that limits islet amyloid deposition and its toxic effects via degradation of IAPP
	MTOR signaling is important to regulate the expression, activity and secretion of matrix metalloproteinases MMP9
	ADAM17 mediates MMP9 expression in lung epithelial cells
	NUMBL could decrease the expression of TRAF6, CCND1, and MMP9 and increase the expression of CASP3
	NFATC1 sequestering the SMAD3 prevents the proteasome mediated degradation of SKIL and SKIL has a role on the regulation of MMP2, MMP9 activity
	HDAC10 binds to the promoter regions of MMP2 and -9, deacetylates histones H3 and H4 in these regions, blocks the binding of RNA polymerase II, and consequently down-regulates MMP2 and -9 expression
	LCK upregulates FOXP3 by tyrosine phosphorylation, resulting in decreased MMP9, SKP2, and VEGFA expression, and suppressed cellular invasion
	MMP9 enhances PRKD2-mediated tumor angiogenesis by releasing extracellular matrix-bound VEGFA, increasing its bioavailability and angiogenesis
	MMP9 inhibits IL23A expression in dendritic cells by targeting membrane stem cell factor affecting lung IL17 response
	RAC1 controls surface mobilization of CD40LG on activated platelets and MMP9 secretion from neutrophils
	MMP9 was a downstream effector of HEY1 that promotes the invasion of osteosarcoma cells
	recruitment of MMP9 to the fibroblast cell surface occurs through its fibronectin-like (FN) domain and the molecule responsible for the recruitment is PLOD3
	CTSK was responsible for the activation of pro-MMP9, with a key link between CTSK expression in tumors and bone and ECM remodeling, through MMP9 activation
	PGF may activate MMP9 via MAPK14 signaling pathway
	MMP9 is active in islets and cleaves IAPP
	CA8 might facilitate cancer cell invasion via the activation of PTK2-MMP9 signaling
	expression of MMP9 was enhanced with an upregulation of HOXC6 expression while HOXC6 downregulation lowered MMP9 gene expression levels
	INVS could upregulate the expression of CDH2, VIM, MMP2, and MMP9
	overexpression of GADD45A activated MMP9 expression by inducing promoter demethylation
	RAB34 plays a crucial role in modulating the secretory network of lysosome-related proteases including MMP9 and CTSK across the ruffled borders of osteoclasts, contributing to the regulation of bone resorption

cell & other

REGULATION

activated by	NRG1 isoform beta_1 in breast cancer
	proteinases and plasmin
	KLF8 (its overexpression induced a strong increase in MMP9 expression and activity)

induced by	FOXO3
		STAT3 and AP-1 (functional cooperation of the STAT3 and AP-1 transcription factors is required for the transcription of MMP9 gene)

inhibited by	TIMPs and TFPI2
	RECK
	irisolidone

repressed by

YY1 in neurons

Other	regulated by S100A4 in prostate carcinoma cells
	regulated by nucleolin (role in posttranscriptional control of MMP9 expression)
	UV radiation may promote the modulation of KRT24 and MMP9 pterygium-related genes and induce the initiation and progression of ocular pterygium

ASSOCIATED DISORDERS

corresponding disease(s)

MAND1

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in cutaneous squamous cell carcinoma with metastatic potential and in in sporadic colorectal cancer tumoral     --low   in diffuse type gastric carcinoma, and in hereditary non-polyposis colorectal carcinoma tumoral     --over   in breast cancer and in prostate cancer with aggressive phenotype constitutional       gain of function in chronic obstructive pulmonary disease constitutional     --over   at the site of abdominal aortic aneurysm rupture constitutional     --over   in arthritis, degrading non-collagen matrix components of the joints constitutional     --over   higher in MADYS1 (mandibuloacral dysplasia type A) sera compared with healthy controls constitutional     --over   in skeletal muscle tissues after nerve injury, heart failure and inflammatory myopathy, and exacerbate dystrophinopathy by augmenting fiber necrosis, ECM degradation, inflammation and fibrosis tumoral     --over   is associated with accumulation of the pleural effusion in malignancy constitutional     --over   hypertension-induced atherosclerosis was associated with significantly increased levels of MMP9 mRNA, which may enhance both the deposition of types I and III collagen and atherosclerotic plaque formation constitutional     --over   may be linked with the intractable epilepsy caused by focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC) constitutional       gain of function SPARC, MMP2 and MM9 were significantly up-regulated in intracranial aneurysms relative to the expression levels in the normal Circle of Willis arteries constitutional     --low   AHSG, MMP9, and MMP3 levels were significantly lower in migraine than controls tumoral     --over   in the invasive group of pituitary adenomas (pMID: 21279695)

Susceptibility

to dementia to toxic epidermal necrolysis and to Stevens-Johnson syndrome to lumbar-disc herniation to exudative form of age-related macular degeneration (AMD) to cleft lip/palate to inflammatory bowel diseases to polymyositis to malignant gliomas to coronary atherosclerosis, and to carotid arteries atherosclerosis to macroangiopathic complications in type 2 diabetes mellitus (T2DM) to multiple sclerosis (MS)

Variant & Polymorphism repeat , other	polymorphism 1562c>t having protective effect against dementia
	longer microsatellites in the promoter of MMP9 are associated to the exudative form of AMD
	(> or =22 CA) in the microsatellite of the promoter, is associated to carotid atherosclerosis
	frequency of the allele T was higher in patients with macroangiopathic complications in type 2 diabetes mellitus (T2DM)
	MMP9 C(-1562)T and (CA)(n) polymorphisms contribute to multiple sclerosis (MS)

Candidate gene
Marker	measurement of serum MMP9 might be clinically useful for pancreatic ductal adenocarcinoma diagnosis
	potential DMD biomarker for disease progression
	urinary MMP9/LCN2 and ADAM12 are potential noninvasive biomarkers for gastric cancer, including early-stage disease
	dysregulated levels of MMP9 may be involved in sepsis pathophysiology and may be utilized as potential diagnostic biomarkers
	TIMP2 and MMP9 expression had a synergistic role as efficient prognostic indicators for CRC patients
	may serve as an additional prognostic biomarker in head and neck squamous cell carcinoma
Therapy target
	System Type Disorder Pubmed immunology autoimmune   target for therapy of autoimmune diseases neuromuscular myopathy degenerative PGF–MMP9–expressing cells restore microcirculation and efficacy of cell therapy in aged dystrophic muscle cancer brain glioma/neuroblstoma inhibition by irisolidone might be a potential therapeutic modality for controlling the growth and invasiveness of gliomas neuromuscular myopathy degenerative one of the most promising therapeutic targets for the prevention of disease progression in DMD neurosensorial visual anterior chamber potential therapeutic targets (MMP-9) against proliferative vitreoretinopathy (PVR) diabete type 2   increasing islet MMP9 activity might be a strategy to limit beta-cell loss in type 2 diabetes cancer head and neck   target to support current head and neck squamous cell carcinoma treatments

ANIMAL & CELL MODELS

	key regulator of grow plate angiogenesis and apoptosis of hypertrophic chondrocytes in mice
	Deletion of Mmp9 gene in mdx mice improved skeletal muscle structure and functions and reduced muscle injury, inflammation and fiber necrosis
	Mmp9 deficiency causes physiological and placental abnormalities in mice, which mimic features of preeclampsia (PE)