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FLASH GENE

Symbol

TIMP3

contributors: mct - updated : 26-03-2020

HGNC name	TIMP metallopeptidase inhibitor 3
HGNC id	11822

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	SFD pseudoinflammatory fundus dystrophy of Sorsby
Location	22q12.3      Physical location : 33.196.801 - 33.259.027
Synonym name	K222 expressed in degenerative retinas
	TIMP metallopeptidase inhibitor 3 (Sorsby fundus dystrophy, pseudoinflammatory)
	tissue inhibitor of metalloproteinase 3
	MIG-5 protein
Synonym symbol(s)	HSMRK222, K222, K222TA2, TIMP-3

DNA

TYPE	functioning gene
SPECIAL FEATURE	gene in gene
text	embedded in intron V of SYN3
STRUCTURE	62.23 kb     5 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   transcription factor
text structure	promoter contain several Sp1 sites

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000362 5 - 5496 NP_000353 - 211 - 2007 1720214 a 23 aa signal peptide of 2.5 kda a 188 aa mature peptide of 21.7 kda

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 liver         Homo sapiens Endocrine adrenal gland       moderately Hearing/Equilibrium ear       highly Nervous nerve       highly Reproductive female system placenta     highly Respiratory lung       highly Visual eye       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective bone     moderately Epithelial barrier/lining retinal pigment epithelium (RPE)

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

one NTR domain

secondary structure

twelve cysteine residues that form six disulfide bridges

conjugated

MetalloP

HOMOLOGY

interspecies	homolog to rattus Timp3 (95.3 pc)
	homolog to murine Timp3 (96.2 pc)

Homologene

FAMILY

protease inhibitor I35 (TIMP) family

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	extracellular
	intracellular
	intracellular,nucleus
text	proteinaceous extracellular matrix
	present at the blood-brain-barrier endothelium

basic FUNCTION	inhibiting VEGF mediated angiogenesis by blockage of the binding of VEGF and VEGFR2
	inhibiting more efficiently TACE, ADAM-10, ADAM-12, and aggrecanases than all the MMPs
	having a proapoptotic activity
	reducing tumor growth when it's overexpressed
	inactivating irreversibly metalloproteinases (such as collagenases) by complexing with them (MMP1, MMP2, MMP3, MMP7, MMP9, MMP13, MMP14, MMP15)
	may form part of a tissue- specific acute response to remodeling stimuli
	candidate tumor suppressor gene in the biliary tree
	protein accumulation is found to be an age-dependent phenomenon
	involved in the regulation of the essential early inductors of adipogenesis, KLF4, EGR2, and CEBPB
	endogenous regulator of metalloproteinases, stimulating hematopoietic stem cells (HSC) proliferation by recruiting quiescent HSCs into the cell cycle
	may act as a molecular cue in response to myelosuppression for recruiting dormant HSCs into active cell cycle and may be clinically useful for facilitating hematopoietic recovery after chemotherapy
	differentially impacts apoptosis and inflammatory cell influx, based on involvement of TNF, during the process of mammary involution
	the regulatory function of TIMP3 is critical in preventing adverse vascular remodeling and abdominal aortic aneurysm
	functions to moderate the differentiation of macrophages into proinflammatory (M1) cells
	TIMP2 and TIMP3 play fundamental and differential roles in mediating pathological remodelling, independent from their MMP-inhibitory function
	stromal protein that inhibits the activity of various proteases and receptors
	may induce apoptosis in Endothelial cells by triggering a caspase-independent cell death pathway and targeting a PTK2-dependent survival pathway
	TIMP3-mediated neuroprotection is critically dependent on activation of the AKT1-MTOR pathway
	has direct neuroprotective effects that can mitigate the deleterious effects associated with traumatic brain injury (TBI), an area with few if any therapeutic options
	TIMP3 acts as a tumor suppressor gene by inhibiting the growth, angiogenesis, migration, and invasion of cancer cells
	is likely a key protective molecule against iron-mediated pathology, and plays a key protective role against iron-mediated pathology
	expression of TIMP3 in NP (nucleus pulposus) may have a key role in the development of discogenic pain
	might play an important role in the pathogenesis of intervertebral disc degeneration (IDD)

CELLULAR PROCESS	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

sensory transduction/vision

a component

INTERACTION

DNA

RNA

small molecule

protein	VEGF and VEGFR2
	binding MMPs in a 1:1 stoechiometry
	inhibiting ADAMTS5 and ADAMTS4
	regulator of MMP2 by RPE cells
	LRP1 is the master regulator of extracellular levels of TIMP3
	ITGA7 binds to tissue inhibitor of metalloproteinase 3 (TIMP3) in prostate cancer cells
	imbalance between ADAMTS4 and TIMP3 may play an important role in the pathogenesis of intervertebral disc degeneration (IDD)
	hepatic TIMP3 can slow progression of Non-alcoholic fatty liver disease (NAFLD), and tumorigenesis, at least in part, through the regulation of ADAM17 activity
	as a novel CLOCK-dependent diurnal gene, TIMP3 inhibits the expression of inflammatory cytokines that are up-regulated by UV irradiation in human keratinocytes
	IL32 may increase TIMP3 expression via hypomethylation through inactivation of NFKB1 activity, and thereby reduce lung tumor growth
	CDKN2A/TIMP3 modulation of inflammatory response and vascularization in the context of intervertebral disk degeneration (IVDD)

cell & other

REGULATION

activated by

TH

induced by	mitogenic stimulation
		hydrocortisone

Other

endocytosed and degraded by a number of cell types including chondrocytes, fibroblasts, and monocytes

ASSOCIATED DISORDERS

corresponding disease(s)

SFD

related resource

CNGA1Mutations Retinal Information Network

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral       loss of function by methylation in uterus breast, colon, brain carcinomas tumoral       loss of function in renal clear cell carcinoma with poor prognosis constitutional     --low   in heart failure tumoral     --low   in uveal melanoma with metastases constitutional     --over   increased in the renal arteries and proximal tubules of subjects with diabetic nephropathy or chronic allograft nephropathy constitutional     --low   is reduced in atherosclerotic plaques from subjects with type 2 diabetes and increased by SIRT1 constitutional     --low   during preadipocyte differentiation, the Sp1-dependent decrease in TIMP3 expression is required for the successful implementation of the adipocyte differentiation program tumoral         silenced by promoter methylation in a consistent fraction of Papillary thyroid carcinoma constitutional     --low   increases inflammation and polarizes macrophages towards a more inflammatory phenotype resulting in increased atherosclerosis constitutional     --over   TIMP3 mRNA expression increases and TIMP3 protein is in the appropriate cellular layers to regulate proteolytic remodeling as the follicle progresses toward ovulation constitutional         induces choroidal neovascularization by moderating the polarization of macrophages in age-related macular degeneration

Susceptibility

to age-related macular degeneration

Variant & Polymorphism SNP , other	SNP may contribute to individual differences in breast cancer susceptibilty and survival
	S156C mutation results in an abnormal localization of protein and increases angiogenesis
	association of variants with age-related macular degeneration
	expression level of TIMP3 was significantly associated with AMD pathology

Candidate gene
Marker	plasma TIMP3 is a potential biomarker for predicting the tumor stage and T status in patients with oral squamous cell carcinoma (OSCC)
	positive correlation between TIMP-3 promoter methylation and gastric cancer risk and indicated that TIMP-3 promoter methylation may be used as a molecular marker for gastric cancer
Therapy target
	System Type Disorder Pubmed cancer head and neck   promoter methylation of TIMP3 (and CDH1) predicts better outcome in head and neck squamous cell carcinoma treated by radiotherapy only cardiovascular     could serve as a therapeutic approach in limiting abdominal aortic aneurysm development or expansion cancer bone   TIMP3 is a new target for inhibition of progression and chemotherapeutic resistance

ANIMAL & CELL MODELS

iron overload in Timp3-/- mice showed twofold higher iron accumulation in the liver compared with WT mice because of constituently lower levels of ferroportin