Affinage

TIMP2

Metalloproteinase inhibitor 2 · UniProt P16035

Length
220 aa
Mass
24.4 kDa
Annotated
2026-04-28
100 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIMP2 is a multifunctional secreted regulator of extracellular matrix remodeling, vascular integrity, and intracellular signaling that operates through both MMP-dependent and MMP-independent mechanisms. As an endogenous MMP inhibitor, TIMP2 forms a ternary complex with MT1-MMP and pro-MMP-2 on the cell surface to control MMP-2 activation and MT1-MMP turnover, with dynamin-dependent endocytosis recycling intact TIMP2 after MT1-MMP engagement (PMID:11178970, PMID:14729066). Independent of MMP inhibition, TIMP2 acts as an extracellular co-chaperone of eHSP90 to terminally inactivate MMP-2 (PMID:31412254), signals through α3β1 integrin to inhibit Src-mediated VE-cadherin internalization and maintain endothelial barrier integrity (PMID:38015626, PMID:36417884), and activates ERK1/2 and AKT pathways via MT1-MMP/Ras to regulate cell survival and proliferation (PMID:26331622). TIMP2 transcription is regulated by EZH2-mediated H3K27me3 silencing and NF-κB-dependent promoter activity, and its mRNA stability is modulated by METTL3-dependent m6A modification through IGF2BP2, with loss of neuronal TIMP2 impairing hippocampal ECM homeostasis, adult neurogenesis, and memory (PMID:28620234, PMID:34995800, PMID:37914840).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1994 High

    Early work established that TIMP2 forms a stable complex with MMP-2 in fibroblasts and that its promoter architecture (CpG island, Sp1/AP-2 sites, negative AP-1 element) resembles a housekeeping gene, distinguishing it from the inducible TIMP-1 promoter.

    Evidence Promoter deletion/luciferase assays in fibroblasts; monoclonal antibody detection of denaturation-resistant TIMP-2:MMP-2 complexes in conditioned media

    PMID:8020585 PMID:8112602

    Open questions at the time
    • No cell-surface receptor for TIMP2 identified at this stage
    • Mechanism of TIMP2:MMP-2 complex regulation by cytokines (IL-1α) unclear
  2. 2001 High

    The ternary complex model was defined: TIMP2 bridges MT1-MMP and pro-MMP-2 on the cell surface to activate MMP-2, while simultaneously inhibiting MT1-MMP autocatalytic turnover — a function not shared by the close homologue TIMP-4.

    Evidence Co-expression of MT1-MMP, TIMP2, and pro-MMP-2 with enzymatic activation assays and competitive inhibition by TIMP-4

    PMID:11178970

    Open questions at the time
    • Fate of TIMP2 after ternary complex engagement not yet resolved
    • Structural determinants of TIMP2 specificity over TIMP-4 for MMP-2 activation not mapped
  3. 2004 High

    TIMP2 recycling was resolved: after MT1-MMP binding, TIMP2 is released intact (>85%) via dynamin-dependent endocytosis, establishing that TIMP2 functions catalytically on the cell surface rather than being consumed.

    Evidence Radiolabeled TIMP-2 binding/release kinetics, dominant-negative dynamin, pharmacologic inhibitors

    PMID:14729066

    Open questions at the time
    • Intracellular trafficking route of internalized MT1-MMP:TIMP2 complex not defined
    • Whether TIMP2 recycling is altered in pathological states unknown
  4. 2014 High

    Multiple studies revealed MMP-independent functions and regulatory complexity: TIMP2 knockout mice showed enhanced cardiac hypertrophy with reduced collagen cross-linking enzymes (LOX, PLOD1) independent of MMP inhibition; NEDD9 was identified as a regulator of surface TIMP2 accumulation controlling MMP14 activity; the TIMP2 binding interface was shown to be multispecific rather than optimized for any single MMP; and an NF-κB-responsive promoter SNP was identified.

    Evidence TIMP2−/− and TIMP3−/− knockout mice with angiotensin II challenge; NEDD9 knockdown/rescue with invasion assays; computational saturation mutagenesis with experimental binding validation; luciferase reporter and EMSA for promoter SNP

    PMID:24202705 PMID:24692173 PMID:24710006 PMID:24799419

    Open questions at the time
    • Direct target of TIMP2's MMP-independent cardiac remodeling function not identified
    • Whether NEDD9-TIMP2 axis operates in non-cancer contexts unknown
    • NF-κB site functional relevance beyond reporter context not validated in vivo
  5. 2015 High

    TIMP2 was shown to activate intracellular signaling (AKT and ERK1/2) through cell-surface MT1-MMP in a protease-independent manner via Ras, with context-dependent effects on apoptosis — protective in 2D serum starvation but pro-apoptotic in 3D collagen.

    Evidence Catalytically dead MT1-MMP mutants, Ras/FGFR1 inhibition, kinase activation assays, apoptosis readouts in 2D vs 3D culture

    PMID:26331622

    Open questions at the time
    • Mechanism by which 3D collagen reverses the survival signal is unknown
    • Whether AKT activation by TIMP2 requires co-receptors beyond MT1-MMP not determined
  6. 2018 High

    Epigenetic silencing of TIMP2 by EZH2 via H3K27me3 was established in ovarian and breast cancers as a mechanism driving MMP-2/9 activation and invasiveness; separately, TIMP2 knockdown in kidney was shown to ameliorate sepsis-induced AKI via NF-κB suppression, and urinary TIMP2 elevation in AKI was mechanistically attributed to reduced tubular reabsorption rather than transcriptional induction.

    Evidence ChIP for EZH2/H3K27me3 at TIMP2 promoter with functional rescue in cancer cells; kidney-specific lentiviral TIMP2 knockdown in CLP sepsis mice; multiple AKI models with mRNA vs protein quantification and endocytic inhibition

    PMID:28620234 PMID:29636998 PMID:29980651 PMID:30562560

    Open questions at the time
    • Whether EZH2-mediated TIMP2 silencing operates in non-cancer tissues not established
    • Mechanism linking TIMP2 to NF-κB pathway in kidney cells not molecularly defined
    • Whether tubular TIMP2 has autocrine protective functions distinct from its filtration marker role is unclear
  7. 2019 High

    A fundamentally new function was uncovered: TIMP2 acts as an extracellular co-chaperone of eHSP90, modulating its ATPase cycle to terminally inactivate MMP-2; the secreted co-chaperone AHA1 competitively displaces TIMP2, reactivating MMP-2, establishing a chaperone-level control of extracellular proteolysis.

    Evidence Co-immunoprecipitation, ATPase activity assays, TIMP2 and AHA1 gene knockout and blocking antibodies, gelatin zymography in HT1080 cells

    PMID:31412254

    Open questions at the time
    • Structural basis of TIMP2:eHSP90 interaction not resolved
    • Whether TIMP2 co-chaperone function extends to other eHSP90 clients beyond MMP-2 unknown
    • In vivo relevance of eHSP90:TIMP2 axis not tested
  8. 2022 Medium

    Two studies expanded TIMP2's barrier-protective and epitranscriptomic regulation: fibroblast-derived TIMP2 was shown to maintain blood-brain barrier integrity after hemorrhage via tight junction protein upregulation, and METTL3-mediated m6A modification of TIMP2 mRNA (read by IGF2BP2) was found to modulate Notch signaling and podocyte injury in diabetic nephropathy.

    Evidence Conditional fibroblast ablation with TIMP2 rescue in ICH mice; METTL3 conditional KO with m6A-seq and podocyte injury readouts in diabetic mice

    PMID:34995800 PMID:36417884

    Open questions at the time
    • Receptor mediating TIMP2's tight junction upregulation in BBB not identified
    • Whether m6A modification alters TIMP2 translation efficiency or mRNA stability not distinguished
    • USP7/EZH2/TIMP2/NF-κB/PD-L1 immune evasion axis validated in single cancer type only
  9. 2023 High

    Two key MMP-independent mechanisms were molecularly defined: TIMP2 binds α3β1 integrin on brain endothelium to inhibit Src-dependent VE-cadherin phosphorylation and internalization, maintaining barrier integrity after TBI; and neuronal TIMP2 controls hippocampal ECM density, adult neurogenesis, dendritic spine turnover, and memory.

    Evidence AlaTIMP2 MMP-dead mutant retaining barrier function, co-IP of TIMP2/α3β1 integrin, VE-cadherin internalization assays, TBI mouse model; neuron-specific TIMP2 conditional KO with ECM quantification, neurogenesis, and behavioral testing

    PMID:37914840 PMID:38015626

    Open questions at the time
    • Downstream signaling from α3β1 integrin beyond Src/Rac1 not fully mapped
    • Identity of TIMP2-sensitive MMP(s) controlling hippocampal ECM not determined
    • Whether neuronal TIMP2's effects on neurogenesis involve integrin signaling or solely MMP inhibition is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of TIMP2's interaction with eHSP90 and α3β1 integrin, the identity of TIMP2-sensitive proteases in hippocampal ECM remodeling, the in vivo relevance of the eHSP90 co-chaperone function, and the degree to which MMP-independent signaling versus canonical MMP inhibition drives TIMP2's physiological roles across tissues.
  • No structural model of TIMP2:α3β1 integrin or TIMP2:eHSP90 complex available
  • Relative contribution of MMP-dependent vs MMP-independent functions in vivo not quantified
  • Whether TIMP2's immune-modulatory effects (NK cell, PD-L1) involve direct receptor engagement or indirect ECM remodeling is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 2 GO:0044183 protein folding chaperone 1
Localization
GO:0005576 extracellular region 4 GO:0005886 plasma membrane 4 GO:0031012 extracellular matrix 2
Pathway
R-HSA-1474244 Extracellular matrix organization 4 R-HSA-162582 Signal Transduction 4 R-HSA-1500931 Cell-Cell communication 2 R-HSA-168256 Immune System 2
Partners
AHSA1EZH2HSP90AA1ITGA3ITGB1MMP14MMP2NEDD9
Complex memberships
MT1-MMP:TIMP2:pro-MMP2 ternary complexTIMP2:MMP-2 inhibitory complexeHSP90:TIMP2 co-chaperone complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 TIMP-2 promotes activation of pro-MMP-2 by MT1-MMP through formation of a ternary complex (MT1-MMP:TIMP-2:pro-MMP-2) on the cell surface; TIMP-2 binding to active MT1-MMP also inhibits MT1-MMP autocatalytic turnover. TIMP-4, a close homologue, does not support pro-MMP-2 activation by MT1-MMP, and competitively reduces TIMP-2-mediated activation when co-expressed. Cell co-expression, enzymatic activation assays, competitive inhibition experiments Biochemical and biophysical research communications High 11178970
2004 After binding to cell-surface MT1-MMP, TIMP-2 is released primarily as an intact, functional molecule (>85%); endocytosis via dynamin is required for this release cycle. Furin-activated (mature) MT1-MMP is required for TIMP-2 binding and endocytosis. Radiolabeled TIMP-2 binding/release assays, dominant-negative dynamin transfection, pharmacologic inhibitors, Western blotting of biotinylated surface MT1-MMP Experimental cell research High 14729066
2015 TIMP-2 binding to MT1-MMP on the cell surface activates the AKT signaling pathway in a dose- and time-dependent, MMP-proteolysis-independent manner; Ras activation is required to transduce the TIMP-2 signal to both ERK1/2 and AKT. FGFR1 mediates TIMP-2-induced ERK1/2 but not AKT activation. This signaling protects tumor cells from serum starvation-induced apoptosis but promotes apoptosis in 3D collagen environments. Cell-based signaling assays, dominant-negative constructs, kinase inhibitors, apoptosis assays, MT1-MMP catalytic mutants PloS one High 26331622
2019 TIMP-2 functions as an extracellular co-chaperone of HSP90 (eHSP90): it binds eHSP90, increases eHSP90 ATPase binding to ATP, and inhibits its ATPase activity. TIMP-2 disrupts the eHSP90:MMP2 client complex and terminally inactivates MMP2, but can also load MMP2 onto eHSP90 in a transient inhibitory state. The secreted co-chaperone AHA1 displaces TIMP-2 from the eHSP90 complex, reactivating MMP2. Gene knockout and blocking antibodies against TIMP-2 and AHA1 in HT1080 cells alter gelatinolytic activity. Co-immunoprecipitation, ATPase assays, gene knockout, blocking antibodies, gelatin zymography Cell reports High 31412254
2023 TIMP-2 interacts with α3β1 integrin on brain endothelial cells, inhibiting Src kinase activation-dependent VE-cadherin phosphorylation, destabilization of the VE-cadherin/catenin complex, and subsequent VE-cadherin internalization, thereby maintaining endothelial barrier integrity after traumatic brain injury. A TIMP-2 MMP-inhibition-dead mutant (AlaTIMP2) retains this protective activity, demonstrating an MMP-independent mechanism. TIMP-2-mediated membrane retention of VE-cadherin also elevates active Rac1, inhibiting stress fiber formation. In vivo TBI mouse model, in vitro endothelial permeability assays, co-immunoprecipitation (TIMP-2/integrin), Src inhibition, VE-cadherin internalization assays, AlaTIMP2 mutant The Journal of clinical investigation High 38015626
2022 Fibroblasts (Col1α1+) promote blood-brain barrier integrity after intracerebral hemorrhage via TIMP2; fibroblast ablation worsens BBB damage and neurological function, and exogenous TIMP2 rescues BBB integrity in fibroblast-ablated mice. The protective mechanism operates through the paracellular pathway (upregulation of tight junction proteins) rather than transcellular pathways. Conditional fibroblast ablation (Col1α1-targeting), in vitro endothelial permeability assays, exogenous TIMP2 administration, tight junction protein immunostaining Cell reports High 36417884
2023 Neuronal TIMP2 in the hippocampus reduces accumulation of extracellular matrix (ECM) around synapses and facilitates newborn neuron migration; conditional neuronal TIMP2 knockout results in increased ECM density, impaired adult neurogenesis, reduced dendritic spine turnover, and hippocampus-dependent memory deficits. Conditional (neuron-specific) TIMP2 knockout mouse, immunostaining, ECM quantification, adult neurogenesis assays, behavioral memory testing Molecular psychiatry High 37914840
2014 In the absence of NEDD9, excess TIMP-2 accumulates on the cell surface and inactivates MMP14 (MT1-MMP), reducing collagenolytic activity of soluble MMP2 and MMP9 and suppressing mesenchymal invasion. Re-expression of NEDD9 restores MMP14 activity and invasive capacity. NEDD9 knockdown/re-expression, cell invasion assays, MMP activity assays, in vivo xenograft metastasis model Molecular cancer research : MCR Medium 24202705
2014 TIMP2 binding interface with MMPs is not optimized for any single MMP target; computational saturation mutagenesis and experimental validation identified numerous affinity-enhancing point mutations in the TIMP2 binding interface that improve affinity to MMP14 by more than 10-fold, demonstrating the multispecific nature of the TIMP2:MMP interaction. Computational saturation mutagenesis, in vitro binding affinity measurements (experimental point mutants), SPR or equivalent binding assays PloS one Medium 24710006
1994 The human TIMP-2 gene promoter contains a TATA-like element, Sp1 and AP-2 motifs, an AP-1 site, and has features of a housekeeping gene (high G-C content, CpG island). A 715-bp 5'-flanking fragment drives promoter activity in transfected fibroblasts; a negative control element lies between positions -661 and -575 (encompassing the AP-1 site). Phorbol ester treatment does not affect TIMP-2 promoter activity, distinguishing it from TIMP-1 regulation. Promoter cloning, deletion analysis, luciferase reporter assays in transfected cells, phorbol ester treatment Gene High 8112602
2011 TIMP2 gene transcription in Sertoli cells is activated by CEBPA under basal conditions; MEHP exposure deactivates CEBPA-driven Timp2 transcription and increases MYC-mediated inhibition, reducing TIMP2 protein levels. FSH rescues MEHP-suppressed TIMP2 via CEBPA nuclear translocation and cAMP signaling. Timp2 promoter deletion analysis, luciferase reporter assays, CEBPA and MYC gain/loss of function, FSH and forskolin treatments in rat Sertoli cells Biology of reproduction Medium 21832167
2022 METTL3-mediated m6A modification of TIMP2 mRNA in an IGF2BP2-dependent manner modulates Notch signaling, promoting pro-inflammatory and pro-apoptotic effects in podocytes under diabetic conditions. Podocyte-conditional METTL3 knockout reduces TIMP2 m6A modification and alleviates podocyte injury and albuminuria. m6A sequencing, METTL3 conditional KO mice, AAV9-shMETTL3 in vivo silencing, IGF2BP2 reader confirmation, Notch signaling assays, streptozotocin diabetic mouse model Molecular therapy Medium 34995800
2018 EZH2 epigenetically silences TIMP2 in ovarian cancer via H3K27 trimethylation and DNA methylation at the TIMP2 promoter, confirmed by chromatin immunoprecipitation. EZH2 overexpression inhibits TIMP2 expression, increases MMP2/9 proteolytic activity, and promotes invasion and migration; these effects are reversed by TIMP2 downregulation. ChIP assay, H3K27me3 inhibition, DNA demethylation, gain/loss-of-function EZH2 and TIMP2, invasion/migration assays in vitro and in vivo Scientific reports High 28620234
2018 EZH2 represses TIMP2 transcription via H3K27me3 in triple-negative breast cancer cells, leading to increased MMP-2 and MMP-9 activity and enhanced invasiveness. Knockdown of EZH2 restores TIMP2 expression and reduces invasion. EZH2 knockdown/overexpression, TIMP2 expression assays, MMP activity zymography, invasion assays American journal of cancer research Medium 29636998
2014 The TIMP2 promoter rs8179096 T allele shows 2.5-fold greater transcriptional activity compared to the C allele in reporter assays; both alleles bind nuclear factor kappa B (NF-κB), indicating NF-κB-dependent TIMP2 transcriptional regulation. Luciferase promoter reporter assay, DNA-protein binding (gel shift/EMSA) for NF-κB Journal of dental research Medium 24799419
2022 TIMP2 mediates PD-L1 expression via the NF-κB signaling pathway in cervical cancer; USP7 stabilizes EZH2, which methylates the TIMP2 promoter to suppress TIMP2, thereby relieving TIMP2-mediated suppression of NF-κB/PD-L1 signaling and promoting immune escape. USP7/EZH2/TIMP2 knockdown and overexpression, ChIP for H3K27me3 at TIMP2 promoter, NF-κB and PD-L1 pathway assays, NK-92 cytotoxicity co-culture, xenograft model Cellular signalling Medium 35523402
2020 TIMP-2 treatment suppresses primary tumor growth (~36-50%) and pulmonary metastasis (>92%) in an orthotopic TNBC mouse model by disrupting EMT, promoting vascular integrity, disrupting periostin localization, and modulating canonical Wnt signaling and PI3K/p27 signaling pathways. Orthotopic mouse model, exogenous TIMP-2 administration, immunostaining, RNA sequencing, pathway analysis Carcinogenesis Medium 31621840
2014 TIMP-2 deficiency (TIMP2-/- mice) results in enhanced myocardial hypertrophy and lack of fibrosis after angiotensin II infusion, associated with reduced cross-linking enzymes LOX and PLOD1, independently of MMP-inhibitory function. This differs from TIMP3-/- (excess fibrosis without hypertrophy), demonstrating distinct and MMP-independent roles for TIMP2 in cardiac remodeling. TIMP2-/- and TIMP3-/- knockout mice, angiotensin II infusion, echocardiography, in vitro cardiomyocyte/fibroblast co-culture, collagen cross-linking enzyme assays Cardiovascular research High 24692173
2009 During osteoblast differentiation, TIMP-2 expression increases from day 14 onward and participates in ECM remodeling through the Ras/Rho/Rac-1/PKC alpha/beta signaling cascade, while RECK (another MMP inhibitor) is associated with earlier proliferation phases via PI3K and GSK-3beta. In vitro osteoblast differentiation, Western blotting of TIMP-2 and signaling proteins (Ras, Rho, Rac-1, PKC, paxillin, FAK), temporal expression analysis Molecular and cellular biochemistry Low 18989628
2018 TIMP2 downregulation in sepsis-induced AKI activates the NF-κB pathway (p-P65), promoting inflammatory cytokine release and tubular cell apoptosis. Kidney-specific TIMP2 knockdown via lentiviral vector ameliorates CLP-induced AKI and proinflammatory cytokine production through NF-κB inhibition. Kidney-specific TIMP2 lentiviral knockdown, CLP sepsis mouse model, LPS-challenged HK-2 cells, NF-κB pathway analysis, serum creatinine, histopathology Biochimica et biophysica acta. Molecular basis of disease Medium 30562560
2018 Increased urinary TIMP2 and IGFBP7 excretion in AKI results primarily from increased glomerular filtration and decreased tubular reabsorption, and from leakage of TIMP2/IGFBP7 from injured proximal tubule cells — not from stress-induced transcriptional upregulation (mRNA levels remain normal). Competitive inhibition of endocytic protein reabsorption in normal mice tripled urinary TIMP2/IGFBP7 levels. AKI mouse models (glycerol, maleate, ischemia), urinary and renal cortical TIMP2/IGFBP7 measurement by ELISA, mRNA quantification, immunohistochemistry, endocytic inhibition experiment Journal of the American Society of Nephrology : JASN High 29980651
1994 TIMP-2 produced in late-passage human fibroblasts forms a denaturation-resistant complex with 72-kDa gelatinase (MMP-2), detected by monoclonal antibodies. IL-1α increases the level of this TIMP-2:MMP-2 complex without changing total 72-kDa gelatinase expression, indicating IL-1α regulates the interaction between these two proteins. Western blotting with monoclonal antibodies, autoradiography of newly synthesized complexes, IL-1α treatment of early/late passage fibroblasts Experimental cell research Medium 8020585
1996 Recombinant TIMP-2 stimulates growth (thymidine incorporation, cell number) of human fibroblasts, lung adenocarcinoma, melanoma, and Burkitt's lymphoma cells in a concentration-dependent manner (maximal at 10-30 pM) when insulin is present as a co-factor. Without insulin, TIMP-2 alone is inhibitory. The effect is cell-type specific — normal colon and lung fibroblasts do not respond, and HL60 cells are inhibited. [3H]thymidine incorporation assays, cell growth assays, concentration-response experiments with recombinant TIMP-2 and insulin Experimental cell research Medium 8612674
2021 Recombinant TIMP-2 protein counteracts TGFβ-induced NK cell polarization toward a decidual-like phenotype (CD56bright CD9+ CD49a+), restores NKG2D activation marker levels, and reduces TIM-3 exhaustion marker upregulation induced by TGFβ, as determined by multicolor flow cytometry. Flow cytometry of NK cell surface markers after TGFβ and recombinant TIMP2 treatment, degranulation assays Cancers Low 34638439

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 TIMP-2 over-expression reduces invasion and angiogenesis and protects B16F10 melanoma cells from apoptosis. International journal of cancer 234 9462715
2022 METTL3-mediated m6A modification of TIMP2 mRNA promotes podocyte injury in diabetic nephropathy. Molecular therapy : the journal of the American Society of Gene Therapy 166 34995800
2007 MMP2 role in breast cancer brain metastasis development and its regulation by TIMP2 and ERK1/2. Clinical & experimental metastasis 125 17505812
2016 Long noncoding RNA DANCR promotes invasion of prostate cancer through epigenetically silencing expression of TIMP2/3. Oncotarget 114 27191265
2015 Urinary biomarkers TIMP-2 and IGFBP7 early predict acute kidney injury after major surgery. PloS one 106 25798585
1994 Characterization of the promoter of the gene encoding human tissue inhibitor of metalloproteinases-2 (TIMP-2). Gene 105 8112602
2001 Expression of MMP2, MMP9, MT1-MMP, TIMP1, and TIMP2 mRNA in valvular lesions of the heart. The Journal of pathology 104 11400152
2014 Oncogenic miR-20a and miR-106a enhance the invasiveness of human glioma stem cells by directly targeting TIMP-2. Oncogene 103 24704830
2003 Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis. Matrix biology : journal of the International Society for Matrix Biology 103 12714042
2014 Differential role of TIMP2 and TIMP3 in cardiac hypertrophy, fibrosis, and diastolic dysfunction. Cardiovascular research 99 24692173
2018 Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 98 29763380
2018 Mechanisms Underlying Increased TIMP2 and IGFBP7 Urinary Excretion in Experimental AKI. Journal of the American Society of Nephrology : JASN 93 29980651
2012 miR-200c is aberrantly expressed in leiomyomas in an ethnic-dependent manner and targets ZEBs, VEGFA, TIMP2, and FBLN5. Endocrine-related cancer 82 22685266
2018 EZH2 promotes migration and invasion of triple-negative breast cancer cells via regulating TIMP2-MMP-2/-9 pathway. American journal of cancer research 79 29636998
2011 Clinical characteristics of TIMP2, MMP2, and MMP9 gene polymorphisms in colorectal cancer. Journal of gastroenterology and hepatology 79 21261731
1993 Human glomeruli express TIMP-1 mRNA and TIMP-2 protein and mRNA. The American journal of physiology 78 8322893
2015 MiR-221/222 promote human glioma cell invasion and angiogenesis by targeting TIMP2. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 72 25731730
2017 EZH2-mediated epigenetic silencing of TIMP2 promotes ovarian cancer migration and invasion. Scientific reports 71 28620234
1996 TIMP-2 growth-stimulatory activity: a concentration- and cell type-specific response in the presence of insulin. Experimental cell research 69 8612674
2001 Differential roles of TIMP-4 and TIMP-2 in pro-MMP-2 activation by MT1-MMP. Biochemical and biophysical research communications 68 11178970
1999 Gelatinase A and TIMP-2 expression in the fibrous sclera of myopic and recovering chick eyes. Investigative ophthalmology & visual science 68 10586929
2019 Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis. Cell reports 65 31412254
2001 Adenoviral delivery of TIMP1 or TIMP2 can modify the invasive behavior of pancreatic cancer and can have a significant antitumor effect in vivo. Cancer gene therapy 64 11773977
2022 Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicry. Cell death & disease 63 35443741
2000 Basement membrane alterations in psoriasis are accompanied by epidermal overexpression of MMP-2 and its inhibitor TIMP-2. The Journal of investigative dermatology 62 11069613
1995 Over-expression of tissue inhibitor of matrix metalloproteinases (TIMP1 and TIMP2) suppresses extravasation of pulmonary metastasis of a rat bladder carcinoma. International journal of cancer 62 7591285
2011 Localization of MMP-2, MMP-9, TIMP-1, and TIMP-2 in human coronal dentine. Journal of dentistry 61 21641958
2020 TIMP-2 suppresses tumor growth and metastasis in murine model of triple-negative breast cancer. Carcinogenesis 59 31621840
2014 MicroRNA-106a targets TIMP2 to regulate invasion and metastasis of gastric cancer. FEBS letters 59 24440352
2019 Current understanding and future directions in the application of TIMP-2 and IGFBP7 in AKI clinical practice. Clinical chemistry and laboratory medicine 58 30179848
2018 Downregulation of TIMP2 attenuates sepsis-induced AKI through the NF-κb pathway. Biochimica et biophysica acta. Molecular basis of disease 58 30562560
2010 Bovine endometrial metallopeptidases MMP14 and MMP2 and the metallopeptidase inhibitor TIMP2 participate in maternal preparation of pregnancy. Molecular and cellular endocrinology 58 20887771
2016 Matrix metalloproteinases MMP1, MMP2, MMP9 and their tissue inhibitors TIMP1, TIMP2, TIMP3 in head and neck cancer: an immunohistochemical study. Otolaryngologia polska = The Polish otolaryngology 57 27386931
2019 LncRNA FENDRR suppresses the progression of NSCLC via regulating miR-761/TIMP2 axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 55 31545237
2010 Exercise ameliorates serum MMP-9 and TIMP-2 levels in patients with type 2 diabetes. Diabetes & metabolism 51 20149706
1993 Expression of TIMP-1, TIMP-2 and collagenase mRNA in periodontitis-affected human gingival tissue. Journal of periodontal research 51 8410600
2020 Microenvironment-induced TIMP2 loss by cancer-secreted exosomal miR-4443 promotes liver metastasis of breast cancer. Journal of cellular physiology 49 31970775
2015 TIMP-2 Interaction with MT1-MMP Activates the AKT Pathway and Protects Tumor Cells from Apoptosis. PloS one 49 26331622
2021 MiR-149-3p promotes the cisplatin resistance and EMT in ovarian cancer through downregulating TIMP2 and CDKN1A. Journal of ovarian research 46 34798882
2013 Impacts and interactions of PDGFRB, MMP-3, TIMP-2, and RNF213 polymorphisms on the risk of Moyamoya disease in Han Chinese human subjects. Gene 46 23769926
2017 MicroRNA-93 promotes proliferation and metastasis of gastric cancer via targeting TIMP2. PloS one 45 29220395
2008 Clinicopathological significance of MMP-2 and its specific inhibitor TIMP-2 in gastric cancer. Histology and histopathology 45 18498066
2014 Affinity- and specificity-enhancing mutations are frequent in multispecific interactions between TIMP2 and MMPs. PloS one 44 24710006
2000 Localisation of matrix metalloproteinases and TIMP-2 in resorbing mouse bone. Cell and tissue research 44 10772252
2008 Ascorbate-induced osteoblast differentiation recruits distinct MMP-inhibitors: RECK and TIMP-2. Molecular and cellular biochemistry 43 18989628
2022 Unravelling the distinct biological functions and potential therapeutic applications of TIMP2 in cancer. Carcinogenesis 42 35436325
2012 MicroRNA-200b is overexpressed in endometrial adenocarcinomas and enhances MMP2 activity by downregulating TIMP2 in human endometrial cancer cell line HEC-1A cells. Nucleic acid therapeutics 41 23205572
2020 TIMP-2 regulates proliferation, invasion and STAT3-mediated cancer stem cell-dependent chemoresistance in ovarian cancer cells. BMC cancer 39 33023532
2017 miRNA-221 acts as an oncogenic role by directly targeting TIMP2 in non-small-cell lung carcinoma. Gene 39 28392366
2004 Expression of TIMP-1 and TIMP-2 in rats with hepatic fibrosis. World journal of gastroenterology 39 14695775
2018 MicroRNA-205-5p suppresses the invasiveness of oral squamous cell carcinoma by inhibiting TIMP‑2 expression. International journal of oncology 38 29393341
2023 TIMP2 ameliorates blood-brain barrier disruption in traumatic brain injury by inhibiting Src-dependent VE-cadherin internalization. The Journal of clinical investigation 36 38015626
2011 Comparative analysis of the immunohistochemical expression of collagen IV, MMP-9, and TIMP-2 in odontogenic cysts and tumors. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics 36 21911204
2019 Chemerin acts via CMKLR1 and GPR1 to stimulate migration and invasion of gastric cancer cells: putative role of decreased TIMP-1 and TIMP-2. Oncotarget 34 30719206
2019 lncRNA ABHD11-AS1, regulated by the EGFR pathway, contributes to the ovarian cancer tumorigenesis by epigenetically suppressing TIMP2. Cancer medicine 33 31568657
1994 Expression of 72-kDa gelatinase and TIMP-2 in early and late passage human fibroblasts. Experimental cell research 33 8020585
2016 Assessment of MMP-1, MMP-8 and TIMP-2 in experimental periodontitis treated with kaempferol. Journal of periodontal & implant science 32 27127689
2022 Fibroblasts repair blood-brain barrier damage and hemorrhagic brain injury via TIMP2. Cell reports 30 36417884
2021 TIMP1 and TIMP2 Downregulate TGFβ Induced Decidual-like Phenotype in Natural Killer Cells. Cancers 30 34638439
2016 MMP3 and TIMP2 gene variants as predisposing factors for Achilles tendon pathologies: Attempted replication study in a British case-control cohort. Meta gene 30 27222816
2015 miRNA-221 promotes proliferation, migration and invasion by targeting TIMP2 in renal cell carcinoma. International journal of clinical and experimental pathology 30 26191221
2013 NEDD9 depletion leads to MMP14 inactivation by TIMP2 and prevents invasion and metastasis. Molecular cancer research : MCR 30 24202705
2012 Expression and Roles of MMP-2, MMP-9, MMP-13, TIMP-1, and TIMP-2 in Allergic Nasal Mucosa. Allergy, asthma & immunology research 29 22754717
2008 Adenovirus-mediated expression of TIMP-1 and TIMP-2 in bone inhibits osteolytic degradation by human prostate cancer. International journal of cancer 29 17847032
1995 Tissue inhibitor of metalloproteinases-2 (TIMP-2) in rat liver cells is increased by lipopolysaccharide and prostaglandin E2. FEBS letters 29 8001673
2015 Pirenzepine Inhibits Myopia in Guinea Pig Model by Regulating the Balance of MMP-2 and TIMP-2 Expression and Increased Tyrosine Hydroxylase Levels. Cell biochemistry and biophysics 28 25388839
2010 Polymorphisms in MMP-9 and TIMP-2 in Chinese patients with varicose veins. The Journal of surgical research 28 21195432
2015 MiR-301a promotes cell proliferation by directly targeting TIMP2 in multiple myeloma. International journal of clinical and experimental pathology 27 26464662
2012 Expression of MMP-2, TIMP-2, TGF-β1, and decorin in Dupuytren's contracture. Connective tissue research 27 22512703
2022 TIMP-2 regulates 5-Fu resistance via the ERK/MAPK signaling pathway in colorectal cancer. Aging 26 35022331
2004 TIMP-2 is released as an intact molecule following binding to MT1-MMP on the cell surface. Experimental cell research 26 14729066
2020 Resveratrol inhibits the tumor migration and invasion by upregulating TET1 and reducing TIMP2/3 methylation in prostate carcinoma cells. The Prostate 25 32542727
2018 Corneal regeneration by conditioned medium of human uterine cervical stem cells is mediated by TIMP-1 and TIMP-2. Experimental eye research 25 30557571
1994 TIMP-2 expression modulates human melanoma cell adhesion and motility. Annals of the New York Academy of Sciences 24 7978796
2022 Apelin Promotes Prostate Cancer Metastasis by Downregulating TIMP2 via Increases in miR-106a-5p Expression. Cells 22 36291151
2012 Underexpression of MMP-2 and its regulators, TIMP2, MT1-MMP and IL-8, is associated with prostate cancer. International braz j urol : official journal of the Brazilian Society of Urology 22 22555040
2023 Neuronal TIMP2 regulates hippocampus-dependent plasticity and extracellular matrix complexity. Molecular psychiatry 21 37914840
2011 Transcriptional suppression of Sertoli cell Timp2 in rodents following mono-(2-ethylhexyl) phthalate exposure is regulated by CEBPA and MYC. Biology of reproduction 21 21832167
1998 TIMP-1 and TIMP-2 levels in vitreous and subretinal fluid. Japanese journal of ophthalmology 21 9822966
2019 Long noncoding RNA LINC00337 accelerates the non-small-cell lung cancer progression through inhibiting TIMP2 by recruiting DNMT1. American journal of translational research 20 31632575
2017 Urinary Biomarkers IGFBP7 and TIMP-2 for the Diagnostic Assessment of Transient and Persistent Acute Kidney Injury in Critically Ill Patients. PloS one 20 28085896
2017 MicroRNA-15b promotes proliferation and invasion of non‑small cell lung carcinoma cells by directly targeting TIMP2. Oncology reports 20 28498424
2014 Expression of MMP-2, MT1-MMP, and TIMP-2 by cultured rabbit corneal fibroblasts under mechanical stretch. Experimental biology and medicine (Maywood, N.J.) 20 24939826
2010 Involvement of MT1-MMP and TIMP-2 in human periodontal disease. Oral diseases 20 20233321
2017 MMP-10, MMP-7, TIMP-1 and TIMP-2 mRNA expression in esophageal cancer. Acta biochimica Polonica 19 28510611
2023 TIMP-2 and IGFBP7 in human kidney biopsies in renal disease. Clinical kidney journal 18 37664566
2019 Are MMP3, MMP8 and TIMP2 gene variants associated with anterior cruciate ligament rupture susceptibility? Journal of science and medicine in sport 18 30755371
2015 An engineered TIMP2-based and enediyne-integrated fusion protein for targeting MMP-14 shows potent antitumor efficacy. Oncotarget 18 26314845
2013 Matrix metalloproteinase 2 (MMP-2) and their tissue inhibitor 2 (TIMP-2) in gastric cancer patients. Advances in medical sciences 18 24384769
2012 Immunohistochemical expression of MMP-9, TIMP-2, E-cadherin and vimentin in ameloblastomas and their implication in the local aggressive behavior of these tumors. Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie 18 23303021
2019 miR-616 promotes breast cancer migration and invasion by targeting TIMP2 and regulating MMP signaling. Oncology letters 17 31452731
2016 Evaluation of MMP-9 and MMP-2 and their suppressor TIMP-1 and TIMP-2 in adenocarcinoma of esophagogastric junction. OncoTargets and therapy 17 27486337
2016 Plasma levels and diagnostic utility of VEGF, MMP-2 and TIMP-2 in the diagnostics of breast cancer patients. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 17 27775427
2014 Functional Significance of MMP3 and TIMP2 Polymorphisms in Cleft Lip/Palate. Journal of dental research 17 24799419
2010 Systemic levels of MMP2/TIMP2 and cardiovascular risk in CAPD patients. Nephron. Clinical practice 17 20424475
1997 Retinitis pigmentosa locus on 17q (RP17): fine localization to 17q22 and exclusion of the PDEG and TIMP2 genes. Human genetics 17 9385361
2022 USP7 inhibits TIMP2 by up-regulating the expression of EZH2 to activate the NF-κB/PD-L1 axis to promote the development of cervical cancer. Cellular signalling 16 35523402
2016 Urinary [TIMP-2]·[IGFBP7] - Novel Biomarkers to Predict Acute Kidney Injury. American journal of nephrology 16 27174659
2008 Regulation of mRNAs encoding MMP-9 and MMP-2, and their inhibitors TIMP-1 and TIMP-2 by androgens in the rat ventral prostate. Molecular and cellular endocrinology 16 18675881
1999 Generation of expression plasmids for angiostatin, endostatin and TIMP-2 for cancer gene therapy. The International journal of biological markers 16 10669955