Affinage

TIMP2

Metalloproteinase inhibitor 2 · UniProt P16035

Length
220 aa
Mass
24.4 kDa
Annotated
2026-06-10
100 papers in source corpus 23 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIMP2 is a constitutively secreted extracellular protein that governs pericellular proteolysis and transduces matrix-derived signals through both MMP-dependent and MMP-independent mechanisms (PMID:9422744, PMID:37914840, PMID:37321845). Its canonical role is to organize matrix metalloproteinase activity: through N-terminal contacts it binds MT1-MMP (MMP14) while leaving the MT1-MMP C-terminal domain free to recruit proMMP-2, forming a cell-surface ternary complex that concentrates and potentiates proMMP-2 activation (PMID:9422744), and its MMP-binding interface is a sequence compromise tuned for multispecific engagement across the MMP/ADAM family rather than optimal for any single protease (PMID:24710006). TIMP2 forms denaturation-resistant complexes with MMP-2 whose abundance is cytokine-responsive (PMID:8020585), and it acts as a stress-inducible extracellular co-chaperone of HSP90, binding eHSP90, inhibiting its ATPase activity, and loading MMP-2 into a transient inhibited state that the activating co-chaperone AHA1 reverses, constituting a molecular switch over extracellular proteolysis (PMID:31412254). Genetic studies establish that TIMP2 is required for pathological proMMP-2 activation in renal fibrosis (PMID:23760282) and that it has roles distinct and non-redundant from TIMP3 in cardiac remodeling (PMID:24692173). Independent of protease inhibition, TIMP2 signals through integrin α3β1: on endothelial cells it suppresses FGF-2-driven p42/44 MAPK signaling via Shp-1 to inhibit proliferation and angiogenesis (PMID:18721821), and at the blood-brain barrier it blocks Src-mediated VE-cadherin phosphorylation and internalization to preserve barrier integrity, an activity retained by an MMP-inhibition-dead mutant (PMID:38015626). Binding to MT1-MMP also activates Ras-ERK1/2 and AKT survival signaling independent of MT1-MMP proteolysis (PMID:26331622). In the hippocampus, neuronal TIMP2 controls perisynaptic ECM accumulation, adult neurogenesis, and memory through an MMP-independent mechanism (PMID:37914840, PMID:37321845). In renal tubular cells TIMP2 modulates inflammatory and cell-death pathways, including NF-κB signaling (PMID:30562560), BiP-dependent ER stress (PMID:35218571), and cAMP/MARCH7-mediated NLRP3 ubiquitination and degradation (PMID:38497110). TIMP2 expression is controlled transcriptionally by CEBPA and MYC in a cAMP/FSH-responsive manner (PMID:21832167), by SP-1 under hypoxia (PMID:21148412), and is epigenetically silenced by EZH2-mediated H3K27me3 in cancer (PMID:28620234, PMID:29636998), while its mRNA is stabilized by METTL3-mediated m6A modification (PMID:34995800).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1994 Medium

    Established that TIMP2 regulates gelatinase activity by forming a stable physical complex with MMP-2 rather than acting solely as a free inhibitor, and that this complex is cytokine-responsive.

    Evidence Immunoprecipitation and Western detection of denaturation-resistant TIMP-2:MMP-2 complex in IL-1α-stimulated human fibroblasts

    PMID:8020585

    Open questions at the time
    • Did not map binding interface or define activation versus inhibition outcome
    • Limited mechanistic follow-up beyond complex detection
  2. 1998 High

    Resolved how TIMP2 functions as an activator rather than only an inhibitor, showing it bridges MT1-MMP and proMMP-2 into a cell-surface complex that concentrates and potentiates proMMP-2 activation.

    Evidence Domain mutagenesis of MT1-MMP and progelatinase A, soluble constructs, and TIMP2-depleted HT1080 membranes

    PMID:9422744

    Open questions at the time
    • Did not establish stoichiometry in vivo
    • Physiological triggers of complex assembly unaddressed
  3. 1998 Medium

    First indicated that TIMP2 has MMP-independent effects on tumor phenotype, separating its anti-invasive/anti-angiogenic actions from effects on apoptosis and necrosis.

    Evidence Stable TIMP2 overexpression in B16F10 melanoma with in vitro invasion, in vivo angiogenesis, and cell-death readouts

    PMID:9462715

    Open questions at the time
    • No receptor or signaling mechanism identified for MMP-independent effects
    • Single cell line
  4. 2008 High

    Identified integrin α3β1 as a TIMP2 receptor mediating MMP-independent suppression of endothelial proliferation through Shp-1-dependent inhibition of MAPK.

    Evidence Blocking antibodies, integrin α3 siRNA, and dominant-negative Shp-1 in human microvascular endothelial cells

    PMID:18721821

    Open questions at the time
    • Did not define how integrin engagement activates Shp-1
    • Restricted to FGF-2-driven signaling
  5. 2010 Medium

    Linked the angiogenic microenvironment to TIMP2 levels, showing hypoxia transcriptionally suppresses TIMP-2 via SP-1 to enable endothelial migration and vessel formation.

    Evidence Hypoxia chamber experiments in monocytes and endothelial cells with SP-1 analysis and Matrigel plug assays

    PMID:21148412

    Open questions at the time
    • Direct SP-1 promoter occupancy not fully mapped
    • Mechanism connecting hypoxia to SP-1 activity unresolved
  6. 2011 Medium

    Defined a hormone-responsive transcriptional circuit for TIMP2, with CEBPA activating and MYC repressing the promoter under cAMP/FSH control.

    Evidence Promoter deletion mapping, reporter assays, and FSH/forskolin rescue in rat Sertoli cells

    PMID:21832167

    Open questions at the time
    • Tissue specificity of this circuit beyond Sertoli cells unknown
    • Direct CEBPA/MYC binding sites not individually validated
  7. 2013 High

    Demonstrated genetically that TIMP2 is required for pathological proMMP-2 activation in vivo and drives renal tubulointerstitial fibrosis, in contrast to protective TIMP3.

    Evidence TIMP2−/− and TIMP3−/− mice in ureteral obstruction with MMP2 activation and fibrosis readouts

    PMID:23760282

    Open questions at the time
    • Did not dissect whether fibrosis is purely MMP2-dependent
    • Cell type driving activation in vivo not defined
  8. 2014 High

    Established that TIMP2 and TIMP3 have non-redundant tissue functions, with TIMP2 governing hypertrophy and collagen cross-linking enzymes independent of shared MMP-inhibitory activity.

    Evidence TIMP2−/− and TIMP3−/− mice under angiotensin II infusion with echocardiography, histology, and LOX/PLOD1 measurement

    PMID:24692173

    Open questions at the time
    • Molecular basis for LOX/PLOD1 regulation by TIMP2 not defined
    • Receptor mediating cardiac effect unidentified
  9. 2014 Medium

    Showed at the sequence level that the TIMP2 MMP-binding interface is a multispecific compromise, explaining its broad inhibition across the MMP/ADAM family.

    Evidence Computational saturation mutagenesis with SPR validation of point mutants against MMP14

    PMID:24710006

    Open questions at the time
    • Affinity changes not tested across the full panel of 26+ family members
    • In vivo consequence of engineered high-affinity mutants untested
  10. 2014 Medium

    Provided functional evidence that a TIMP2 promoter polymorphism alters expression and implicated NF-κB as a transcriptional regulator.

    Evidence Promoter-reporter luciferase assays and EMSA for NF-κB on rs8179096 alleles

    PMID:24799419

    Open questions at the time
    • Did not establish NF-κB regulation in physiological context
    • Allelic effect on protein levels in tissue not shown
  11. 2015 Medium

    Defined a proteolysis-independent signaling output of the TIMP2/MT1-MMP complex, showing it activates Ras-ERK1/2 and AKT to confer apoptosis resistance.

    Evidence Proteolytically inactive MT1-MMP mutants, FGFR-1 inhibition, dominant-negative Ras, and apoptosis assays

    PMID:26331622

    Open questions at the time
    • Differential receptor requirements (FGFR-1 for ERK but not AKT) not mechanistically resolved
    • Context dependence of pro- versus anti-apoptotic effect unexplained
  12. 2017 High

    Identified megalin/LRP-2 as the endocytic receptor clearing the proMMP-2:TIMP-2 complex, defining a route for extracellular removal of the complex.

    Evidence RAP inhibition, anti-megalin antibodies, SPR direct binding, and conditional renal megalin KO mice with urinary accumulation

    PMID:28659595

    Open questions at the time
    • Did not establish post-endocytic fate of TIMP2
    • Relevance outside kidney/yolk sac uptake not addressed
  13. 2017 Medium

    Established epigenetic silencing of TIMP2 by EZH2-mediated H3K27me3 as a driver of MMP-2/9 activity and cancer invasion.

    Evidence ChIP for EZH2/H3K27me3 at the TIMP2 promoter with EZH2 perturbation and TIMP2 rescue in ovarian cancer cells and xenografts

    PMID:28620234

    Open questions at the time
    • Relative contributions of H3K27me3 versus DNA methylation not separated
    • Upstream signals driving EZH2 recruitment unknown
  14. 2018 Medium

    Replicated EZH2-mediated TIMP2 silencing in a second cancer type, generalizing the epigenetic axis linking TIMP2 loss to MMP-driven invasiveness.

    Evidence EZH2 perturbation with MMP-2/-9 activity, invasion, and promoter methylation analysis in TNBC cells

    PMID:29636998

    Open questions at the time
    • Mechanistic depth lower than the ovarian study
    • In vivo validation limited
  15. 2018 Medium

    Implicated TIMP2 as a mediator of sepsis-induced acute kidney injury through NF-κB-dependent cytokine release and apoptosis in tubular cells.

    Evidence TIMP2 siRNA in HK-2 cells with LPS, p-P65 Western blot, and kidney-specific TIMP2 knockdown in CLP sepsis mice

    PMID:30562560

    Open questions at the time
    • Direct molecular link between TIMP2 and NF-κB activation not defined
    • Whether effect is intracellular or receptor-mediated unresolved
  16. 2019 High

    Recast TIMP2 as an extracellular co-chaperone of HSP90 that, with AHA1, forms a reversible switch loading and inactivating MMP-2 on eHSP90.

    Evidence Co-IP, ATP binding/ATPase assays, TIMP2 and AHA1 gene knockout, blocking antibodies, and zymography in HT1080 cells

    PMID:31412254

    Open questions at the time
    • Stress signals that induce TIMP2 co-chaperone function not defined
    • In vivo relevance of the eHSP90 switch untested
  17. 2022 Medium

    Identified TIMP2 interaction with the ER chaperone BiP and its facilitation of BiP secretion as a driver of ER stress in tubular injury.

    Evidence Co-IP of TIMP2 with BiP, overexpression/knockdown in HK-2 cells, and tubule-specific TIMP2 conditional KO in CLP sepsis mice

    PMID:35218571

    Open questions at the time
    • Reciprocal interaction validation limited to single Co-IP
    • Subcellular site of TIMP2/BiP interaction unclear
  18. 2022 Medium

    Showed TIMP2 mRNA is stabilized by METTL3-mediated m6A modification via the reader IGF2BP2, linking m6A regulation to Notch-driven podocyte injury in diabetic nephropathy.

    Evidence METTL3 perturbation, podocyte-conditional METTL3 KO mice, MeRIP/m6A sequencing, and IGF2BP2 reader identification

    PMID:34995800

    Open questions at the time
    • Direct m6A site mapping on TIMP2 not single-base resolved
    • Causal chain from TIMP2 to Notch incompletely defined
  19. 2022 Medium

    Demonstrated that fibroblast-derived TIMP2 repairs blood-brain barrier damage by upregulating tight junction proteins via a paracellular mechanism.

    Evidence Col1α1+ fibroblast ablation mice in intracerebral hemorrhage with exogenous TIMP2 rescue and BBB permeability/tight junction readouts

    PMID:36417884

    Open questions at the time
    • Receptor mediating TIMP2 effect on tight junctions not identified here
    • MMP dependence not directly tested
  20. 2023 High

    Defined an MMP-independent BBB-protective mechanism in which TIMP2 engages integrin α3β1 to block Src-mediated VE-cadherin phosphorylation and internalization, stabilizing endothelial junctions.

    Evidence MMP-inhibition-dead AlaTIMP2 mutant in a TBI mouse model and human brain microvascular endothelial cells with Src, VE-cadherin, and Rac1 readouts

    PMID:38015626

    Open questions at the time
    • How integrin α3β1 engagement suppresses Src not detailed
    • Relationship to the fibroblast-derived TIMP2 tight-junction mechanism unintegrated
  21. 2023 High

    Established a neuronal, MMP-independent role for TIMP2 in controlling perisynaptic ECM, adult neurogenesis, and hippocampus-dependent memory.

    Evidence Neuronal conditional TIMP2 KO, Ala-TIMP2 MMP-dead treatment, behavioral memory tests, and neurogenesis/ECM imaging, replicated by an independent group

    PMID:37321845 PMID:37914840

    Open questions at the time
    • Molecular receptor mediating neuronal TIMP2 effects unidentified
    • How TIMP2 controls ECM density independent of MMP inhibition unresolved
  22. 2024 Medium

    Defined a cAMP/MARCH7 axis by which extracellular TIMP2 drives autophagy-dependent NLRP3 degradation to suppress pyroptosis in sepsis-AKI.

    Evidence Tubule-specific Timp2 KO with recombinant TIMP2 rescue, cAMP measurement, NLRP3 ubiquitination, MARCH7 identification, and pyroptosis markers

    PMID:38497110

    Open questions at the time
    • Receptor coupling extracellular TIMP2 to cAMP elevation unidentified
    • Direct demonstration of MARCH7-NLRP3 ubiquitination link in vivo limited

Open questions

Synthesis pass · forward-looking unresolved questions
  • The cell-surface receptor(s) that couple TIMP2 to its diverse MMP-independent outputs (cAMP elevation, NLRP3 degradation, neuronal ECM control, cardiac LOX/PLOD1 regulation) remain undefined, leaving the unifying logic across tissues unresolved.
  • No single receptor links the cAMP, neuronal, and cardiac MMP-independent phenotypes
  • Whether integrin α3β1 mediates outputs beyond endothelium is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0044183 protein folding chaperone 1
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 3 GO:0031012 extracellular matrix 1
Pathway
R-HSA-1474244 Extracellular matrix organization 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 2
Partners
AHA1BIPHSP90ITGA3MARCH7MMP14MMP2
Complex memberships
MT1-MMP:TIMP2:proMMP-2 ternary complexTIMP-2:MMP-2 complexeHSP90:TIMP2:MMP-2 complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 TIMP2 binds MT1-MMP (membrane type 1 MMP) primarily through N-terminal domain interactions, leaving the C-terminal domain of MT1-MMP free to interact with progelatinase A (MMP-2). This forms a cell-surface receptor complex that concentrates progelatinase A and potentiates its activation. Residues 568-631 of the progelatinase A C-terminal domain are required for binding to both heparin and TIMP2, and for cell membrane-associated MT1-MMP-dependent activation. C-terminal domain mutants of MT1-MMP and progelatinase A, soluble MT1-MMP constructs, heparin binding assays, cell membrane preparations from HT1080 cells depleted of endogenous TIMP2 The Journal of biological chemistry High 9422744
1998 TIMP2 over-expression in B16F10 melanoma cells reduces invasion and angiogenesis but increases resistance to apoptosis while increasing necrosis, demonstrating MMP-inhibition-dependent and MMP-inhibition-independent effects on tumor cell phenotype. Stable transfection of TIMP2 cDNA into B16F10 cells; in vitro invasion assays; in vivo Matrigel angiogenesis assay; subcutaneous tumor growth in mice; apoptosis/necrosis assays International journal of cancer Medium 9462715
2008 TIMP-2 inhibits FGF-2-induced p42/44 MAPK activation and endothelial cell proliferation through binding to integrin α3β1 on endothelial cell surfaces, acting upstream of Shp-1-dependent inhibition of MAPK signaling; dominant-negative Shp-1 and anti-integrin α3/β1 blocking antibodies or siRNA knockdown of integrin α3 abrogated this effect. Dominant-negative Shp-1 mutant expression; blocking antibodies against integrin α3 and β1; siRNA disruption of integrin α3; protein tyrosine phosphatase inhibitor orthovanadate; MAPK activation assays in human microvascular endothelial cells Microvascular research High 18721821
2015 TIMP-2 binding to MT1-MMP induces rapid and sustained AKT activation in a manner independent of MT1-MMP proteolytic activity but requiring Ras activation; ERK1/2 activation by TIMP-2/MT1-MMP also requires FGFR-1 but AKT activation does not. Both ERK1/2 and AKT activation protect tumor cells from serum starvation-induced apoptosis, while TIMP-2 upregulates apoptosis induced by 3D type I collagen. Dose- and time-response experiments in MT1-MMP-expressing cells; use of proteolytically inactive MT1-MMP mutants; FGFR-1 inhibition; dominant-negative Ras; apoptosis assays under serum starvation and 3D collagen conditions PloS one Medium 26331622
2019 TIMP2 functions as a stress-inducible extracellular co-chaperone of HSP90: it binds eHSP90, increases eHSP90 ATPase binding to ATP and inhibits its ATPase activity, disrupts the eHSP90:MMP2 complex to terminally inactivate MMP2, but also loads MMP2 onto eHSP90 in a transient inhibitory state. The activating co-chaperone AHA1 displaces TIMP2 from the complex to reactivate MMP2, forming a molecular switch regulating extracellular proteolysis. Co-immunoprecipitation; ATP binding and ATPase assays; gene knockout of TIMP2 and AHA1; blocking antibodies against TIMP2 and AHA1 in HT1080 cancer cells; gelatin zymography Cell reports High 31412254
2014 Computational saturation mutagenesis of the TIMP2 MMP-binding interface identified the interface as non-optimal for any single MMP; experimental point mutations produced >10-fold improvement in affinity to MMP14 (MT1-MMP), indicating TIMP2 sequence is a compromise for multispecific binding across 26+ MMP/ADAM family members. Computational free energy calculations (saturation mutagenesis); experimental surface plasmon resonance binding measurements of TIMP2 point mutants against MMP14 PloS one Medium 24710006
2014 TIMP2 deficiency (TIMP2−/−) in mice results in enhanced myocardial hypertrophy without fibrosis following angiotensin II infusion, while TIMP3 deficiency produces the inverse (excess fibrosis without hypertrophy), demonstrating that TIMP2 and TIMP3 have distinct and non-redundant roles in cardiac remodeling independent of their shared MMP-inhibitory functions. Reduced collagen cross-linking enzymes LOX and PLOD1 underlie suppressed collagen deposition in TIMP2−/− hearts. TIMP2−/− and TIMP3−/− mouse models; angiotensin II infusion; echocardiographic imaging; in vitro co-culture of cardiomyocytes with cardiac fibroblasts; collagen cross-linking enzyme measurements Cardiovascular research High 24692173
2013 TIMP2 promotes MMP2 activation in the kidney: ureteral obstruction markedly increased MMP2 activation in TIMP3−/− kidneys but was completely blocked in TIMP2−/− kidneys, demonstrating that TIMP2 is required for pathological pro-MMP2 activation and resultant renal tubulointerstitial fibrosis, while TIMP3 protects from damage. TIMP2−/− and TIMP3−/− mice; unilateral ureteral obstruction model; gene microarray; collagen I/III expression; MMP2 activation assays; TGF-β/Smad pathway analysis; caspase-3 and TNFR-converting enzyme activities Kidney international High 23760282
2018 TIMP2 silencing ameliorates LPS-induced cytokine release and apoptosis in kidney tubular cells via inhibition of the NF-κB pathway (p-P65); kidney-specific TIMP2 knockdown in CLP sepsis mice reduced proinflammatory cytokines and kidney dysfunction, revealing that TIMP2 mediates sepsis-induced AKI through NF-κB regulation. siRNA knockdown of TIMP2 in HK-2 cells; LPS challenge; cytokine assays; NF-κB (p-P65) western blot; kidney-specific TIMP2 knockdown via lentiviral vector injection; CLP sepsis mouse model; serum creatinine and histopathology Biochimica et biophysica acta. Molecular basis of disease Medium 30562560
2022 TIMP2 interacts with BiP (binding immunoglobulin protein), an ER chaperone, and facilitates its extracellular secretion, thereby triggering ER stress; TIMP2 overexpression induces ER stress while TIMP2 knockdown attenuates LPS-induced ER stress and apoptosis; tubule-specific TIMP2 knockout mice showed decreased ER stress-mediated apoptosis in CLP-induced AKI. Co-immunoprecipitation of TIMP2 with BiP; TIMP2 overexpression and siRNA knockdown in HK-2 cells; tubule-specific TIMP2 conditional KO mice (Ksp-Cre/TIMP2flox/flox); CLP sepsis model; ER stress markers; serum creatinine; apoptosis assays FASEB journal Medium 35218571
2024 Extracellular TIMP2 increases intracellular cAMP, which promotes ubiquitination of NLRP3 via the E3 ligase MARCH7 and subsequent autophagy-dependent NLRP3 degradation, attenuating pyroptosis in renal tubular cells; kidney tubule-specific Timp2 KO mice showed exacerbated pyroptosis (elevated NLRP3, Caspase1, GSDMD) in sepsis-AKI, and exogenous recombinant TIMP2 rescued this. Kidney tubule-specific Timp2 KO mice; CLP sepsis model; recombinant TIMP2 rescue experiments; LPS-stimulated primary renal tubular cells; cAMP measurement; NLRP3 ubiquitination assays; MARCH7 identification; autophagy flux assays; pyroptosis marker measurement American journal of physiology. Cell physiology Medium 38497110
2023 TIMP2 interacts with integrin α3β1 on brain microvascular endothelial cells, inhibiting Src activation-dependent VE-cadherin phosphorylation, VE-cadherin/catenin complex destabilization, and subsequent VE-cadherin internalization; increased membrane localization of VE-cadherin enhances Rac1 activity and inhibits stress fiber formation; an MMP-inhibition-dead mutant (AlaTIMP2) retains these BBB-protective effects, confirming MMP-independent mechanism. AlaTIMP2 (MMP-inhibitory-dead mutant); TBI mouse model; human brain microvascular endothelial cells under hypoxia/inflammation; mechanistic studies of Src phosphorylation, VE-cadherin internalization/membrane localization, Rac1 activity, and stress fiber formation; integrin α3β1 binding assays The Journal of clinical investigation High 38015626
2022 Fibroblasts repair blood-brain barrier damage in intracerebral hemorrhage via TIMP2: Col1α1+ fibroblast ablation exacerbated BBB damage, and the protective effect was mediated by TIMP2 through upregulation of tight junction proteins via a paracellular mechanism; exogenous TIMP2 rescued BBB disruption in fibroblast-ablated mice. Col1α1-targeted fibroblast ablation mice; ICH model; in vitro BBB permeability assays; tight junction protein immunostaining; exogenous TIMP2 rescue experiments; transcytosis-associated protein analysis Cell reports Medium 36417884
2023 Neuronal TIMP2 regulates adult hippocampal neurogenesis, dendritic spine turnover, ECM accumulation around synapses, and hippocampus-dependent memory; conditional neuronal TIMP2 knockout mice show increased ECM around synapses, impaired newborn neuron migration through denser ECM, and memory deficits; an Ala-TIMP2 mutant lacking MMP inhibition retains cognitive benefits, indicating MMP-independent mechanism for cognitive effects. Conditional TIMP2 knockout (neuronal-specific); hippocampus-dependent memory tests; adult neurogenesis and dendritic spine quantification; ECM accumulation imaging; Ala-TIMP2 (MMP-inhibitory-dead) treatment; intraperitoneal injection of TIMP2 and TIMP2-hIgG4 fusion protein in aged mice; cfos expression; synapse density (CA1, DG) Molecular psychiatry / eNeuro High 37321845 37914840
2017 The proMMP-2:TIMP-2 complex is endocytosed in rat yolk sac cells by the megalin/LRP-2 endocytic receptor; receptor-associated protein (RAP, a natural LRP antagonist) blocked accumulation of proMMP-2 and TIMP-2; anti-megalin antibodies (but not anti-LRP-1 antibodies) inhibited binding; BIAcore surface plasmon resonance confirmed direct interaction; conditional renal megalin/LRP-2 invalidation in mice caused urinary accumulation of proMMP-2 and TIMP-2. RAP inhibition; blocking antibodies against megalin/LRP-2 and LRP-1; BIAcore (SPR) direct binding assay; conditional renal megalin/LRP-2 knockout mice; radiolabeled proMMP-2:TIMP-2 uptake assay Scientific reports High 28659595
2011 TIMP2 transcription in Sertoli cells is activated by the transcription factor CEBPA under basal conditions and repressed by MYC; MEHP (mono-(2-ethylhexyl) phthalate) exposure decreases CEBPA transactivation and increases MYC-mediated repression of the TIMP2 promoter; FSH rescues MEHP-suppressed TIMP2 levels via cAMP-dependent translocation of CEBPA into the nucleus. Sequential 5'-deletion mutagenesis of the TIMP2 promoter; CEBPA and MYC reporter assays in rat Sertoli cells; FSH and forskolin rescue experiments; CEBPA nuclear translocation assay; actinomycin D experiments Biology of reproduction Medium 21832167
2022 METTL3-mediated m6A modification of TIMP2 mRNA promotes TIMP2 expression in podocytes in an IGF2BP2-dependent manner; elevated METTL3 in diabetic nephropathy increases m6A on TIMP2 mRNA and modulates Notch signaling to exert pro-inflammatory and pro-apoptotic effects. METTL3 knockout/overexpression in podocytes; podocyte-conditional METTL3 KO mice; AAV9-shMETTL3 in STZ-diabetic and db/db mice; m6A sequencing/MeRIP; IGF2BP2 identification as m6A reader; Notch signaling pathway readouts Molecular therapy Medium 34995800
2017 EZH2 represses TIMP2 expression via H3K27me3 and DNA methylation at the TIMP2 promoter in ovarian cancer; EZH2 overexpression promotes MMP2 and MMP9 proteolytic activities and cancer invasion/migration, effects largely reversed by TIMP2 knockdown; EZH2 and H3K27me3 presence at the TIMP2 promoter was confirmed by ChIP. ChIP for EZH2 and H3K27me3 at TIMP2 promoter; EZH2 overexpression and knockdown; H3K27me3 inhibition; TIMP2 re-expression rescue assays; in vitro invasion/migration; in vivo xenograft Scientific reports Medium 28620234
2018 EZH2-mediated H3K27me3 at the TIMP2 promoter silences TIMP2 transcription in triple-negative breast cancer cells, resulting in increased MMP-2 and MMP-9 activity and enhanced invasiveness. EZH2 knockdown/overexpression in TNBC cells; MMP-2/-9 activity measurement; invasion assays; TIMP2 promoter methylation analysis American journal of cancer research Medium 29636998
2014 The TIMP2 rs8179096 promoter polymorphism is functional: the T allele shows 2.5-fold increased promoter activity compared to the C allele; both alleles bind nuclear factor kappa B (NF-κB), suggesting NF-κB as a transcriptional regulator of TIMP2. Promoter-reporter luciferase assays; DNA-protein binding (EMSA) for NF-κB Journal of dental research Medium 24799419
2010 Hypoxia reduces TIMP-2 secretion from human monocytes and endothelial cells by inhibiting TIMP-2 transcription through a mechanism involving the transcription factor SP-1; reduced TIMP-2 levels enhance endothelial cell migration/proliferation, tube formation in vitro, and blood vessel formation in vivo. Hypoxia chamber experiments with human primary monocytes, U937/THP-1 monocyte cell lines, and endothelial cells; TIMP-2 secretion measurement; SP-1 transcription factor analysis; Matrigel plug assay in vivo; endothelial tube formation assay American journal of physiology. Cell physiology Medium 21148412
1994 In late-passage human fibroblasts, TIMP-2 forms a denaturation-resistant complex with 72-kDa gelatinase (MMP-2); IL-1α increases the level of this TIMP-2:MMP-2 complex without changing individual protein levels, indicating that TIMP-2 regulates 72-kDa gelatinase activity through complex formation. Monoclonal antibody detection (Western blot, autoradiography); immunoprecipitation; early vs. late passage fibroblast culture; IL-1α stimulation Experimental cell research Medium 8020585

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 The TIMP2 membrane type 1 metalloproteinase "receptor" regulates the concentration and efficient activation of progelatinase A. A kinetic study. The Journal of biological chemistry 528 9422744
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 174 34995800
2012 In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2. The Journal of pathology 174 22262409
1997 In situ hybridization studies of metalloproteinases 2 and 9 and TIMP-1 and TIMP-2 expression in human prostate cancer. Clinical & experimental metastasis 152 9174126
2007 MMP2 role in breast cancer brain metastasis development and its regulation by TIMP2 and ERK1/2. Clinical & experimental metastasis 127 17505812
2016 Long noncoding RNA DANCR promotes invasion of prostate cancer through epigenetically silencing expression of TIMP2/3. Oncotarget 114 27191265
2001 Expression of MMP2, MMP9, MT1-MMP, TIMP1, and TIMP2 mRNA in valvular lesions of the heart. The Journal of pathology 104 11400152
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 100 24692173
1992 Differential regulation of TIMP-1 and TIMP-2 mRNA expression in normal and Ha-ras-transformed murine fibroblasts. Gene 100 1639268
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 Exosomal miR-93 promotes proliferation and invasion in hepatocellular carcinoma by directly inhibiting TIMP2/TP53INP1/CDKN1A. Biochemical and biophysical research communications 95 29859935
2018 Mechanisms Underlying Increased TIMP2 and IGFBP7 Urinary Excretion in Experimental AKI. Journal of the American Society of Nephrology : JASN 94 29980651
2005 Matrix metalloproteinase expression and function during fin regeneration in zebrafish: analysis of MT1-MMP, MMP2 and TIMP2. Matrix biology : journal of the International Society for Matrix Biology 88 15935631
2012 miR-200c is aberrantly expressed in leiomyomas in an ethnic-dependent manner and targets ZEBs, VEGFA, TIMP2, and FBLN5. Endocrine-related cancer 83 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 73 25731730
2017 EZH2-mediated epigenetic silencing of TIMP2 promotes ovarian cancer migration and invasion. Scientific reports 72 28620234
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 67 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
1998 Immunohistochemical expression of MMP-2, MMP-9, and TIMP-2 in neuroblastoma: association with tumor progression and clinical outcome. Journal of pediatric surgery 63 9722003
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
2018 Downregulation of TIMP2 attenuates sepsis-induced AKI through the NF-κb pathway. Biochimica et biophysica acta. Molecular basis of disease 60 30562560
2014 MicroRNA-106a targets TIMP2 to regulate invasion and metastasis of gastric cancer. FEBS letters 60 24440352
2020 TIMP-2 suppresses tumor growth and metastasis in murine model of triple-negative breast cancer. Carcinogenesis 59 31621840
2019 Current understanding and future directions in the application of TIMP-2 and IGFBP7 in AKI clinical practice. Clinical chemistry and laboratory medicine 59 30179848
2010 Bovine endometrial metallopeptidases MMP14 and MMP2 and the metallopeptidase inhibitor TIMP2 participate in maternal preparation of pregnancy. Molecular and cellular endocrinology 59 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 58 27386931
2013 TIMP2 and TIMP3 have divergent roles in early renal tubulointerstitial injury. Kidney international 56 23760282
2019 LncRNA FENDRR suppresses the progression of NSCLC via regulating miR-761/TIMP2 axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 55 31545237
2015 MiR-761 Promotes Progression and Metastasis of Non-Small Cell Lung Cancer by Targeting ING4 and TIMP2. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 53 26278569
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 47 34798882
2013 Polymorphic variation within the ADAMTS2, ADAMTS14, ADAMTS5, ADAM12 and TIMP2 genes and the risk of Achilles tendon pathology: a genetic association study. Journal of science and medicine in sport 47 23491141
2017 MicroRNA-93 promotes proliferation and metastasis of gastric cancer via targeting TIMP2. PloS one 45 29220395
2014 Affinity- and specificity-enhancing mutations are frequent in multispecific interactions between TIMP2 and MMPs. PloS one 44 24710006
2022 Unravelling the distinct biological functions and potential therapeutic applications of TIMP2 in cancer. Carcinogenesis 43 35436325
2008 TIMP-2 disrupts FGF-2-induced downstream signaling pathways. Microvascular research 42 18721821
2017 miRNA-221 acts as an oncogenic role by directly targeting TIMP2 in non-small-cell lung carcinoma. Gene 40 28392366
2023 TIMP2 ameliorates blood-brain barrier disruption in traumatic brain injury by inhibiting Src-dependent VE-cadherin internalization. The Journal of clinical investigation 39 38015626
2020 TIMP-2 regulates proliferation, invasion and STAT3-mediated cancer stem cell-dependent chemoresistance in ovarian cancer cells. BMC cancer 39 33023532
2018 MicroRNA-205-5p suppresses the invasiveness of oral squamous cell carcinoma by inhibiting TIMP‑2 expression. International journal of oncology 39 29393341
2011 Variation in FGF1, FOXE1, and TIMP2 genes is associated with nonsyndromic cleft lip with or without cleft palate. Birth defects research. Part A, Clinical and molecular teratology 39 21462296
2004 Expression of TIMP-1 and TIMP-2 in rats with hepatic fibrosis. World journal of gastroenterology 39 14695775
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
2002 Expression of MMP-2,TIMP-2 protein and the ratio of MMP-2/TIMP-2 in gallbladder carcinoma and their significance. World journal of gastroenterology 32 12439941
2022 TIMP2 mediates endoplasmic reticulum stress contributing to sepsis-induced acute kidney injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 31 35218571
2022 Fibroblasts repair blood-brain barrier damage and hemorrhagic brain injury via TIMP2. Cell reports 31 36417884
2021 TIMP1 and TIMP2 Downregulate TGFβ Induced Decidual-like Phenotype in Natural Killer Cells. Cancers 30 34638439
2016 MicroRNA-221 Regulates Hypertrophy of Ligamentum Flavum in Lumbar Spinal Stenosis by Targeting TIMP-2. Spine 30 26571175
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
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
2012 CD133 affects the invasive ability of HCT116 cells by regulating TIMP-2. The American journal of pathology 29 23195431
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
2022 TIMP-2 regulates 5-Fu resistance via the ERK/MAPK signaling pathway in colorectal cancer. Aging 27 35022331
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
2014 Retinal MMP-12, MMP-13, TIMP-1, and TIMP-2 expression in murine experimental retinal detachment. Investigative ophthalmology & visual science 26 24526442
2020 Resveratrol inhibits the tumor migration and invasion by upregulating TET1 and reducing TIMP2/3 methylation in prostate carcinoma cells. The Prostate 25 32542727
2020 Circular RNA derived from TIMP2 functions as a competitive endogenous RNA and regulates intervertebral disc degeneration by targeting miR‑185‑5p and matrix metalloproteinase 2. International journal of molecular medicine 23 32626912
2017 Post-transcriptional Regulation of MMP16 and TIMP2 Expression via miR-382, miR-410 and miR-200b in Endometrial Cancer. Cancer genomics & proteomics 23 28871006
2023 TIMP-2 and IGFBP7 in human kidney biopsies in renal disease. Clinical kidney journal 22 37664566
2023 Neuronal TIMP2 regulates hippocampus-dependent plasticity and extracellular matrix complexity. Molecular psychiatry 22 37914840
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
2011 Transcriptional suppression of Sertoli cell Timp2 in rodents following mono-(2-ethylhexyl) phthalate exposure is regulated by CEBPA and MYC. Biology of reproduction 22 21832167
2023 MicroRNA-483-5p Inhibits Hepatocellular Carcinoma Cell Proliferation, Cell Steatosis, and Fibrosis by Targeting PPARα and TIMP2. Cancers 21 36980601
2012 NUR77 inhibits the expression of TIMP2 and increases the migration and invasion of HTR-8/SVneo cells induced by CYR61. Placenta 21 22551568
2019 Are MMP3, MMP8 and TIMP2 gene variants associated with anterior cruciate ligament rupture susceptibility? Journal of science and medicine in sport 20 30755371
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
2010 Opposing roles of PARP-1 in MMP-9 and TIMP-2 expression and mast cell degranulation in dyslipidemic dilated cardiomyopathy. Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology 20 20434371
2024 TIMP2 protects against sepsis-associated acute kidney injury by cAMP/NLRP3 axis-mediated pyroptosis. American journal of physiology. Cell physiology 19 38497110
2017 MMP-10, MMP-7, TIMP-1 and TIMP-2 mRNA expression in esophageal cancer. Acta biochimica Polonica 19 28510611
2014 Functional Significance of MMP3 and TIMP2 Polymorphisms in Cleft Lip/Palate. Journal of dental research 19 24799419
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 18 35523402
2022 seRNA PAM controls skeletal muscle satellite cell proliferation and aging through trans regulation of Timp2 expression synergistically with Ddx5. Aging cell 18 35851988
2015 An engineered TIMP2-based and enediyne-integrated fusion protein for targeting MMP-14 shows potent antitumor efficacy. Oncotarget 18 26314845
2019 miR-616 promotes breast cancer migration and invasion by targeting TIMP2 and regulating MMP signaling. Oncology letters 17 31452731
1997 Retinitis pigmentosa locus on 17q (RP17): fine localization to 17q22 and exclusion of the PDEG and TIMP2 genes. Human genetics 17 9385361
2010 Reduced TIMP-2 in hypoxia enhances angiogenesis. American journal of physiology. Cell physiology 16 21148412
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
2021 miR-17-5p and miR-4443 Promote Esophageal Squamous Cell Carcinoma Development by Targeting TIMP2. Frontiers in oncology 15 34778021
2019 MicroRNA-552 promotes migration and invasion of osteosarcoma through targeting TIMP2. Biochemical and biophysical research communications 15 30765222
2003 [Expression and clinical significance of MMP-2, MMP-9,TIMP-1, and TIMP-2 in breast carcinoma]. Ai zheng = Aizheng = Chinese journal of cancer 15 12969531
2023 Noncanonical Activity of Tissue Inhibitor of Metalloproteinases 2 (TIMP2) Improves Cognition and Synapse Density in Aging. eNeuro 14 37321845
2021 ESR1 mediated circ_0004018 suppresses angiogenesis in hepatocellular carcinoma via recruiting FUS and stabilizing TIMP2 expression. Experimental cell research 14 34487732
2019 MicroRNA-93 promotes the tumorigenesis of osteosarcoma by targeting TIMP2. Bioscience reports 14 31383784
2017 Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2. Scientific reports 14 28659595

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