Affinage

TIMP1

Metalloproteinase inhibitor 1 · UniProt P01033

Length
207 aa
Mass
23.2 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIMP-1 is a secreted glycoprotein that operates as both an endogenous metalloproteinase inhibitor and a cytokine-like signaling ligand that controls cell survival, proliferation, differentiation, migration, and immune cell activation (PMID:8798626, PMID:24895412, PMID:26001794). As a protease inhibitor it is a slow, tight-binding noncompetitive inhibitor of fibroblast collagenase (MMP-1) that engages the enzyme C-terminal domain in an initial rapid step before forming a tight complex (PMID:8798626), and it also inhibits ADAM-10 with sub-nanomolar potency, distinguishing it from TACE (PMID:10818225). This proteolytic activity tunes substrate availability in tissue contexts: TIMP-1 restrains MMP-mediated generation of active HGF to limit Met/p38-driven hepatocyte cell-cycle progression (PMID:15726641), blocks ADAM-10-mediated shedding of Met to sustain receptor signaling in tumor cells (PMID:21789719), and limits MMP-9 activity to preserve barrier integrity and matrix structure (PMID:23532086, PMID:37675562). Independently of its MMP-inhibitory domain, TIMP-1 functions as a receptor ligand—principally through the tetraspanin CD63 and its co-receptors β1-integrin and a cell-surface proMMP-9/CD44 complex—to trigger JAK2/PI3K/Akt, FAK, ERK1/2, and Wnt/β-catenin signaling (PMID:19010442, PMID:24635319, PMID:26001794, PMID:30121936). Through these axes TIMP-1 promotes anti-apoptotic survival signaling (PMID:19010442, PMID:26366732), drives EMT via TWIST1 induction (PMID:24895412), directs adhesion and chemotaxis of neural stem cells and dendritic cells (PMID:24635319, PMID:30635444), stimulates granulopoiesis and neutrophilia (PMID:26001794), and modulates osteogenic and oligodendrocyte differentiation (PMID:30121936, PMID:30473539). MMP-independence of these signaling outputs is established with structural TIMP-1 mutants lacking inhibitory activity that retain full signaling competence (PMID:24895412, PMID:26001794, PMID:26366732). Additional surface partners include CD82, which binds the TIMP-1 N-terminus and mediates its endocytosis (PMID:28030805), and APP/APLP2, engaged via the TIMP-1 C-terminal domain to drive monocyte glucose uptake and proinflammatory cytokine expression (PMID:36629908). In stromal and tumor settings TIMP-1 is itself a transcriptional output of TGF-β/SMAD3, NF-κB, ERK1/2, and STAT1/3 signaling, integrating it into reciprocal tumor–stroma crosstalk (PMID:35787446, PMID:21903858, PMID:11918744, PMID:15451430).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1996 High

    Establishing the kinetic mechanism of TIMP-1 inhibition defined how it neutralizes collagenase, answering whether inhibition was simple competitive blockade or a multi-step process.

    Evidence Reconstituted enzyme kinetics with nonlinear regression and C-terminal-truncated mini-collagenase

    PMID:8798626

    Open questions at the time
    • Does not address inhibition of other MMP family members
    • Structural basis of the slow tight-binding transition not resolved
  2. 2000 High

    Demonstrating sub-nanomolar inhibition of ADAM-10 but not TACE extended TIMP-1's target range beyond classical MMPs and defined selectivity among sheddases.

    Evidence In vitro quenched fluorescent substrate assay with recombinant catalytic domains

    PMID:10818225

    Open questions at the time
    • Cellular consequences of ADAM-10 inhibition not tested here
    • No structural model of the TIMP-1/ADAM-10 complex
  3. 2004 Medium

    Dissecting TIMP-1's effect on endothelial migration into MMP-dependent and MMP-independent arms first signaled that TIMP-1 has signaling functions separable from protease inhibition.

    Evidence Parallel recombinant TIMP-1 and synthetic MMP inhibitor treatment with FAK/PTEN/paxillin readouts

    PMID:15530852

    Open questions at the time
    • Receptor mediating the MMP-independent arm not identified
    • PTEN induction mechanism unresolved
  4. 2005 High

    Reciprocal mouse genetics placed TIMP-1 upstream of HGF/Met/p38 in liver regeneration, showing protease inhibition controls growth factor availability and cell-cycle timing.

    Evidence Timp-1 knockout and transgenic overexpression mice with cell-cycle and phospho-Met readouts

    PMID:15726641

    Open questions at the time
    • Which MMP generates active HGF in vivo not pinpointed
    • Does not separate inhibitory from signaling contributions
  5. 2008 High

    Identifying the surface proMMP-9/CD44 complex as the platform for TIMP-1 anti-apoptotic signaling provided the first defined receptor context for its survival activity.

    Evidence Co-IP, proMMP-9 siRNA, MMP-9 blocking antibodies, and survival assays in UT-7 cells

    PMID:19010442

    Open questions at the time
    • How the ternary complex transduces signal across the membrane unclear
    • Generalizability beyond erythroid cells untested here
  6. 2011 Medium

    Two studies linked TIMP-1 to ADAM-10/Met regulation in tumors and to NF-κB-driven anti-apoptotic CD63/Akt signaling, connecting protease inhibition and receptor signaling to cancer cell behavior.

    Evidence siRNA knockdown of Timp-1/Adam-10 in liver metastasis model and BRAF/NF-κB epistasis in thyroid carcinoma cells

    PMID:21789719 PMID:21903858

    Open questions at the time
    • Direct CD63 binding not structurally mapped in these studies
    • Single-lab pathway placements
  7. 2013 Medium

    Multiple studies established that thrombin/STAT1/3, ERK1/2, and NF-κB drive TIMP-1 transcription, and that TIMP-1 governs Reelin processing, topoisomerase phosphorylation, BBB integrity, and CAF expansion, broadening its functional reach.

    Evidence EMSA/antisense (STAT), SILAC phosphoproteomics, organotypic epilepsy and ALF models, in vivo CAF assays

    PMID:11918744 PMID:23493620 PMID:23532086 PMID:23909892 PMID:24143225

    Open questions at the time
    • Kinase assignments in topoisomerase study are computational
    • Receptor identity in several contexts not established
  8. 2014 High

    CD63 was directly defined as the TIMP-1 receptor driving EMT via TWIST1 and, with β1-integrin, Akt/FAK-dependent migration, anchoring the signaling model with domain mutants proving MMP-independence.

    Evidence TIMP-1 overexpression, TWIST1 RNAi rescue, structural MMP-domain mutants, CD63 shRNA, β1-integrin blockade in MCF10A and hNSCs

    PMID:24635319 PMID:24895412

    Open questions at the time
    • Stoichiometry of CD63/β1-integrin co-receptor complex unresolved
    • Proximal signaling step downstream of CD63 not defined
  9. 2015 High

    Domain-dissecting variants combined with CD63 knockout proved that the CD63-binding signaling domain alone drives granulopoiesis, while Bcl-2 interaction and p90RSK/BAD signaling explain MMP-independent apoptosis suppression.

    Evidence CD63 knockout mice, TIMP-1 functional domain variants, BrdU labeling, T2G mutant and Bcl-2 Co-IP, plus TGF-β/CD63/FAK crosstalk in HCC

    PMID:26001794 PMID:26366732 PMID:26549110

    Open questions at the time
    • How CD63 couples to JAK2/Akt versus FAK in different cells unresolved
    • Direct vs indirect nature of TIMP-1/Bcl-2 interaction not structurally defined
  10. 2017 Medium

    CD82 was identified as a distinct N-terminal-binding partner mediating TIMP-1 endocytosis and anti-migration, expanding the receptor repertoire beyond CD63.

    Evidence Co-IP, domain mapping, CD82 siRNA, endocytosis and migration assays in pancreatic carcinoma cells

    PMID:28030805

    Open questions at the time
    • Relationship between CD82 and CD63 receptor usage unclear
    • Single-lab finding without reciprocal in vivo validation
  11. 2018 Medium

    TIMP-1/CD63 physical interaction was directly confirmed in glioblastoma tissue and shown to couple CD63/β1-integrin to Akt/β-catenin in oligodendrocyte differentiation, reinforcing the receptor model and tying it to Wnt signaling.

    Evidence Proximity ligation assay and Co-IP in glioblastoma; pathway inhibitor and receptor-blocking analysis in OPCs

    PMID:29523123 PMID:30121936

    Open questions at the time
    • Mechanism linking CD63 to β-catenin not detailed
    • Crosstalk with canonical Wnt only partially defined
  12. 2019 High

    Studies tied TIMP-1/CD63/ITGB1/FAK to pathogen-induced dendritic cell hypermotility and TIMP-1/Wnt/β-catenin to MSC osteogenesis, demonstrating context-dependent suppression or promotion of cell behavior.

    Evidence shRNA of TIMP-1/CD63/ITGB1 with FAK/SRC/PI3K inhibitors in DCs; reciprocal TIMP-1 gain/loss with Wnt epistasis in hBMSCs

    PMID:30473539 PMID:30635444

    Open questions at the time
    • How identical CD63/FAK axis yields opposite migratory outcomes unresolved
    • Direct receptor for Wnt/β-catenin effect in MSCs not mapped
  13. 2023 High

    Discovery of APP/APLP2 as C-terminal-domain TIMP-1 receptors and of ADAMTS-7 as a protease that degrades TIMP-1 added a new signaling axis and a regulatory mechanism controlling TIMP-1 abundance.

    Evidence Unbiased ligand-receptor capture, pull-down, confocal and domain variants (APP); Co-IP, in vitro degradation, FRET, and double-KO mice (ADAMTS-7)

    PMID:36629908 PMID:37675562

    Open questions at the time
    • Downstream signaling from APP/TIMP-1 engagement beyond glucose uptake/cytokines undefined
    • Physiological breadth of ADAMTS-7-mediated TIMP-1 turnover beyond plaques unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single CD63-centered receptor system selects between Akt, FAK, ERK, and Wnt outputs to produce opposing context-specific phenotypes, and how the protease-inhibitory and cytokine-like functions are coordinated in vivo, remains unresolved.
  • No structural model of TIMP-1/CD63/co-receptor signaling complex
  • Determinants of pro- versus anti-migratory and pro- versus anti-proliferative outcomes unknown
  • Integration of inhibitory and signaling roles in physiology not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0060089 molecular transducer activity 5 GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005576 extracellular region 4
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1266738 Developmental Biology 2
Partners
ADAMTS7APLP2APPCD44CD63CD82ITGB1MMP9
Complex memberships
CD63/β1-integrin receptor complexTIMP-1/proMMP-9/CD44 ternary complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 TIMP-1 inhibits the catalytic activity of ADAM-10 with an apparent inhibition constant of approximately 0.1 nM, as measured by a quenched fluorescent substrate assay, distinguishing ADAM-10 inhibition from TACE (which is only inhibited by TIMP-3). In vitro enzyme inhibition assay (quenched fluorescent substrate assay) with recombinant proteins FEBS letters High 10818225
1996 TIMP-1 is a slow, tight-binding inhibitor of fibroblast-type collagenase (MMP-1) operating via a noncompetitive two-step mechanism: rapid formation of a reversible complex (Kd ~8 nM) followed by slow formation of a tight complex (global Kd ~0.1 nM). The C-terminal domain of collagenase is required for the initial rapid binding step. Enzyme kinetics — time-course inhibition assays analyzed by nonlinear regression and numerical integration; comparison with C-terminal domain-truncated 'mini-collagenase' The Journal of biological chemistry High 8798626
2005 TIMP-1 negatively regulates hepatocyte growth factor (HGF) activity during liver regeneration: TIMP-1 loss-of-function in Timp-1−/− mice elevated MMP activity and increased active HGF, leading to enhanced phosphorylation of Met and its downstream effector p38, accelerating hepatocyte cell cycle progression (earlier cyclin D1, PCNA, phospho-histone H3). Conversely, TIMP-1 gain-of-function delayed cell cycle progression. Genetic loss-of-function (Timp-1−/− mice) and gain-of-function (transgenic overexpression); real-time RT-PCR; immunostaining for cell cycle markers and phospho-Met Hepatology High 15726641
2008 TIMP-1 binds specifically to proMMP-9 at the cell surface, where proMMP-9 is anchored to the plasma membrane via CD44. Formation of this ternary TIMP-1/proMMP-9/CD44 complex is necessary for TIMP-1-induced anti-apoptotic signaling (JAK2/PI3K/Akt pathway) in UT-7 erythroid cells; silencing proMMP-9 abrogated the TIMP-1 survival effect, and MMP-9-function-blocking antibodies that prevent TIMP-1 binding also abolished cell survival without reproducing the effect themselves. Co-immunoprecipitation, proMMP-9 siRNA knockdown, MMP-9 function-blocking antibodies, synthetic MMP inhibitor, cell survival assays The international journal of biochemistry & cell biology High 19010442
2011 Tumor cell-derived TIMP-1 maintains Met receptor signaling by inhibiting ADAM-10-mediated shedding of Met; knockdown of tumor-cell Timp-1 suppressed Met phosphorylation and HGF-induced Met activation, whereas knockdown of ADAM-10 mimicked Timp-1 overexpression by increasing Met phosphorylation and tumor cell scattering in the liver. siRNA knockdown of Timp-1 and Adam-10 in syngeneic murine experimental liver metastasis model; in vitro Met phosphorylation assays; immunolocalization in metastatic foci Clinical & experimental metastasis High 21789719
2013 TIMP-1 binding to its surface receptor CD63 activates intracellular signaling that induces EMT in human breast epithelial MCF10A cells, evidenced by loss of E-cadherin and gain of vimentin, N-cadherin, and fibronectin, through upregulation of the transcription factor TWIST1; RNAi knockdown of TWIST1 rescued E-cadherin expression. This function is independent of TIMP-1's MMP-inhibitory domain, as demonstrated with structural TIMP-1 mutants. TIMP-1 overexpression, RNAi knockdown of TWIST1, structural MMP-inhibitory domain mutants, immunofluorescence for EMT markers Molecular cancer research High 24895412
2014 TIMP-1 signals through CD63 to activate β1-integrin-mediated Akt and FAK phosphorylation, promoting adhesion and chemotaxis of human neural stem cells (hNSCs); shRNA silencing of CD63 or blocking of β1-integrin abrogated the TIMP-1-induced migration, focal adhesion formation, and cytoskeletal reorganization. shRNA knockdown of CD63, β1-integrin blocking antibody, PI3K inhibitor, migration assays, immunofluorescence for focal adhesions and F-actin The Biochemical journal High 24635319
2015 TIMP-1 triggers granulopoiesis and neutrophilia via CD63-mediated signaling: elevated systemic TIMP-1 increased myeloid progenitor proliferation (BrdU incorporation) and granulopoiesis gene expression in bone marrow. TIMP-1 variants with intact CD63-binding (signaling) domain but lacking MMP-inhibitory activity were sufficient to induce neutrophilia, and genetic ablation of CD63 abolished both TIMP-1-induced neutrophilia and granulopoiesis. In vivo TIMP-1 elevation in mice; BrdU pulse-labeling; TIMP-1 functional domain variants; CD63 knockout mice Haematologica High 26001794
2015 TIMP-1 mediates TGF-β-dependent crosstalk between hepatic stellate cells (HSCs) and hepatocellular carcinoma (HCC) cells by activating FAK signaling via interaction with CD63: TGF-β signaling in HSCs increased TIMP-1 secretion, which then activated FAK in HCC cells; this promoted HCC proliferation, motility, and survival. Conditioned medium experiments, TGF-β signaling inhibition (EW-7197), in vivo orthotopic xenograft model, FAK/Akt signaling assessment Scientific reports Medium 26549110
2011 BRAF(V600E) mutation in papillary thyroid carcinoma activates NF-κB, which upregulates TIMP-1; TIMP-1 then binds its surface receptor CD63, activating Akt signaling and conferring anti-apoptotic behavior. Silencing BRAF in BCPAP cells (harboring BRAF(V600E)) reduced TIMP-1 expression and NF-κB activity; sorafenib (but not MEK inhibitor) inhibited both NF-κB and TIMP-1/Akt signaling, indicating the pathway is MEK-independent. siRNA knockdown of BRAF, specific pathway inhibitors, luciferase NF-κB reporter, invasion assays, immunohistochemistry in 56 PTC specimens Endocrine-related cancer Medium 21903858
2004 TIMP-1 inhibits endothelial cell migration through two distinct mechanisms: (1) MMP-dependent pathway involving increased expression and junctional accumulation of VE-cadherin and PECAM-1; (2) MMP-independent pathway involving stimulation of PTEN expression with subsequent dephosphorylation of focal adhesion kinase (FAK, pY397) and paxillin and reduction of F-actin stress fibers and focal adhesions. Recombinant TIMP-1 and synthetic MMP inhibitor treatment; immunofluorescence; Western blot for FAK, paxillin, PTEN, VE-cadherin, PECAM-1 Experimental cell research Medium 15530852
2018 TIMP-1 promotes oligodendrocyte progenitor cell (OPC) differentiation into oligodendrocytes via a CD63/β1-integrin receptor complex that activates Akt and downstream β-catenin signaling; this trophic action is independent of TIMP-1's MMP-inhibitory function, and was counteracted (but not abolished) by canonical Wnt7a signaling. Pharmacological inhibitors, receptor blocking, signaling pathway analysis (Akt, β-catenin), comparison with MMP-inhibitory function Molecular neurobiology Medium 30121936
2019 Toxoplasma gondii-induced TIMP-1 secretion from dendritic cells drives DC hypermotility via a CD63-ITGB1(β1-integrin)-FAK signaling axis; shRNA silencing of TIMP-1, CD63, or ITGB1, and pharmacological inhibition of FAK, SRC, or PI3K each abolished parasite-induced DC hypermotility. shRNA gene silencing of TIMP-1, CD63, ITGB1, FAK; pharmacological antagonism of FAK, SRC, PI3K; DC migration assays Journal of cell science High 30635444
2013 TIMP-1 inhibits MMP activity in epileptic conditions, thereby preventing proteolytic processing of Reelin; kainate treatment upregulated TIMP-1 in hippocampal neurons, functional inhibition of TIMP-1 prevented kainate-induced impairment of Reelin cleavage, and application of recombinant TIMP-1 alone was sufficient to impair Reelin processing and induce granule cell dispersion (GCD). Organotypic hippocampal slice cultures, kainate epilepsy model, TIMP-1 functional inhibition, recombinant TIMP-1 application, immunolabeling for TIMP-1 and Reelin processing FASEB journal Medium 23493620
2023 TIMP-1 is a novel ligand for Amyloid Precursor Protein (APP) and APP-like protein 2 (APLP2); TIMP-1 binding to APP on human monocytes triggers glucose uptake and proinflammatory cytokine expression. Mechanistically, TIMP-1 acts via its C-terminal domain and through APP, as demonstrated by recombinant TIMP-1 C-terminal domain variants and in silico docking, and confirmed by unbiased ligand-receptor capture screening, pull-down assays, and confocal microscopy. Unbiased ligand-receptor capture screening, pull-down assays, confocal microscopy, recombinant TIMP-1 domain variants, in silico docking, glucose uptake assay, cytokine expression The Journal of cell biology High 36629908
2023 ADAMTS-7 degrades TIMP-1 by direct binding via its catalytic domain (demonstrated by co-immunoprecipitation and in vitro degradation assays), thereby reducing TIMP-1's inhibitory capacity toward MMP-9 and increasing collagen degradation in atherosclerotic plaques. Co-immunoprecipitation, in vitro degradation assay, FRET-based protein-protein interaction assay, mass spectrometry of atherosclerotic plaques from Apoe−/−Adamts7−/− vs. Apoe−/− mice, Picrosirius red collagen staining Circulation research High 37675562
2022 In lung adenocarcinoma, TIMP-1 overexpression in tumor-associated fibroblasts (TAFs) is driven specifically by the TGF-β1/SMAD3 pathway; fibroblast-secreted TIMP-1 enhances growth and invasion of ADC cancer cells in a manner requiring cancer cell surface receptor CD63; SMAD3 or TIMP-1 knockdown in TAFs attenuated tumor aggressiveness in vivo. shRNA/siRNA knockdown of SMAD3, TIMP-1, CD63; co-culture assays; in vivo co-injection xenograft model; gene expression analyses in human ADC vs SCC specimens Matrix biology High 35787446
2015 TIMP-1 inhibits apoptosis in lung adenocarcinoma cells via interaction with Bcl-2 (demonstrated by co-immunoprecipitation) and activation of p90RSK with phosphorylation of BAD at serine 112, reducing Bax levels and increasing mitochondrial permeability; this anti-apoptotic function is independent of MMP inhibition (TIMP-1 T2G mutant lacking MMP inhibitory activity retains full anti-apoptotic effect). Co-immunoprecipitation, TIMP-1 T2G structural mutant (MMP-inhibitory domain ablated), Western blot for PARP cleavage/BAD phosphorylation/Bax, staurosporine apoptosis assay PloS one High 26366732
2002 STAT1 and STAT3 mediate thrombin-induced TIMP-1 gene transcription in human glomerular mesangial cells; thrombin induced STAT-DNA binding activity, and antisense oligonucleotides against STAT1 or STAT3 inhibited both STAT-DNA binding and TIMP-1 mRNA expression; the SIF band on EMSA contained both STAT1 and STAT3. Northern blot, EMSA, supershift assay, antisense oligonucleotides for STAT1 and STAT3 Kidney international Medium 11918744
1993 Recombinant TIMP-1 (and TIMP-2) inhibit stimulated bone resorption (induced by PTH or 1,25-dihydroxyvitamin D3) in cultured neonatal mouse calvariae in a dose-dependent, reversible manner, with complete inhibition at 1 μg/ml; neither TIMP affected protein synthesis, DNA synthesis, or PTH-enhanced β-glucuronidase secretion, suggesting the inhibitory effect is targeted at matrix metalloproteinase-mediated resorption steps. Recombinant protein treatment in organ culture (calvarial bone resorption assay); dose-response analysis; controls for cell toxicity and PTH signaling Biochimica et biophysica acta Medium 8485170
2013 TIMP-1-overexpressing cancer cells exhibit increased expression and phosphorylation of topoisomerases 1, 2A, and 2B, which correlates with resistance to topoisomerase inhibitors; pathway analysis implicates protein kinases CK2a, CDK1, PLK1, and ATM in topoisomerase hyperphosphorylation in TIMP-1-high MCF-7 cells. SILAC-based quantitative mass spectrometry of global proteome and phosphoproteome in TIMP-1-high vs. TIMP-1-low MCF-7 cells; NetworKIN kinase prediction Journal of proteome research Medium 23909892
2018 TIMP-1 and CD63 proteins are co-expressed at the cellular level in glioblastoma cells, located in close molecular proximity (demonstrated by proximity ligation assay), and co-immunoprecipitate, confirming a physical protein-protein interaction between TIMP-1 and its surface receptor CD63 in glioblastoma. Proximity ligation assay, co-immunoprecipitation, immunofluorescence co-localization in human glioblastoma tissue BMC cancer Medium 29523123
2017 CD82 (KAI1/tetraspanin) is a binding partner of TIMP-1 on the surface of pancreatic adenocarcinoma cells; CD82 binds TIMP-1 via its large extracellular loop interacting with the N-terminal region of TIMP-1, co-localizes with TIMP-1, and facilitates membrane-bound TIMP-1 endocytosis, contributing to the anti-migration effect of TIMP-1; CD82 silencing partially eliminates these functions. Co-immunoprecipitation, co-localization, CD82 siRNA silencing, TIMP-1 endocytosis assay, cell migration assay Oncotarget Medium 28030805
2019 TIMP-1 inhibits proliferation and osteogenic differentiation of human bone marrow-derived MSCs (hBMSCs) through the Wnt/β-catenin signaling pathway: TIMP-1 knockdown upregulated β-catenin and cyclin D1, enhanced osteogenic markers (Sox9, osteocalcin, RUNX-2), and restored Dickkopf-1-inhibited β-catenin/cyclin D1/RUNX-2 expression; conversely, TIMP-1 overexpression attenuated Wnt3a-induced β-catenin/cyclin D1/RUNX-2 upregulation. Stable TIMP-1 overexpression and knockdown in hBMSCs; Alizarin Red S staining; ALP activity; Western blot for β-catenin, cyclin D1, RUNX-2; Wnt3a and Dickkopf-1 pathway manipulation Bioscience reports Medium 30473539
2006 TIMP-1 gene-deficient fibrosarcoma cells show significantly increased sensitivity to chemotherapy-induced apoptosis compared to genetically identical wild-type cells, demonstrating that endogenous TIMP-1 protects cells from apoptosis independently of exogenous supplementation. TIMP-1 gene-deficient vs. wild-type fibrosarcoma cells derived from mouse lung tissue; chemotherapy-induced apoptosis assays British journal of cancer Medium 17047657
2013 TIMP-1 promotes cellular proliferation in gastric cancer in an NF-κB-dependent manner: TNF-α and NF-κB activation induced TIMP-1 expression, NF-κB inhibition (BAY11-7082) downregulated TIMP-1, and TFF1 reconstitution suppressed NF-κB and inhibited TIMP-1-mediated proliferative potential (EDU assay). NF-κB inhibitor BAY11-7082, TFF1 reconstitution with recombinant protein, quantitative RT-PCR, EDU proliferation assay, gastric organoids from Tff1-KO mice Molecular carcinogenesis Medium 30035371
2004 Pancreatic cancer-conditioned medium stimulates pancreatic stellate cell (PSC) proliferation and TIMP-1 gene expression through the MAP kinase (ERK1/2) pathway; inhibition of ERK1/2 phosphorylation with U0126 prevented both growth and TIMP-1 upregulation. PSC culture with PANC-1 conditioned medium, ERK1/2 inhibitor U0126, real-time PCR for TIMP-1 mRNA, DNA synthesis and cell counting Biochemical and biophysical research communications Medium 15451430
2006 GPI-anchored TIMP-1 inserted into the plasma membrane of renal cell carcinoma (RCC) cells altered the association of MMPs with the cell surface, inhibited RCC proliferation, and rendered normally FAS-resistant RCC cells sensitive to FAS-induced apoptosis by shifting the balance of pro- and anti-apoptotic BCL-2-family proteins; perforin-mediated lysis was not affected. GPI-TIMP-1 fusion protein treatment of RCC cell lines; FAS apoptosis assays; perforin lysis assay; BCL-2-family Western blotting Oncogene Medium 16261161
2013 TIMP-1 attenuates blood-brain barrier (BBB) permeability in acute liver failure by inhibiting MMP-9, reducing activation of EGFR and p38 MAPK signaling, and restoring tight junction protein occludin; intracerebroventricular delivery of TIMP-1 cDNA or pegylated TIMP-1 protein provided similar protection. Intracerebroventricular TIMP-1 cDNA injection and pegylated-TIMP-1 protein treatment in murine ALF model; sodium fluorescein permeability assay; EGFR and p38 MAPK Western blot; occludin immunostaining Journal of cerebral blood flow and metabolism Medium 23532086
2013 TIMP-1 promotes cancer associated fibroblast (CAF) accumulation in prostate and colon cancer and enhances CAF proliferation and migration in vitro; TIMP-1 activates ERK1/2 kinase signaling in prostate CAFs. In vivo tumor growth assays with TIMP-1-overexpressing cells; in vitro CAF proliferation/migration assays; Western blot for ERK1/2 phosphorylation PloS one Medium 24143225
1999 TIMP-1 (and TIMP-2) at nanomolar concentrations stimulate osteoclastic bone resorption in vitro through a mechanism related to the functional activity of osteoclasts (not osteoclast number), which cannot be replicated by synthetic MMP inhibitors, indicating the bone resorption-stimulating activity of TIMP-1 is independent of its MMP-inhibitory effect. Removal/reconstitution of TIMPs from FCS in osteoclast bone resorption cultures; TRAP-positive cell counting; comparison with synthetic metalloproteinase inhibitors BE16627B and R94138 Journal of bone and mineral metabolism Medium 10575588

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment? American journal of physiology. Lung cellular and molecular physiology 335 10956632
2000 The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS letters 334 10818225
2013 Cytokine functions of TIMP-1. Cellular and molecular life sciences : CMLS 247 23982756
1996 Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds. The British journal of dermatology 177 8776359
2010 Salivary MMP-8, TIMP-1, and ICTP as markers of advanced periodontitis. Journal of clinical periodontology 153 20507371
2005 Metalloproteinase inhibitor TIMP-1 affects hepatocyte cell cycle via HGF activation in murine liver regeneration. Hepatology (Baltimore, Md.) 120 15726641
2013 TIMP-1 promotes accumulation of cancer associated fibroblasts and cancer progression. PloS one 106 24143225
1992 Differential regulation of TIMP-1 and TIMP-2 mRNA expression in normal and Ha-ras-transformed murine fibroblasts. Gene 100 1639268
2007 Role of TIMP-1 and TIMP-2 in the progression of cerebral aneurysms. Stroke 99 17569872
2004 MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in patients with rheumatoid arthritis and psoriatic arthritis. Clinical and experimental rheumatology 87 15144129
2004 TIMP-1 inhibits microvascular endothelial cell migration by MMP-dependent and MMP-independent mechanisms. Experimental cell research 86 15530852
2002 TIMP-1 overexpression in pancreatic cancer attenuates tumor growth, decreases implantation and metastasis, and inhibits angiogenesis. The Journal of surgical research 85 11792150
2022 Cut loose TIMP-1: an emerging cytokine in inflammation. Trends in cell biology 81 36163148
2002 Modulation of matrix metalloproteinase and TIMP-1 expression by cytokines in human RPE cells. Investigative ophthalmology & visual science 78 12147614
1993 Human glomeruli express TIMP-1 mRNA and TIMP-2 protein and mRNA. The American journal of physiology 78 8322893
2001 Serum TIMP-1, TIMP-2, and MMP-1 in patients with systemic sclerosis, primary Raynaud's phenomenon, and in normal controls. Annals of the rheumatic diseases 75 11502611
2001 Differential expression and localization of TIMP-1 and TIMP-4 in human gliomas. British journal of cancer 73 11437402
1998 Localization of TIMP-1, TIMP-2, TIMP-3, gelatinase A and gelatinase B in pathological human corneas. Current eye research 72 9543631
2002 Elevation of serum and urine levels of TIMP-1 and tenascin in patients with renal disease. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 71 12032189
2005 Beneficial and detrimental influences of tissue inhibitor of metalloproteinase-1 (TIMP-1) in tumor progression. Biochimie 70 15781325
2003 Effects of Th2 cytokines on expression of collagen, MMP-1, and TIMP-1 in conjunctival fibroblasts. Investigative ophthalmology & visual science 69 12506073
1994 Expression of stromelysin-1 and TIMP-1 in the involuting mammary gland and in early invasive tumors of the mouse. International journal of cancer 66 7960227
2011 BRAFV600E mutation, TIMP-1 upregulation, and NF-κB activation: closing the loop on the papillary thyroid cancer trilogy. Endocrine-related cancer 65 21903858
2008 Serum levels of MMP-9 and TIMP-1 in primary hypertension and effect of antihypertensive treatment. European journal of internal medicine 65 19524176
2014 TIMP-1 via TWIST1 induces EMT phenotypes in human breast epithelial cells. Molecular cancer research : MCR 62 24895412
2011 Localization of MMP-2, MMP-9, TIMP-1, and TIMP-2 in human coronal dentine. Journal of dentistry 62 21641958
2006 TIMP-1 gene deficiency increases tumour cell sensitivity to chemotherapy-induced apoptosis. British journal of cancer 62 17047657
1996 Enhanced RNA expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) in human breast cancer. International journal of cancer 61 8608981
1993 Inhibition of stimulated bone resorption in vitro by TIMP-1 and TIMP-2. Biochimica et biophysica acta 61 8485170
2015 TIMP-1 mediates TGF-β-dependent crosstalk between hepatic stellate and cancer cells via FAK signaling. Scientific reports 59 26549110
2014 Urinary TIMP-1 and MMP-2 levels detect the presence of pancreatic malignancies. British journal of cancer 58 25137018
2004 TIMP-1 alters susceptibility to carcinogenesis. Cancer research 58 14871825
2010 Effect of TIMP-1 and MMP in pterygium invasion. Investigative ophthalmology & visual science 56 20207965
2003 Homocysteine enhances TIMP-1 expression and cell proliferation associated with NADH oxidase in rat mesangial cells. Kidney international 56 12631082
2017 TIMP-1 is upregulated, but not essential in hepatic fibrogenesis and carcinogenesis in mice. Scientific reports 52 28386095
2007 MMP-13 and TIMP-1 determinations in progressive chronic periodontitis. Journal of clinical periodontology 52 17716308
1993 Expression of TIMP-1, TIMP-2 and collagenase mRNA in periodontitis-affected human gingival tissue. Journal of periodontal research 51 8410600
2015 Differential effects of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 on atherosclerosis and monocyte/macrophage invasion. Cardiovascular research 49 26645981
2015 TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice. Haematologica 47 26001794
2011 Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met-signaling via inhibition of Adam-10. Clinical & experimental metastasis 47 21789719
2014 MMP-2, MMP-3, TIMP-1, TIMP-2, and TIMP-3 protein levels in human aqueous humor: relationship with axial length. Investigative ophthalmology & visual science 46 24876280
2023 ADAMTS-7 Modulates Atherosclerotic Plaque Formation by Degradation of TIMP-1. Circulation research 45 37675562
2004 Pancreatic cancer stimulates pancreatic stellate cell proliferation and TIMP-1 production through the MAP kinase pathway. Biochemical and biophysical research communications 45 15451430
2014 TIMP-1 modulates chemotaxis of human neural stem cells through CD63 and integrin signalling. The Biochemical journal 44 24635319
2008 TIMP-1 expression in human colorectal cancer is associated with TGF-B1, LOXL2, INHBA1, TNF-AIP6 and TIMP-2 transcript profiles. Molecular oncology 42 19383344
1999 Timp-1, -2 and -3 show coexpression with gelatinases A and B during mouse tooth morphogenesis. European journal of oral sciences 42 10232461
2008 TIMP-1 binding to proMMP-9/CD44 complex localized at the cell surface promotes erythroid cell survival. The international journal of biochemistry & cell biology 41 19010442
2018 TIMP-1 Promotes Oligodendrocyte Differentiation Through Receptor-Mediated Signaling. Molecular neurobiology 40 30121936
2013 TIMP-1 attenuates blood-brain barrier permeability in mice with acute liver failure. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 40 23532086
2013 Tissue inhibitor of metalloproteinase 1 (TIMP-1) as a biomarker in gastric cancer: a review. Scandinavian journal of gastroenterology 40 23834019
2012 TIMP-1 deficiency leads to lethal partial hepatic ischemia and reperfusion injury. Hepatology (Baltimore, Md.) 39 22407827
2004 Expression of TIMP-1 and TIMP-2 in rats with hepatic fibrosis. World journal of gastroenterology 39 14695775
2022 Aberrant TIMP-1 overexpression in tumor-associated fibroblasts drives tumor progression through CD63 in lung adenocarcinoma. Matrix biology : journal of the International Society for Matrix Biology 37 35787446
2015 TIMP-1 overexpression in lung carcinoma enhances tumor kinetics and angiogenesis in brain metastasis. Journal of neuropathology and experimental neurology 37 25756591
2019 TIMP-1 promotes hypermigration of Toxoplasma-infected primary dendritic cells via CD63-ITGB1-FAK signaling. Journal of cell science 35 30635444
2013 TIMP-1 increases expression and phosphorylation of proteins associated with drug resistance in breast cancer cells. Journal of proteome research 35 23909892
2007 Metalloproteinases-2, -9 and TIMP-1 expression in stable and unstable coronary plaques undergoing PCI. International journal of cardiology 35 17706812
2006 Correlation between TIMP-1 expression and liver fibrosis in two rat liver fibrosis models. World journal of gastroenterology 35 16718785
1996 The mechanism of inhibition of collagenase by TIMP-1. The Journal of biological chemistry 35 8798626
2012 The immunohistochemical characterization of MMP-2, MMP-10, TIMP-1, TIMP-2, and podoplanin in oral squamous cell carcinoma. Oral surgery, oral medicine, oral pathology and oral radiology 34 22769410
2015 TIMP-1 Inhibits Apoptosis in Lung Adenocarcinoma Cells via Interaction with Bcl-2. PloS one 33 26366732
2013 TIMP-1 inhibits the proteolytic processing of Reelin in experimental epilepsy. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 23493620
2010 Epidermal growth factor (EGF) induces motility and upregulates MMP-9 and TIMP-1 in bovine trophoblast cells. Molecular reproduction and development 33 20578063
2003 Synovial MMP-3 and TIMP-1 levels and their correlation with cytokine expression in canine rheumatoid arthritis. Veterinary immunology and immunopathology 33 12586482
2002 Latanoprost's effects on TIMP-1 and TIMP-2 expression in human ciliary muscle cells. Investigative ophthalmology & visual science 33 12454040
2020 The Behavior of MMP-2, MMP-7, MMP-9, and Their Inhibitors TIMP-1 and TIMP-2 in Adenoma-Colorectal Cancer Sequence. Digestive diseases (Basel, Switzerland) 31 32961536
2018 Co-expression of TIMP-1 and its cell surface binding partner CD63 in glioblastomas. BMC cancer 30 29523123
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
2021 Diagnostic values of MMP-7, MMP-9, MMP-11, TIMP-1, TIMP-2, CEA, and CA19-9 in patients with colorectal cancer. The Journal of international medical research 28 33942633
2014 Effect of osteopontin on TIMP-1 and TIMP-2 mRNA in chondrocytes of human knee osteoarthritis in vitro. Experimental and therapeutic medicine 28 25009588
2023 TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes. The Journal of cell biology 26 36629908
2019 TIMP-1 inhibits proliferation and osteogenic differentiation of hBMSCs through Wnt/β-catenin signaling. Bioscience reports 26 30473539
2018 Involvement of TIMP-1 in PECAM-1-mediated tumor dissemination. International journal of oncology 26 29845213
2014 Retinal MMP-12, MMP-13, TIMP-1, and TIMP-2 expression in murine experimental retinal detachment. Investigative ophthalmology & visual science 26 24526442
2012 Expression of STAT3, MMP-1 and TIMP-1 in gastric cancer and correlation with pathological features. Molecular medicine reports 26 22469989
2023 TIMP-1 Protects Tight Junctions of Brain Endothelial Cells From MMP-Mediated Degradation. Pharmaceutical research 24 37700105
2006 GPI-anchored TIMP-1 treatment renders renal cell carcinoma sensitive to FAS-meditated killing. Oncogene 23 16261161
2021 The role of matrix metalloproteinase-9 and its inhibitor TIMP-1 in burn injury: a systematic review. International journal of burns and trauma 22 34557330
2018 TIMP-1 Promotes the Immune Response in Influenza-Induced Acute Lung Injury. Lung 22 30167842
2018 TFF1 antagonizes TIMP-1 mediated proliferative functions in gastric cancer. Molecular carcinogenesis 21 30035371
1998 TIMP-1 and TIMP-2 levels in vitreous and subretinal fluid. Japanese journal of ophthalmology 21 9822966
2019 TIMP-1 is Overexpressed and Secreted by Platinum Resistant Epithelial Ovarian Cancer Cells. Cells 20 31861382
2017 Correlation between the COL4A3, MMP-9, and TIMP-1 polymorphisms and risk of keratoconus. Japanese journal of ophthalmology 20 28197741
2002 STAT1 and STAT3 mediate thrombin-induced expression of TIMP-1 in human glomerular mesangial cells. Kidney international 20 11918744
2017 MMP-10, MMP-7, TIMP-1 and TIMP-2 mRNA expression in esophageal cancer. Acta biochimica Polonica 19 28510611
2013 TIMP-1 polymorphisms in a Chinese Han population with intracerebral hemorrhage. The International journal of neuroscience 19 23841813
2022 Increase in Serum MMP-9 and TIMP-1 Concentrations during Alcohol Intoxication in Adolescents-A Preliminary Study. Biomolecules 18 35625637
2019 MMP-9 and TIMP-1 in placenta of hypertensive disorder complicating pregnancy. Experimental and therapeutic medicine 18 31258700
2018 Effects of Controlling Abnormal Joint Movement on Expression of MMP13 and TIMP-1 in Osteoarthritis. Cartilage 18 29938527
1998 Equine TIMP-1 and TIMP-2: identification, activity and cellular sources. Equine veterinary journal 18 9758100
2018 TIMP-1 association with collagen type I overproduction in hereditary gingival fibromatosis. Oral diseases 17 29989318
2017 TIMP-1 and CD82, a promising combined evaluation marker for PDAC. Oncotarget 17 28030805
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
2013 Identification of miR-1293 potential target gene: TIMP-1. Molecular and cellular biochemistry 17 23943285
2012 Expression of MMPs and TIMP-1 in smoker and nonsmoker chronic periodontitis patients before and after periodontal treatment. Journal of periodontal research 17 22472034
2011 Combinatorial effect of TIMP-1 and α1AT gene polymorphisms on development of chronic obstructive pulmonary disease. Clinical biochemistry 17 21763297
2007 Expression of mRNA MMP-7 and mRNA TIMP-1 in non-small cell lung cancer. Anticancer research 17 17695477
1999 Increased TIMP-1 activity results in increased expression of gelatinases and altered cell motility. Journal of cellular biochemistry 17 10502306
1999 Tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) stimulate osteoclastic bone resorption. Journal of bone and mineral metabolism 17 10575588

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