Affinage

TIMP1

Metalloproteinase inhibitor 1 · UniProt P01033

Round 2 corrected
Length
207 aa
Mass
23.2 kDa
Annotated
2026-04-28
130 papers in source corpus 38 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIMP-1 is a secreted, disulfide-rich glycoprotein that functions both as a broad-spectrum inhibitor of matrix metalloproteinases (MMPs) and ADAM-10, and as a multifunctional cytokine that signals through several cell-surface receptor complexes to regulate cell survival, proliferation, differentiation, and migration. Its N-terminal wedge inserts into the MMP active-site cleft with Cys1 bidentately coordinating the catalytic zinc, achieving sub-nanomolar inhibition via a two-step slow tight-binding mechanism; inhibition of ADAM-10 uniquely requires the C-terminal domain (PMID:9288970, PMID:8798626, PMID:18215140). Independent of MMP inhibition, TIMP-1 engages CD63/β1-integrin to activate FAK, PI3K/Akt, and ERK survival signaling, binds a proMMP-9/CD44 ternary complex on erythroid cells to trigger JAK2/PI3K/Akt, signals through CD74 to activate ZAP-70 in monocytes, and interacts with APP/APLP2 to drive monocyte glucose uptake and proinflammatory cytokine expression (PMID:16917503, PMID:19010442, PMID:34391782, PMID:36629908). In vivo, TIMP-1 controls HGF bioavailability during liver regeneration, promotes oligodendrocyte differentiation in the CNS, drives granulopoiesis via CD63, and modulates angiogenesis by regulating the ratio of free to complexed proMMP-9 (PMID:15726641, PMID:21508247, PMID:26001794, PMID:24174628).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1985 High

    Molecular cloning resolved TIMP-1's primary structure and established its identity with erythroid-potentiating activity (EPA), unifying two previously separate biological activities under one gene product.

    Evidence cDNA cloning and protein sequencing by two independent laboratories

    PMID:3839290 PMID:3903517

    Open questions at the time
    • No three-dimensional structure available
    • Mechanism of metalloproteinase inhibition unknown
    • Receptor for EPA activity unidentified
  2. 1990 High

    Assignment of all six disulfide bonds defined the covalent framework that constrains the two-domain architecture critical for TIMP-1 function.

    Evidence Reverse-phase HPLC of proteolytic digests with Edman sequencing and FAB-MS

    PMID:2163605

    Open questions at the time
    • Three-dimensional fold unknown
    • Functional roles of individual disulfides not tested
  3. 1996 High

    Kinetic analysis revealed TIMP-1 inhibits MMP-1 via a two-step slow tight-binding mechanism—a rapid initial complex (Kd ~8 nM) isomerizes to an extremely tight form (global Kd ~0.1 nM)—and showed the MMP C-terminal hemopexin domain is required for the fast first step.

    Evidence Time-course kinetic analysis with graphic, nonlinear regression, and numeric integration methods; comparison with truncated mini-collagenase

    PMID:8798626

    Open questions at the time
    • Structural basis of isomerization step unknown
    • Generality to other MMPs not tested
  4. 1997 High

    The crystal structure of TIMP-1/MMP-3 revealed the canonical wedge-shaped inhibitory mechanism: Cys1 bidentately coordinates the catalytic zinc while Thr2 occupies the specificity pocket, explaining how a single inhibitor blocks diverse MMPs.

    Evidence X-ray crystallography of MMP-3 catalytic domain complexed with TIMP-1

    PMID:9288970

    Open questions at the time
    • Conformational dynamics in solution not captured
    • Basis of TIMP selectivity among MMPs incompletely explained
  5. 1998 High

    NMR-based solution mapping confirmed the crystallographic TIMP-1/MMP-3 interface and additionally revealed allosteric conformational changes in MMP-3 helix C upon TIMP-1 binding, extending the inhibitory model beyond the active site.

    Evidence NMR amide proton line-broadening with paramagnetic Gd-EDTA probe and hydrogen exchange assays

    PMID:9657677

    Open questions at the time
    • Functional significance of allosteric changes in MMP-3 helix C untested
    • Full-length TIMP-1 vs N-TIMP-1 comparison not performed
  6. 1996 High

    TIMP-1 was shown to signal as a growth factor—activating tyrosine kinase, MAP kinase, and phosphotyrosine cascades independently of MMP inhibition—establishing its dual identity as both protease inhibitor and cytokine.

    Evidence Thymidine incorporation, selective kinase inhibitors, phosphotyrosine immunoblotting, MAP kinase activity assay in MG-63 cells

    PMID:8906876

    Open questions at the time
    • Cell-surface receptor unknown
    • MMP-independence not yet proven by mutagenesis
  7. 2000 High

    Extending TIMP-1's inhibitory range beyond MMPs, quantitative enzymology showed TIMP-1 inhibits ADAM-10 at sub-nanomolar Ki but not ADAM-17, distinguishing these two sheddases pharmacologically.

    Evidence Quenched fluorescent substrate assay and MBP degradation assay with recombinant ADAM-10

    PMID:10818225

    Open questions at the time
    • Structural basis for ADAM-10 selectivity unknown
    • Domain requirements for ADAM-10 inhibition untested
  8. 2001 High

    LRP was identified as a clearance receptor for MMP-9·TIMP-1 complexes, providing a mechanism for systemic catabolism of the inhibitor–enzyme pair.

    Evidence 125I-labeling internalization assays, RAP antagonism, and LRP-deficient cell lines

    PMID:11279011

    Open questions at the time
    • Whether free TIMP-1 also binds LRP unclear
    • In vivo significance for TIMP-1 levels not demonstrated
  9. 2002 High

    The T2G mutant (MMP-inactive) demonstrated that TIMP-1's anti-apoptotic effect in hepatic stellate cells is MMP-dependent, while in breast epithelial cells it is MMP-independent, revealing cell-type-specific signaling modes.

    Evidence T2G mutagenesis, synthetic MMP inhibitor comparison, apoptosis assays in HSCs and MCF10A cells; corroborated in vivo

    PMID:11796725 PMID:12904305

    Open questions at the time
    • Receptor mediating MMP-independent signaling in breast epithelial cells unknown at this point
    • Structural determinants of the cytokine-like surface not mapped
  10. 2005 High

    Genetic gain- and loss-of-function in mice revealed TIMP-1 negatively regulates hepatocyte cell cycle progression during liver regeneration by limiting HGF bioavailability through MMP inhibition.

    Evidence Timp-1−/− and transgenic overexpressing mice, partial hepatectomy, HGF activity assays, cell cycle marker immunostaining

    PMID:15726641

    Open questions at the time
    • Which specific MMPs cleave pro-HGF in this context not identified
    • Whether TIMP-1's cytokine function also contributes unclear
  11. 2006 High

    CD63 was identified as the cell-surface receptor for TIMP-1's MMP-independent signaling: CD63 knockdown abolished TIMP-1 binding, integrin β1 activation, cell survival, and epithelial polarization, establishing the CD63/β1-integrin axis.

    Evidence Yeast two-hybrid, co-immunoprecipitation, confocal microscopy, shRNA knockdown, 3D matrigel assay

    PMID:16917503

    Open questions at the time
    • Direct binding site on TIMP-1 for CD63 not mapped
    • Stoichiometry of CD63/integrin β1/TIMP-1 complex undefined
  12. 2008 High

    A distinct ternary receptor complex—proMMP-9/CD44—was shown to mediate TIMP-1's anti-apoptotic signaling in erythroid cells via JAK2/PI3K/Akt, demonstrating that different cell types employ different TIMP-1 receptor assemblies.

    Evidence siRNA knockdown of proMMP-9 and CD44, function-blocking antibodies, flow cytometry in UT-7 cells

    PMID:19010442

    Open questions at the time
    • Whether proMMP-9/CD44 and CD63 complexes coexist on the same cell untested
    • Structural basis of TIMP-1/proMMP-9 interaction at the cell surface not resolved
  13. 2008 High

    Domain-dissection showed the C-terminal domain of TIMP-1 is required for ADAM-10 inhibition—unlike MMPs which are inhibited by N-TIMP-1 alone—explaining differential domain requirements for metalloproteinase versus sheddase inhibition.

    Evidence Inhibition assays comparing full-length TIMP-1 vs N-TIMP-1 against ADAM-10, ADAM-17, and MMPs

    PMID:18215140

    Open questions at the time
    • Specific C-terminal residues mediating ADAM-10 contact not identified
    • No co-crystal structure of TIMP-1/ADAM-10
  14. 2011 High

    Two independent studies established TIMP-1 as a paracrine regulator in specialized tissues: astrocyte-derived TIMP-1 promotes oligodendrocyte differentiation and CNS myelination (MMP-independent), while tumor-derived TIMP-1 maintains Met signaling by inhibiting ADAM-10-mediated Met shedding in metastatic foci.

    Evidence TIMP-1 KO mice and neurosphere cultures with GM6001 control (myelination); reciprocal Timp-1/Adam-10 knockdown in syngeneic liver metastasis model (Met signaling)

    PMID:21508247 PMID:21789719

    Open questions at the time
    • Receptor for TIMP-1's MMP-independent trophic action on OPCs not yet identified at this time point
    • Whether ADAM-10 inhibition is the sole mechanism maintaining Met in metastatic cells not excluded
  15. 2013 High

    TIMP-1 was shown to control angiogenesis by determining the ratio of TIMP-1-free to TIMP-1-complexed proMMP-9: M2 macrophages downregulate TIMP-1, releasing pro-angiogenic free proMMP-9, while re-complexing with exogenous TIMP-1 abolishes angiogenic activity.

    Evidence Macrophage polarization, TIMP-1 siRNA, in vivo angiogenesis assay, Mmp9-null macrophages, proMMP-9 reconstitution

    PMID:24174628

    Open questions at the time
    • Mechanism by which free proMMP-9 promotes angiogenesis not fully resolved
    • Relevance to tumor-associated macrophage biology in vivo not directly tested
  16. 2015 High

    Domain-dissecting TIMP-1 variants in CD63-null mice proved that the CD63-binding signaling domain alone is necessary and sufficient for TIMP-1-driven granulopoiesis and neutrophilia, establishing in vivo functional separation of protease-inhibitory and cytokine activities.

    Evidence TIMP-1 domain variants, CD63-null mice, BrdU pulse-labeling, bone marrow gene expression

    PMID:26001794

    Open questions at the time
    • Precise structural interface between TIMP-1 and CD63 not mapped at residue level
    • Whether other TIMP-1 receptors contribute to hematopoiesis not excluded
  17. 2018 Medium

    The downstream signaling pathway for TIMP-1-driven oligodendrocyte differentiation was delineated as CD63/β1-integrin→Akt→β-catenin stabilization, linking TIMP-1's cytokine function to Wnt pathway crosstalk in OPCs.

    Evidence Recombinant TIMP-1 treatment of OPCs, CD63/β1-integrin blocking, Akt inhibitors, β-catenin reporter, Wnt7a co-treatment

    PMID:30121936

    Open questions at the time
    • Single-lab finding; independent replication needed
    • Direct β-catenin stabilization mechanism not biochemically resolved
  18. 2021 High

    CD74 (invariant chain) was identified as a third TIMP-1 receptor: the N-terminal domain of TIMP-1 binds CD74 and triggers ZAP-70 phosphorylation, establishing a proinflammatory signaling axis distinct from the CD63 and proMMP-9/CD44 pathways.

    Evidence Unbiased ligand-receptor capture, co-immunoprecipitation, confocal microscopy, in silico docking, recombinant N-TIMP-1, blocking peptide, ZAP-70 phosphorylation

    PMID:34391782

    Open questions at the time
    • Downstream transcriptional programs activated by TIMP-1/CD74/ZAP-70 not characterized
    • Whether CD74 and CD63 compete for TIMP-1 binding unclear
  19. 2023 High

    APP and APLP2 were identified as a fourth TIMP-1 receptor pair—mediated by TIMP-1's C-terminal domain—through which TIMP-1 drives glucose uptake and proinflammatory cytokine expression in monocytes, revealing yet another signaling axis.

    Evidence Unbiased ligand-receptor capture, pull-down assays, confocal microscopy, C-terminal domain variants, glucose uptake and cytokine assays

    PMID:36629908

    Open questions at the time
    • Signaling intermediates between APP and glucose uptake unknown
    • Whether APP mediates TIMP-1 effects in neurons or other APP-expressing tissues untested
  20. 2023 High

    ADAMTS-7 was identified as a protease that directly degrades TIMP-1, derepressing MMP-9 activity and reducing collagen in atherosclerotic plaques—revealing a proteolytic mechanism that regulates TIMP-1 availability in vivo.

    Evidence Mass spectrometry of Apoe−/−Adamts7−/− vs Apoe−/− plaques, co-immunoprecipitation, in vitro degradation assays, FRET, immunofluorescence

    PMID:37675562

    Open questions at the time
    • Cleavage sites on TIMP-1 not precisely mapped
    • Whether other ADAMTS family members also degrade TIMP-1 untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: how TIMP-1 simultaneously engages multiple receptor complexes (CD63, proMMP-9/CD44, CD74, APP/APLP2) with apparently different domain surfaces; the atomic-resolution structure of TIMP-1/CD63 and TIMP-1/CD74 complexes; and the in vivo hierarchy and tissue specificity among these signaling axes.
  • No co-crystal structure of TIMP-1 with any of its cytokine receptors
  • Relative contributions of each receptor pathway in specific tissues or disease contexts largely unknown
  • Intracellular TIMP-1 functions, if any, remain uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 7 GO:0098772 molecular function regulator activity 7
Localization
GO:0005576 extracellular region 4 GO:0031012 extracellular matrix 2
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1474244 Extracellular matrix organization 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2
Partners
ADAM10APPCD44CD63CD74ITGB1MMP3MMP9

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1985 TIMP-1 was sequenced from its cDNA and found to be identical to erythroid-potentiating activity (EPA), a glycoprotein that irreversibly forms inactive complexes with metalloproteinases. The protein consists of 184 amino acid residues with a 23-amino acid leader peptide, two N-linked oligosaccharide sites, and six disulfide bonds. cDNA cloning, protein sequencing, expression in E. coli and transfected animal cells Nature / Proceedings of the National Academy of Sciences High 3839290 3903517
1990 The six disulfide bonds of human TIMP-1 were assigned: Cys1-Cys70, Cys3-Cys99, Cys13-Cys124, Cys127-Cys174, Cys132-Cys137, and Cys145-Cys166, defining the structural framework of the protein. Reverse-phase HPLC of proteolytic digests, reduction, Edman sequencing, and fast-atom-bombardment mass spectrometry The Biochemical Journal High 2163605
1997 Crystal structure of the TIMP-1/MMP-3 (stromelysin-1) complex revealed that TIMP-1 occupies the entire active-site cleft of MMP-3 with its long edge; Cys1 bidentately coordinates the catalytic zinc of MMP-3, and the Thr2 side chain inserts into the large specificity pocket, defining the canonical wedge-shaped inhibitory mechanism. X-ray crystallography of MMP-3 catalytic domain complexed with TIMP-1 Nature High 9288970
1996 TIMP-1 inhibits fibroblast collagenase (MMP-1) via a two-step noncompetitive mechanism: a rapidly formed reversible complex (Kd ~8 nM) slowly isomerizes into an extremely tight complex (global Kd ~0.1 nM). The C-terminal domain of collagenase is required for the initial rapid binding step; mini-collagenase lacking this domain forms only the simpler tight complex with lower affinity. Time-course kinetic analysis by graphic analysis, nonlinear regression of analytic integrals, and numeric integration of rate equations; comparison with truncated mini-collagenase The Journal of Biological Chemistry High 8798626
1998 NMR and paramagnetic surface probing mapped the TIMP-1/MMP-3 interface in solution: TIMP-1 protects MMP-3 residues Tyr155, Asn162, Val163, Leu164, His166, Ala167, Ala169, and Phe210 from Gd-EDTA broadening, consistent with the crystal structure. N-TIMP-1 binding also induces conformational changes in MMP-3 helix C (Asp238, Asn240, Gly241, Ser244) and alters hydrogen bonding near the active site, confirming N-terminal displacement in solution. NMR amide proton line-broadening with paramagnetic Gd-EDTA probe, hydrogen exchange assays Biochemistry High 9657677
2000 TIMP-1 inhibits ADAM-10 with an apparent inhibition constant of ~0.1 nM, whereas TIMP-2 and TIMP-4 cannot inhibit ADAM-10; TIMP-3 inhibits ADAM-10 with Ki ~0.9 nM. This selectivity distinguishes ADAM-10 from TACE (ADAM-17), which is inhibited only by TIMP-3, providing a tool to differentiate the two sheddases in cell-based assays. Quenched fluorescent substrate assay and myelin basic protein degradation assay with recombinant ADAM-10 Fc fusion protein FEBS Letters High 10818225
2008 The full-length N-terminal domain of TIMP-1 (N-TIMP-1) alone is insufficient to inhibit ADAM-10, in contrast to its inhibition of MMPs and ADAM-17 by TIMP-3 N-terminal domain; the C-terminal domain of TIMP-1 (or structural context beyond the N-terminal domain alone) is required for ADAM-10 inhibition. Inhibition assays comparing full-length TIMPs vs. isolated N-terminal domains against ADAM-10, ADAM-17, and MMPs The Biochemical Journal High 18215140
1996 TIMP-1 (and TIMP-2) stimulate cell proliferation via tyrosine kinase-dependent signaling: tyrosine kinase inhibitors (genistein, erbstatin, herbimycin A) block TIMP-1-induced [3H]thymidine incorporation, while PKC and PKA inhibitors do not; TIMP-1 treatment elevates phosphotyrosine-containing proteins and activates MAP kinase, establishing a growth-signaling pathway independent of MMP inhibition. [3H]Thymidine incorporation, selective kinase inhibitors, phosphotyrosine immunoblotting, MAP kinase activity assay in MG-63 osteosarcoma cells FEBS Letters High 8906876
2002 TIMP-1 activates Ras (increases Ras-GTP) via a tyrosine kinase (TYK)/MAPK pathway (herbimycin A-sensitive), whereas TIMP-2 activates Ras through a PKA-mediated pathway (H89-sensitive); the two TIMPs thus use distinct upstream signaling routes to reach a common Ras effector, with TIMP-2 also promoting Ras-GTP/PI3K complex formation. Ras-GTP pull-down assay, selective kinase inhibitors (herbimycin A, H89) in MG-63 cells Biochemical and Biophysical Research Communications Medium 12147251
2002 TIMP-1 inhibits apoptosis of activated hepatic stellate cells (HSCs) via MMP inhibition: a T2G mutant of TIMP-1 (selectively ablates MMP inhibitory activity) fails to prevent apoptosis, and synthetic MMP inhibitors also block HSC apoptosis, placing MMP inhibition upstream of the anti-apoptotic effect in HSCs. Site-directed mutagenesis (T2G mutant), synthetic MMP inhibitor treatment, apoptosis assays (serum deprivation, cycloheximide, nerve growth factor) in cultured HSCs and in vivo fibrosis model The Journal of Biological Chemistry High 11796725
2003 TIMP-1 activates cell survival signaling in human breast epithelial cells via focal adhesion kinase (FAK), PI3K, and ERK pathways independent of MMP inhibition: the T2G MMP-inactive mutant retains anti-apoptotic activity, synthetic MMP inhibitors do not protect these cells, and TIMP-1 still enhances survival in the presence of synthetic MMP inhibitors, revealing a cell-type-specific, MMP-independent signaling mechanism. T2G mutant, synthetic MMP inhibitor, TIMP-1 knockdown/overexpression, kinase pathway inhibitors, caspase activity assays in MCF10A breast epithelial cells The Journal of Biological Chemistry High 12904305
2006 CD63, a tetraspanin, was identified as a TIMP-1 cell-surface binding partner by yeast two-hybrid screening, confirmed by co-immunoprecipitation and confocal microscopy. CD63 co-localizes with TIMP-1 and integrin β1 on the cell surface; shRNA knockdown of CD63 reduces TIMP-1 cell-surface binding, abrogates TIMP-1-mediated integrin β1 activation and cell survival signaling, and restores normal polarization of breast epithelial cells in 3D matrigel, establishing CD63 as the functional receptor mediating TIMP-1's MMP-independent cytokine-like effects. Yeast two-hybrid, co-immunoprecipitation, confocal microscopy, shRNA knockdown, 3D matrigel polarization assay, integrin activation assays The EMBO Journal High 16917503
2008 TIMP-1's anti-apoptotic signaling in erythroid (UT-7) cells requires formation of a ternary complex: TIMP-1 binds specifically to proMMP-9 at the cell surface (silencing proMMP-9 abrogates TIMP-1 signaling), and proMMP-9 is anchored to the plasma membrane by CD44. The anti-apoptotic effect is MMP-independent (MMP-9-blocking antibodies and synthetic MMP inhibitors cannot replicate it), but these agents prevent TIMP-1 binding to proMMP-9, abolishing downstream JAK2/PI3K/Akt survival signaling. siRNA knockdown of proMMP-9 and CD44, function-blocking antibodies, synthetic MMP inhibitor, flow cytometry, binding/co-localization assays in UT-7 erythroid cells The International Journal of Biochemistry & Cell Biology High 19010442
2001 The MMP-9·TIMP-1 complex binds LRP (low-density lipoprotein receptor-related protein) with high affinity, and LRP mediates cellular internalization and catabolism of MMP-9·TIMP-1 complexes; cells genetically deficient in LRP show diminished capacity for MMP-9·TIMP-1 catabolism, revealing LRP as a clearance receptor for the TIMP-1/MMP-9 complex. RAP (receptor-associated protein) antagonism, 125I-labeling internalization assays, LRP-deficient cell lines, in vitro binding assays The Journal of Biological Chemistry High 11279011
2005 In liver regeneration, TIMP-1 negatively regulates hepatocyte cell cycle progression by limiting HGF bioavailability: TIMP-1 loss-of-function (Timp-1−/− mice) accelerates expression of cyclin D1, PCNA, and phospho-histone H3, elevates MMP activity, increases active HGF in the ECM, and enhances phospho-Met and p38 signaling; conversely, TIMP-1 gain-of-function delays cell cycle progression. Timp-1−/− and transgenic overexpressing mice, real-time RT-PCR, HGF activity assays, immunostaining of cell cycle markers, partial hepatectomy model Hepatology High 15726641
2011 Tumor cell-derived TIMP-1 maintains pro-metastatic Met signaling by inhibiting ADAM-10-mediated Met shedding: knockdown of tumor cell Timp-1 suppresses Met phosphorylation in metastatic foci and inhibits metastasis formation; conversely, knockdown of ADAM-10 triggers Met auto-phosphorylation and increased responsiveness to HGF, phenocopying Timp-1 overexpression. siRNA knockdown of Timp-1 and Adam-10 in syngeneic murine liver metastasis model, Met phosphorylation assays, HGF stimulation assays, tumor cell scattering assay Clinical & Experimental Metastasis High 21789719
2011 TIMP-1 secreted by astrocytes promotes oligodendrocyte precursor cell (OPC) differentiation and CNS myelination via a mechanism independent of MMP inhibition: recombinant TIMP-1 increases NG2+ OPC numbers and O1+ mature oligodendrocyte numbers in a dose-dependent fashion, whereas the broad-spectrum MMP inhibitor GM6001 does not replicate this effect; TIMP-1 KO mice show delayed myelination and reduced white matter astrocytes. TIMP-1 KO mice, neurosphere cultures, A2B5+ immunopanned OPCs, recombinant TIMP-1 treatment, anti-TIMP-1 antisera, MMP inhibitor control (GM6001), developmental histology The Journal of Neuroscience High 21508247
2014 TIMP-1 acts as a chemoattractant for human neural stem cells (hNSCs) via CD63 and β1 integrin signaling: TIMP-1 binding to CD63 activates β1 integrin-mediated Akt and FAK phosphorylation and cytoskeletal reorganization; shRNA-mediated CD63 knockdown or β1 integrin blocking antibody abrogates TIMP-1-induced focal adhesion formation and migration. Microarray/proteomics identification, shRNA knockdown of CD63, β1-integrin blocking antibody, PI3K inhibition, focal adhesion and F-actin imaging, Boyden chamber migration assay The Biochemical Journal High 24635319
2015 TIMP-1-mediated signaling via CD63 is necessary and sufficient to induce granulopoiesis and neutrophilia in mice: TIMP-1 variants that dissociate protease-inhibitory activity from CD63 binding reveal that the CD63-binding signaling domain alone drives bone marrow myeloid progenitor expansion and granulopoiesis; CD63 ablation abolishes both neutrophilia and TIMP-1-enhanced granulopoiesis. Systemic TIMP-1 elevation in mice, TIMP-1 domain-dissecting variants, BrdU pulse-labeling, CD63-null mice, bone marrow granulopoiesis-associated gene expression Haematologica High 26001794
2015 TIMP-1 mediates TGF-β-dependent crosstalk between hepatic stellate cells and HCC cells via FAK signaling downstream of its receptor CD63: TGF-β signaling in HSCs induces TIMP-1 secretion; TIMP-1 then activates FAK via CD63 on HCC cells, promoting their proliferation, motility, and survival; inhibition of TGF-β signaling (EW-7197) blocks TIMP-1 secretion and downstream FAK/Akt activation. Secreted protein identification from HSCs, CD63 interaction studies, FAK phosphorylation assays, orthotopic xenograft mouse model, pharmacological TGF-β receptor inhibition Scientific Reports Medium 26549110
2018 TIMP-1 promotes oligodendrocyte differentiation via a CD63/β1-integrin/Akt/β-catenin signaling axis: recombinant TIMP-1 activates Akt and stabilizes β-catenin in OPCs in a CD63- and β1-integrin-dependent manner; this trophic action is independent of TIMP-1's MMP-inhibitory function and is counteracted (but not abrogated) by Wnt7a-mediated canonical Wnt signaling. Recombinant TIMP-1 treatment of OPCs, CD63/β1-integrin blocking, Akt inhibitors, β-catenin reporter assays, Wnt7a co-treatment Molecular Neurobiology Medium 30121936
2011 BRAFV600E drives TIMP-1 upregulation via NF-κB activation in papillary thyroid carcinoma: BRAF silencing in BCPAP cells decreases TIMP-1 expression and NF-κB binding activity; TIMP-1 then binds its surface receptor CD63, leading to Akt phosphorylation and anti-apoptotic/pro-invasive behavior. The BRAF→NF-κB→TIMP-1→CD63→Akt signaling axis is MEK-independent (sorafenib but not MEK inhibitors reduce TIMP-1 and Akt phosphorylation). BRAF gene silencing, specific MAPK/NF-κB inhibitors, TIMP-1 expression analysis, Akt phosphorylation assays, invasion assay in BCPAP cells Endocrine-Related Cancer Medium 21903858
2012 TIMP-1 promotes cell survival in breast cancer via a CD63/NOS2 pathway: TIMP-1 protein nitration and TIMP-1/CD63 co-immunoprecipitation occur at NO concentrations that induce PI3K/Akt/BAD pro-survival signaling; TIMP-1 antisense silencing blocks NO-induced PI3K/Akt/BAD phosphorylation in MDA-MB-231 cells. Antisense knockdown, co-immunoprecipitation of TIMP-1/CD63, immunohistochemistry, phosphorylation assays PLoS One Medium 22957045
2021 CD74 (invariant chain) was identified as a functional receptor for TIMP-1: co-immunoprecipitation and confocal microscopy confirmed TIMP-1-CD74 interaction; in silico docking (HADDOCK) predicted the N-terminal domain of TIMP-1 (N-TIMP-1) as the CD74 binding region, experimentally confirmed by showing recombinant N-TIMP-1 alone binds CD74; TIMP-1-CD74 interaction triggers intracellular ZAP-70 activation, and a synthetic peptide targeting the CD74 cytokine-binding site abrogates this activation. Ligand-receptor capture screening, co-immunoprecipitation, confocal microscopy, in silico docking (HADDOCK), recombinant N-TIMP-1 domain, ZAP-70 phosphorylation assays, blocking peptide The Journal of Biological Chemistry High 34391782
2023 TIMP-1 interacts with Amyloid Precursor Protein (APP) and Amyloid Precursor-like Protein-2 (APLP2) as a novel receptor pair: unbiased ligand-receptor capture screening revealed this interaction, confirmed by pull-down assays and confocal microscopy; TIMP-1 triggers glucose uptake and proinflammatory cytokine expression in human monocytes via its C-terminal domain and through APP, establishing APP as a TIMP-1 receptor mediating proinflammatory monocyte activation. Unbiased ligand-receptor capture screening, pull-down assays, confocal microscopy, in silico docking, recombinant TIMP-1 C-terminal domain variants, glucose uptake assays, cytokine expression assays The Journal of Cell Biology High 36629908
2023 ADAMTS-7 directly degrades TIMP-1: in coimmunoprecipitation experiments the catalytic domain of ADAMTS-7 binds TIMP-1, which is degraded by ADAMTS-7 in vitro; ADAMTS-7 reduces TIMP-1's inhibitory capacity toward MMP-9, increasing net MMP-9 activity and collagen degradation in atherosclerotic plaques; Apoe−/−Adamts7−/− mice accumulate more Timp-1 and more collagen than Apoe−/− controls. Mass spectrometry of atherosclerotic plaques (Apoe−/−Adamts7−/− vs Apoe−/− mice), coimmunoprecipitation, in vitro degradation assays, FRET-based protein-protein interaction assay, immunofluorescence, picrosirius red staining Circulation Research High 37675562
2000 The human TIMP-1 gene contains transcriptional repressive elements: a region upstream of the basal promoter (−1718/−1458) represses reporter gene expression by ~50%, and the first intron strongly represses transcription from any promoter; deletion analysis and protein binding/mutational studies identified a repressive element at intron +684/+748 that binds Sp1, Sp3, and an unidentified Ets-related factor. Reporter gene constructs, deletion analysis, electrophoretic mobility shift assay (EMSA), mutational analysis, protein binding studies The Journal of Biological Chemistry Medium 11032844
2002 Thrombin induces TIMP-1 gene transcription in human mesangial cells via STAT1 and STAT3: thrombin-induced STAT-DNA binding and TIMP-1 mRNA elevation are both blocked by STAT1 and STAT3 antisense oligonucleotides; supershift assays confirm STAT1 and STAT3 proteins are in the thrombin-induced DNA-binding complex. Northern blot, EMSA, supershift assay, antisense oligonucleotides in human glomerular mesangial cells Kidney International Medium 11918744
2013 TIMP-1 expression is a direct target of miR-1293: luciferase reporter assay with wild-type and mutant TIMP-1 3′UTR constructs showed miR-1293 inhibitor upregulates reporter activity; Western blot confirmed elevated TIMP-1 protein with miR-1293 inhibitor, establishing direct post-transcriptional regulation of TIMP-1 by miR-1293. Luciferase reporter assay with wild-type and mutant 3′UTR, Western blot, miR-1293 mimic and inhibitor co-transfection in 293T cells Molecular and Cellular Biochemistry Medium 23943285
2014 TIMP-1 induces pro-tumorigenic miR-210 upregulation in lung adenocarcinoma cells via a CD63/PI3K/Akt/HIF-1α-dependent pathway: TIMP-1 induces PI3K p110/p85 signaling and Akt phosphorylation, elevates HIF-1α protein, and upregulates HIF-1-regulated miR-210; downstream targets of miR-210 (FGFRL1, E2F3, VMP-1, RAD52, SDHD) are decreased; TIMP-1-containing exosomes accumulate miR-210 and promote HUVEC tube formation. Exogenous TIMP-1 treatment and TIMP-1 overexpression, PI3K/Akt inhibitors, HIF-1α monitoring, miR-210 quantification, target gene expression, exosome isolation and functional tube formation assay, in vivo xenograft Oncogene High 25263437
2013 TIMP-1 promotes cancer-associated fibroblast (CAF) accumulation and activates ERK1/2 signaling in prostate CAFs: TIMP-1 overexpression in xenograft models increases in vivo tumor growth and CAF accumulation; recombinant TIMP-1 enhances prostate CAF proliferation, migration, and ERK1/2 phosphorylation in vitro. TIMP-1 overexpressing constructs in xenograft mouse models (prostate and colon cancer), in vitro CAF proliferation/migration assays, ERK1/2 phosphorylation assays PLoS One Medium 24143225
2016 TIMP-1 promotes colon cancer cell proliferation and metastasis via FAK-PI3K/AKT and MAPK signaling: TIMP-1 suppression decreases proliferation and metastasis while increasing apoptosis; mechanistic analyses confirm these effects are mediated through TIMP-1-specific regulation of FAK-PI3K/AKT and MAPK pathways in colon cancer cell lines. TIMP-1 knockdown and overexpression, proliferation/apoptosis/metastasis assays in vitro and in vivo (xenograft), FAK/Akt/MAPK phosphorylation assays, clinical specimen analysis (94 colon cancer cases) Journal of Experimental & Clinical Cancer Research Medium 27644693
2013 TIMP-1 reduces angiogenesis by restricting TIMP-1-free proMMP-9: in M2-polarized macrophages, downregulation of TIMP-1 produces TIMP-1-free proMMP-9 that is strongly angiogenic; re-complexing M2 proMMP-9 with exogenous TIMP-1 abolishes angiogenic activity; TIMP-1 silencing in M0/M1 macrophages renders them angiogenic; Mmp9-null M2 macrophages are nonangiogenic despite low TIMP-1. Macrophage polarization (M0/M1/M2), TIMP-1 ELISA, TIMP-1 siRNA silencing, in vivo angiogenesis assay, Mmp9-null murine macrophages, proMMP-9 reconstitution with exogenous TIMP-1 Blood High 24174628
1993 TIMP-1 inhibits stimulated bone resorption in a dose-dependent and reversible manner in vitro: recombinant TIMP-1 (and TIMP-2) blocked both PTH- and 1,25-dihydroxyvitamin D3-induced bone resorption in neonatal mouse calvarial cultures, without affecting protein synthesis, DNA synthesis, or cell viability markers. Neonatal mouse calvarial culture, PTH and vitamin D3 stimulation, dose-response with recombinant TIMPs, reversibility experiments Biochimica et Biophysica Acta Medium 8485170
2004 TIMP-1 inhibits endothelial cell migration through both MMP-dependent and MMP-independent mechanisms: MMP-dependent inhibition involves upregulation of VE-cadherin and PECAM-1 at cell-cell junctions; MMP-independent inhibition involves stimulation of PTEN expression with subsequent dephosphorylation of FAK (pY397) and paxillin, reduced F-actin stress fibers, and fewer focal adhesions. HDMVEC migration assay, synthetic MMP inhibitors (GM6001, MMP-2/9 inhibitor III), recombinant TIMP-1, VE-cadherin/PECAM-1/FAK/paxillin/PTEN immunostaining, F-actin cytoskeleton analysis Experimental Cell Research Medium 15530852
2019 TIMP-1 inhibits proliferation and osteogenic differentiation of human bone marrow MSCs through the Wnt/β-catenin signaling pathway: TIMP-1 knockdown upregulates β-catenin and cyclin D1 and promotes osteogenesis; TIMP-1 overexpression attenuates Wnt3a-induced upregulation of cyclin D1 and RUNX-2, while TIMP-1 knockdown restores Dkk1-inhibited β-catenin and cyclin D1 expression. Stable TIMP-1 overexpression and knockdown in hBMSCs, osteogenic differentiation assays (Alizarin Red, ALP activity, qPCR), β-catenin/cyclin D1/RUNX-2 Western blotting, Wnt3a and Dkk1 epistasis experiments Bioscience Reports Medium 30473539
2004 EGF-induced secretion of TIMP-1 (and MMP-9) in extravillous trophoblasts requires activation of both PI3K and MAPK pathways: PI3K inhibitor LY294002 blocks Akt phosphorylation and abrogates TIMP-1 induction without affecting ERK; MEK inhibitor U0126 blocks ERK phosphorylation without affecting Akt; constitutively active Akt alone is insufficient to induce TIMP-1 secretion, placing TIMP-1 induction downstream of both pathways acting in parallel. PI3K inhibitor (LY294002), MEK inhibitor (U0126), constitutively active Akt constructs, RT-PCR, Western blot, zymography in HTR8/SVneo trophoblast cells Reproduction Medium 15333786

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2020 The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases. International journal of molecular sciences 1233 33419373
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1985 Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature 671 3903517
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2003 Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood 616 14630798
2003 The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. Blood 603 12714508
1997 Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1. Nature 499 9288970
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2002 Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. The Journal of biological chemistry 360 11796725
2005 Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. Journal of proteome research 350 16335952
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 338 10956632
2000 The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS letters 334 10818225
1986 Primary structure and cDNA cloning of human fibroblast collagenase inhibitor. Proceedings of the National Academy of Sciences of the United States of America 306 3010309
1996 Activation of a recombinant membrane type 1-matrix metalloproteinase (MT1-MMP) by furin and its interaction with tissue inhibitor of metalloproteinases (TIMP)-2. FEBS letters 294 8804434
2006 Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. The EMBO journal 277 16917503
1985 Molecular characterization and expression of the gene encoding human erythroid-potentiating activity. Nature 271 3839290
2022 CST1 inhibits ferroptosis and promotes gastric cancer metastasis by regulating GPX4 protein stability via OTUB1. Oncogene 259 36369321
2005 Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart. Circulation 258 16103240
2013 Cytokine functions of TIMP-1. Cellular and molecular life sciences : CMLS 246 23982756
2016 TIMP1 is a prognostic marker for the progression and metastasis of colon cancer through FAK-PI3K/AKT and MAPK pathway. Journal of experimental & clinical cancer research : CR 235 27644693
2013 Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9. Blood 206 24174628
2001 The low density lipoprotein receptor-related protein modulates levels of matrix metalloproteinase 9 (MMP-9) by mediating its cellular catabolism. The Journal of biological chemistry 182 11279011
1990 Disulphide bond assignment in human tissue inhibitor of metalloproteinases (TIMP). The Biochemical journal 176 2163605
2006 Identification of N-linked glycoproteins in human saliva by glycoprotein capture and mass spectrometry. Journal of proteome research 173 16740002
2007 Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1. Journal of the National Cancer Institute 171 18159069
1997 Cytokine and chemokine regulation of proMMP-9 and TIMP-1 production by human peripheral blood lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 171 9036981
2014 Tissue inhibitor of metalloproteinases-1 induces a pro-tumourigenic increase of miR-210 in lung adenocarcinoma cells and their exosomes. Oncogene 165 25263437
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2003 Expression and regulation of tissue inhibitor of metalloproteinase-1 and matrix metalloproteinases by intestinal myofibroblasts in inflammatory bowel disease. The American journal of pathology 164 12651627
2003 Tissue inhibitor of metalloproteinase-1 protects human breast epithelial cells against intrinsic apoptotic cell death via the focal adhesion kinase/phosphatidylinositol 3-kinase and MAPK signaling pathway. The Journal of biological chemistry 159 12904305
2003 Tissue inhibitor of metalloproteinase (TIMP)-1: the TIMPed balance of matrix metalloproteinases in the central nervous system. Journal of neuroscience research 159 14648584
2010 Salivary MMP-8, TIMP-1, and ICTP as markers of advanced periodontitis. Journal of clinical periodontology 153 20507371
2004 EGF-induced trophoblast secretion of MMP-9 and TIMP-1 involves activation of both PI3K and MAPK signalling pathways. Reproduction (Cambridge, England) 137 15333786
2018 Recognizing the Molecular Multifunctionality and Interactome of TIMP-1. Trends in cell biology 130 30243515
2015 Emerging EPO and EPO receptor regulators and signal transducers. Blood 130 25887776
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
2011 Astrocytic tissue inhibitor of metalloproteinase-1 (TIMP-1) promotes oligodendrocyte differentiation and enhances CNS myelination. The Journal of neuroscience : the official journal of the Society for Neuroscience 104 21508247
2007 Role of TIMP-1 and TIMP-2 in the progression of cerebral aneurysms. Stroke 99 17569872
2009 Neuroprotective effects of overexpressing tissue inhibitor of metalloproteinase TIMP-1. Journal of neurotrauma 97 19469687
1996 Tyrosine phosphorylation is crucial for growth signaling by tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2). FEBS letters 87 8906876
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 84 11792150
2006 MMP-12, MMP-3, and TIMP-1 are markedly upregulated in chronic demyelinating theiler murine encephalomyelitis. Journal of neuropathology and experimental neurology 80 16896312
2022 Cut loose TIMP-1: an emerging cytokine in inflammation. Trends in cell biology 78 36163148
2002 Modulation of matrix metalloproteinase and TIMP-1 expression by cytokines in human RPE cells. Investigative ophthalmology & visual science 78 12147614
1992 Identification of TIMP-2 in human alveolar macrophages. Regulation of biosynthesis is opposite to that of metalloproteinases and TIMP-1. The Journal of biological chemistry 72 1629188
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
1996 Endogenous TGF-beta activity is modified during cellular aging: effects on metalloproteinase and TIMP-1 expression. Experimental cell research 70 8912720
2003 Effects of Th2 cytokines on expression of collagen, MMP-1, and TIMP-1 in conjunctival fibroblasts. Investigative ophthalmology & visual science 69 12506073
2002 Both tissue inhibitors of metalloproteinases-1 (TIMP-1) and TIMP-2 activate Ras but through different pathways. Biochemical and biophysical research communications 67 12147251
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
2006 TIMP-1 gene deficiency increases tumour cell sensitivity to chemotherapy-induced apoptosis. British journal of cancer 62 17047657
2011 Localization of MMP-2, MMP-9, TIMP-1, and TIMP-2 in human coronal dentine. Journal of dentistry 61 21641958
1996 Enhanced RNA expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) in human breast cancer. International journal of cancer 61 8608981
1995 Growth factor effects on the expression of collagenase and TIMP-1 in periodontal ligament cells. Journal of periodontology 61 7562346
1993 Inhibition of stimulated bone resorption in vitro by TIMP-1 and TIMP-2. Biochimica et biophysica acta 61 8485170
1999 Induction of TIMP-1 expression in rat hepatic stellate cells and hepatocytes: a new role for homocysteine in liver fibrosis. Biochimica et biophysica acta 60 10524225
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
2012 Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation. PloS one 57 22957045
2010 Effect of TIMP-1 and MMP in pterygium invasion. Investigative ophthalmology & visual science 56 20207965
1997 Divergent regulation of 92-kDa gelatinase and TIMP-1 by HBECs in response to IL-1beta and TNF-alpha. The American journal of physiology 54 9357863
2007 MMP-13 and TIMP-1 determinations in progressive chronic periodontitis. Journal of clinical periodontology 52 17716308
2004 Elements of the nitric oxide pathway can degrade TIMP-1 and increase gelatinase activity. Molecular vision 52 15105792
2017 TIMP-1 is upregulated, but not essential in hepatic fibrogenesis and carcinogenesis in mice. Scientific reports 51 28386095
1999 'Proteolytic switching': opposite patterns of regulation of gelatinase B and its inhibitor TIMP-1 during human melanoma progression and consequences of gelatinase B overexpression. British journal of cancer 50 10408860
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 46 21789719
2014 TIMP-1 modulates chemotaxis of human neural stem cells through CD63 and integrin signalling. The Biochemical journal 44 24635319
2012 Evaluation of plasmatic MMP-8, MMP-9, TIMP-1 and MPO levels in obese and lean women. Clinical biochemistry 44 22285381
2010 Leptin regulates MMP-2, TIMP-1 and collagen synthesis via p38 MAPK in HL-1 murine cardiomyocytes. Cellular & molecular biology letters 42 20683677
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
2023 ADAMTS-7 Modulates Atherosclerotic Plaque Formation by Degradation of TIMP-1. Circulation research 40 37675562
2013 Tissue inhibitor of metalloproteinase 1 (TIMP-1) as a biomarker in gastric cancer: a review. Scandinavian journal of gastroenterology 40 23834019
2018 TIMP-1 Promotes Oligodendrocyte Differentiation Through Receptor-Mediated Signaling. Molecular neurobiology 39 30121936
2013 MMP-7 and TIMP-1, new targets in predicting poor wound healing in apical periodontitis. Journal of endodontics 39 23953287
2012 TIMP-1 deficiency leads to lethal partial hepatic ischemia and reperfusion injury. Hepatology (Baltimore, Md.) 39 22407827
2001 Oxidized LDL differentially regulates MMP-1 and TIMP-1 expression in vascular endothelial cells. Atherosclerosis 39 11369004
2015 TIMP-1 overexpression in lung carcinoma enhances tumor kinetics and angiogenesis in brain metastasis. Journal of neuropathology and experimental neurology 37 25756591
2010 Angiogenesis in vestibular schwannomas: expression of extracellular matrix factors MMP-2, MMP-9, and TIMP-1. The Laryngoscope 37 20205165
1998 TIMP-1 contact sites and perturbations of stromelysin 1 mapped by NMR and a paramagnetic surface probe. Biochemistry 36 9657677
2012 The endogenous protease inhibitor TIMP-1 mediates protection and recovery from cutaneous photodamage. The Journal of investigative dermatology 35 22718114
2013 TIMP-1 increases expression and phosphorylation of proteins associated with drug resistance in breast cancer cells. Journal of proteome research 34 23909892
2008 The isolated N-terminal domains of TIMP-1 and TIMP-3 are insufficient for ADAM10 inhibition. The Biochemical journal 34 18215140
2006 Correlation between TIMP-1 expression and liver fibrosis in two rat liver fibrosis models. World journal of gastroenterology 34 16718785
1996 The mechanism of inhibition of collagenase by TIMP-1. The Journal of biological chemistry 34 8798626
2010 Epidermal growth factor (EGF) induces motility and upregulates MMP-9 and TIMP-1 in bovine trophoblast cells. Molecular reproduction and development 33 20578063
2015 Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis. Expert opinion on therapeutic targets 32 26419263
2000 The human tissue inhibitor of metalloproteinases (TIMP)-1 gene contains repressive elements within the promoter and intron 1. The Journal of biological chemistry 31 11032844
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) 30 32961536
1993 Characterization of a human corneal metalloproteinase inhibitor (TIMP-1). Current eye research 29 7507419
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
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 27 33942633
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
2018 Genetic variants of erythropoietin (EPO) and EPO receptor genes in familial erythrocytosis. International journal of laboratory hematology 26 30507031
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
2005 Proinflammatory adipocytokines induce TIMP-1 expression in 3T3-L1 adipocytes. FEBS letters 25 16288749
1999 Tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA is elevated in advanced stages of thyroid carcinoma. British journal of cancer 25 10098765
2008 Bronchoalveolar lavage MMP-9 and TIMP-1 in preschool wheezers and their relationship to persistent wheeze. Pediatric research 24 18391843
2003 Serum MMP-1 and TIMP-1 levels are increased in patients with psoriatic arthritis and their siblings. Rheumatology (Oxford, England) 24 14523226
2010 Upregulation of MMP-13 and TIMP-1 expression in response to mechanical strain in MC3T3-E1 osteoblastic cells. BMC research notes 23 21080973
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 Inhibition of skin carcinogenesis by suppression of NF-κB dependent ITGAV and TIMP-1 expression in IL-32γ overexpressed condition. Journal of experimental & clinical cancer research : CR 22 30486830
2017 Association of COL4A3 (rs55703767), MMP-9 (rs17576)and TIMP-1 (rs6609533) gene polymorphisms with susceptibility to type 2 diabetes. Biomedical reports 22 28451395
2021 Identification of invariant chain CD74 as a functional receptor of tissue inhibitor of metalloproteinases-1 (TIMP-1). The Journal of biological chemistry 20 34391782
2019 TIMP-1 is Overexpressed and Secreted by Platinum Resistant Epithelial Ovarian Cancer Cells. Cells 20 31861382
2018 TFF1 antagonizes TIMP-1 mediated proliferative functions in gastric cancer. Molecular carcinogenesis 20 30035371
2017 Correlation between the COL4A3, MMP-9, and TIMP-1 polymorphisms and risk of keratoconus. Japanese journal of ophthalmology 20 28197741
2010 Bone loss induced by Runx2 over-expression in mice is blunted by osteoblastic over-expression of TIMP-1. Journal of cellular physiology 20 19780057
2008 The role of MMP-9 and TIMP-1 in nasal polyp formation. Swiss medical weekly 20 19043814
2002 STAT1 and STAT3 mediate thrombin-induced expression of TIMP-1 in human glomerular mesangial cells. Kidney international 20 11918744
2017 Endotoxemia shifts neutrophils with TIMP-free gelatinase B/MMP-9 from bone marrow to the periphery and induces systematic upregulation of TIMP-1. Haematologica 19 28775117
2012 Gambogic acid inhibits invasion of osteosarcoma via upregulation of TIMP-1. International journal of molecular medicine 19 23175213
1996 Glomerular expression of tissue inhibitor of metalloproteinase (TIMP-1) in normal and diabetic rats. Journal of the American Society of Nephrology : JASN 19 8808115
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
2014 Diagnostic significance of TIMP-1 level in serum and its immunohistochemical expression in colorectal cancer patients. Polish journal of pathology : official journal of the Polish Society of Pathologists 18 25693084
2013 Identification of miR-1293 potential target gene: TIMP-1. Molecular and cellular biochemistry 17 23943285
1999 Tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) stimulate osteoclastic bone resorption. Journal of bone and mineral metabolism 17 10575588