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Drug-Target Interaction

Drug

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PubChem ID:6436247
Structure:
Synonyms:
70563-58-5
AC1O5LAW
AIDS-071761
AIDS071761
Antibiotic Tan 420F
CID6436247
Geldanamycin, 17-demethoxy-15-methoxy-11-O-methyl-, (15R)-
Herbimycin
Herbimycin A
LS-71126
NSC 305978
NSC305978
[(2R,3S,5S,6R,7S,8E,10S,11S,12E,14E)-2,5,6,11-tetramethoxy-3,7,9,15-tetram

Target

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Uniprot ID:MMP2_HUMAN
Synonyms:
72 kDa gelatinase
72 kDa type IV collagenase
Gelatinase A
Matrix metalloproteinase-2
MMP-2
TBE-1
EC-Numbers:3.4.24.24
Organism:Homo sapiens
Human
PDB IDs:1CK7 1CXW 1EAK 1GEN 1GXD 1HOV 1J7M 1KS0 1QIB 1RTG
Structure:
1RTG

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----

References:

10515879
Fibronectin upregulates gelatinase B (MMP-9) and induces coordinated expression of gelatinase A (MMP-2) and its activator MT1-MMP (MMP-14) by human T lymphocyte cell lines. A process repressed through RAS/MAP kinase signaling pathways.. J Esparza; C Vilardell; J Calvo; M Juan; J Vives; A Urbano-Márquez; J Yagüe; M C Cid (1999) Blood display abstract
T-lymphocyte migration into tissues requires focal degradation of the basement membrane. In this study, we show that transient adherence to fibronectin induces the production of activated forms of matrix metalloproteinase-2 (MMP-2) and MMP-9, as well as downregulation of tissue inhibitor of metalloproteinase-2 (TIMP-2) by T-cell lines. MMP-2 activation was likely achieved by inducing a coordinated expression of membrane-type matrix metalloproteinase-1 (MMP-14), a major activator of MMP-2. Blocking monoclonal antibodies against alpha4, alpha5, and alphav integrins strongly reduced MMP-2 and MMP-9 production induced by fibronectin. Disrupting actin cytoskeleton organization by cytochalasin D strongly enhanced fibronectin-induced MMP-2 and MMP-9 expression. Inhibiting Src tyrosine kinases with herbimycin A reduced MMP-2 and MMP-9 production with no effect on cell attachment. By contrast, G-protein inhibition by pertussis toxin, or transfection with a dominant negative mutant of Ha-Ras strongly increased fibronectin-induced MMP-2 and MMP-9. Inhibition of PI3 kinase, MAPkinase (MEK1), or p38 MAPkinase by wortmannin, PD 98059, or SB 202190, respectively, strongly promoted fibronectin-induced MMP2 and MMP-9. Cells at high density lost their ability to synthesize MMP-2 and MMP-9 in response to fibronectin and MMP expression was restored by transfection with a dominant-negative mutant of Ha-Ras or by treatment with wortmannin, PD 98059, or SB 202190. Our findings suggest that adhesion to fibronectin transduces both stimulatory (through Src-type tyrosin kinases) and inhibitory signals (through Ras/MAPKinase signaling pathways) for MMP-2 and MMP-9 expression by T lymphocytes and that their relative predominance is regulated by additional stimuli related to cell adhesion, motility, and growth.