TIMP-2: identification and characterization of a new member of the metalloproteinase inhibitor family.
Human melanoma cells secrete a 21 kDa protein which binds with 1:1 molar stoichiometry to the matrix metalloproteinase type IV collagenase proenzyme (70 kDa gelatinase) secreted by the same cells. We have purified this binding protein and determined its complete primary structure by directly sequencing overlapping peptide fragments which span the entire protein. We refer to this protein as CSC-21K based on the amino-terminal amino acids CSC and the apparent molecular weight of 21,000 daltons on gel electrophoresis. The amino acid sequence of CSC-21K demonstrates that this protein shares significant homology with human TIMP (tissue inhibitor of metalloproteinase), including conservation of the positions of the twelve cysteine residues and three of four tryptophan residues. The identification of CSC-21K now indicates that a family of TIMP-related proteins exists. Individual members of this family may possess selective affinities for different members of the matrix metalloproteinase family. Based on its sequence homology to TIMP and ability to inhibit type IV collagenolysis we propose the name TIMP-2 for this inhibitor. TIMP-2 produced by tumor cells can also be considered as an onco-suppressor gene product, because it could play an important role in regulating the metalloproteinases involved in tumor invasion and angiogenesis.
Stetler-Stevenson
W G
WG
Tumor Invasion and Metastasis Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892.
Krutzsch
H C
HC
Liotta
L A
LA
D000595:Amino Acid Sequence; D002846:Chromatography, Affinity; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D018093:Gelatinases; D016147:Genes, Tumor Suppressor; D006023:Glycoproteins / Q000737:chemistry; D006801:Humans; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D008545:Melanoma / Q000737:chemistry; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D008970:Molecular Weight; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology; D010434:Pepsin A / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases; D014407:Tumor Cells, Cultured
D004792:Enzyme Precursors; D006023:Glycoproteins; D061965:Matrix Metalloproteinase Inhibitors; D009363:Neoplasm Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D010434:Pepsin A; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase; D020780:Matrix Metalloproteinase 9