Journal of Cell Science, Vol 107, Issue 9 2373-2379, Copyright © 1994 by Company of Biologists

JOURNAL ARTICLES

Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2)

T Hayakawa, K Yamashita, E Ohuchi and A Shinagawa
Department of Biochemistry, School of Dentistry, Aichi-Gakuin University, Nagoya, Japan.

Human tissue inhibitor of metalloproteinases-2 (TIMP-2) has a potent growth-promoting activity for wide range of human, bovine and mouse cells, having an optimal concentration (10 ng/ml, 0.46 nM) that is ten-times lower than that of TIMP-1 (Hayakawa et al. (1992) FEBS Lett. 298, 29). Neither TIMP-1 complexed with progelatinase B nor TIMP-2 complexed with progelatinase A, both of which have full inhibitory activity against active forms of matrix metalloproteinases (MMPs), showed any cell growth-promoting activity. On the contrary, both reductively alkylated TIMPs had no MMP inhibitory activity, but significantly stimulated cell proliferation. These facts clearly indicate that the cell-proliferation. These facts clearly indicate that the cell-proliferating activity of TIMPs is independent of MMP inhibitory activity. We also demonstrated that [3H]thymidine was significantly incorporated into Raji cells, a Burkitt lymphoma cell line, in the presence of either 4 ng/ml of TIMP-1 or 0.1 ng/ml of TIMP-2. Under steady-state conditions at 4 degrees C, high-(Kd = 0.15 nM) and low-(35 nM) affinity binding sites for TIMP-2 were identified on Raji cells with 20,000 and 1.4 x 10(5) sites/cell, respectively. Both high- and low-affinity binding of 125I-TIMP-2 to Raji cells were competitively inhibited by unlabeled TIMP-2 but not by unlabeled TIMP-1, suggesting the presence of receptors for TIMP-2 independent from those for TIMP-1. TIMP-2 seems to be another new TIMP cell-growth factor in serum, besides TIMP-1.

This article has been cited by other articles:

				W. G. Stetler-Stevenson Tissue Inhibitors of Metalloproteinases in Cell Signaling: Metalloproteinase-Independent Biological Activities Sci. Signal., July 8, 2008; 1(27): re6 - re6. [Abstract] [Full Text] [PDF]

				S. D'Alessio, G. Ferrari, K. Cinnante, W. Scheerer, A. C. Galloway, D. F. Roses, D. V. Rozanov, A. G. Remacle, E.-S. Oh, S. A. Shiryaev, et al. Tissue Inhibitor of Metalloproteinases-2 Binding to Membrane-type 1 Matrix Metalloproteinase Induces MAPK Activation and Cell Growth by a Non-proteolytic Mechanism J. Biol. Chem., January 4, 2008; 283(1): 87 - 99. [Abstract] [Full Text] [PDF]

				J. Verstappen and J.W. Von den Hoff Tissue Inhibitors of Metalloproteinases (TIMPs): Their Biological Functions and Involvement in Oral Disease. J. Dent. Res., December 1, 2006; 85(12): 1074 - 1084. [Abstract] [Full Text] [PDF]

				M. M. Kelly, R. Leigh, S. E. Gilpin, E. Cheng, G. E. M. Martin, K. Radford, G. Cox, and J. Gauldie Cell-specific Gene Expression in Patients with Usual Interstitial Pneumonia Am. J. Respir. Crit. Care Med., September 1, 2006; 174(5): 557 - 565. [Abstract] [Full Text] [PDF]

				J.-B. Park, J.-K. Lee, S.-J. Park, and K. D. Riew Hypertrophy of Ligamentum Flavum in Lumbar Spinal Stenosis Associated with Increased Proteinase Inhibitor Concentration J. Bone Joint Surg. Am., December 1, 2005; 87(12): 2750 - 2757. [Abstract] [Full Text] [PDF]

				K.-H. Kim, K. Burkhart, P. Chen, C. W. Frevert, J. Randolph-Habecker, R. C. Hackman, P. D. Soloway, and D. K. Madtes Tissue Inhibitor of Metalloproteinase-1 Deficiency Amplifies Acute Lung Injury in Bleomycin-Exposed Mice Am. J. Respir. Cell Mol. Biol., September 1, 2005; 33(3): 271 - 279. [Abstract] [Full Text] [PDF]

				S O Wurtz, A-S Schrohl, N M. Sorensen, U Lademann, I J Christensen, H Mouridsen, and N Brunner Tissue inhibitor of metalloproteinases-1 in breast cancer Endocr. Relat. Cancer, June 1, 2005; 12(2): 215 - 227. [Abstract] [Full Text] [PDF]

				L. Perez-Martinez and D. M. Jaworski Tissue Inhibitor of Metalloproteinase-2 Promotes Neuronal Differentiation by Acting as an Anti-Mitogenic Signal J. Neurosci., May 18, 2005; 25(20): 4917 - 4929. [Abstract] [Full Text] [PDF]

				I. S. Aljada, N. Ramnath, K. Donohue, S. Harvey, J. J. Brooks, S. M. Wiseman, T. Khoury, G. Loewen, H. K. Slocum, T. M. Anderson, et al. Upregulation of the Tissue Inhibitor of Metalloproteinase-1 Protein Is Associated With Progression of Human Non-Small-Cell Lung Cancer J. Clin. Oncol., August 15, 2004; 22(16): 3218 - 3229. [Abstract] [Full Text] [PDF]

				Y. Zhou, C. Yu, X. Miao, W. Tan, G. Liang, P. Xiong, T. Sun, and D. Lin Substantial reduction in risk of breast cancer associated with genetic polymorphisms in the promoters of the matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 genes Carcinogenesis, March 1, 2004; 25(3): 399 - 404. [Abstract] [Full Text] [PDF]

				H. Gakiopoulou, L. Nakopoulou, A. Siatelis, I. Mavrommatis, E. G. Panayotopoulou, I. Tsirmpa, C. Stravodimos, and A. Giannopoulos Tissue Inhibitor of Metalloproteinase-2 as a Multifunctional Molecule of Which the Expression Is Associated with Adverse Prognosis of Patients with Urothelial Bladder Carcinomas Clin. Cancer Res., November 15, 2003; 9(15): 5573 - 5581. [Abstract] [Full Text] [PDF]

				C. A. Fernandez, C. Butterfield, G. Jackson, and M. A. Moses Structural and Functional Uncoupling of the Enzymatic and Angiogenic Inhibitory Activities of Tissue Inhibitor of Metalloproteinase-2 (TIMP-2): LOOP 6 IS A NOVEL ANGIOGENESIS INHIBITOR J. Biol. Chem., October 17, 2003; 278(42): 40989 - 40995. [Abstract] [Full Text] [PDF]

				Y.-W. Tien, P.-H. Lee, R.-H. Hu, S.-M. Hsu, and K.-J. Chang The Role of Gelatinase in Hepatic Metastasis of Colorectal Cancer Clin. Cancer Res., October 15, 2003; 9(13): 4891 - 4896. [Abstract] [Full Text] [PDF]

				R. Visse and H. Nagase Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases: Structure, Function, and Biochemistry Circ. Res., May 2, 2003; 92(8): 827 - 839. [Abstract] [Full Text] [PDF]

				S. R. Wesolowski, M. F. Allan, M. K. Nielsen, and D. Pomp Evaluation of hypothalamic gene expression in mice divergently selected for heat loss Physiol Genomics, April 16, 2003; 13(2): 129 - 137. [Abstract] [Full Text] [PDF]

				H. S.-T. Kai, G. S. Butler, C. J. Morrison, A. E. King, G. R. Pelman, and C. M. Overall Utilization of a Novel Recombinant Myoglobin Fusion Protein Expression System to Characterize the Tissue Inhibitor of Metalloproteinase (TIMP)-4 and TIMP-2 C-terminal Domain and Tails by Mutagenesis. THE IMPORTANCE OF ACIDIC RESIDUES IN BINDING THE MMP-2 HEMOPEXIN C DOMAIN J. Biol. Chem., December 6, 2002; 277(50): 48696 - 48707. [Abstract] [Full Text] [PDF]

				A. Cho and M. A. Reidy Matrix Metalloproteinase-9 Is Necessary for the Regulation of Smooth Muscle Cell Replication and Migration After Arterial Injury Circ. Res., November 1, 2002; 91(9): 845 - 851. [Abstract] [Full Text] [PDF]

				K. R. Schilperoort-Haun and A. R. Menino Jr. Factors affecting cellular outgrowth from porcine inner cell masses in vitro J Anim Sci, October 1, 2002; 80(10): 2671 - 2681. [Abstract] [Full Text] [PDF]

				K.A. Young, J.D. Hennebold, and R.L. Stouffer Dynamic expression of mRNAs and proteins for matrix metalloproteinases and their tissue inhibitors in the primate corpus luteum during the menstrual cycle Mol. Hum. Reprod., September 1, 2002; 8(9): 833 - 840. [Abstract] [Full Text] [PDF]

				D. Zhang, R. C. M. Simmen, F. J. Michel, G. Zhao, D. Vale-Cruz, and F. A. Simmen Secretory Leukocyte Protease Inhibitor Mediates Proliferation of Human Endometrial Epithelial Cells by Positive and Negative Regulation of Growth-associated Genes J. Biol. Chem., August 9, 2002; 277(33): 29999 - 30009. [Abstract] [Full Text] [PDF]

				M. Bond, G. Murphy, M. R. Bennett, A. C. Newby, and A. H. Baker Tissue Inhibitor of Metalloproteinase-3 Induces a Fas-associated Death Domain-dependent Type II Apoptotic Pathway J. Biol. Chem., April 12, 2002; 277(16): 13787 - 13795. [Abstract] [Full Text] [PDF]

				A. H. Baker, D. R. Edwards, and G. Murphy Metalloproteinase inhibitors: biological actions and therapeutic opportunities J. Cell Sci., January 10, 2002; 115(19): 3719 - 3727. [Abstract] [Full Text] [PDF]

				E. Oelmann, H. Herbst, M. Zuhlsdorf, O. Albrecht, A. Nolte, C. Schmitmann, O. Manzke, V. Diehl, H. Stein, and W. E. Berdel Tissue inhibitor of metalloproteinases 1 is an autocrine and paracrine survival factor, with additional immune-regulatory functions, expressed by Hodgkin/Reed-Sternberg cells Blood, January 1, 2002; 99(1): 258 - 267. [Abstract] [Full Text] [PDF]

				B. Vaillant, M. G. Chiaramonte, A. W. Cheever, P. D. Soloway, and T. A. Wynn Regulation of Hepatic Fibrosis and Extracellular Matrix Genes by the Th Response: New Insight into the Role of Tissue Inhibitors of Matrix Metalloproteinases J. Immunol., December 15, 2001; 167(12): 7017 - 7026. [Abstract] [Full Text] [PDF]

				B. V. S. Kallakury, S. Karikehalli, A. Haholu, C. E. Sheehan, N. Azumi, and J. S. Ross Increased Expression of Matrix Metalloproteinases 2 and 9 and Tissue Inhibitors of Metalloproteinases 1 and 2 Correlate with Poor Prognostic Variables in Renal Cell Carcinoma Clin. Cancer Res., October 1, 2001; 7(10): 3113 - 3119. [Abstract] [Full Text] [PDF]

				E. E.J.M. Creemers, J. P.M. Cleutjens, J. F.M. Smits, and M. J.A.P. Daemen Matrix Metalloproteinase Inhibition After Myocardial Infarction: A New Approach to Prevent Heart Failure? Circ. Res., August 3, 2001; 89(3): 201 - 210. [Abstract] [Full Text] [PDF]

				L. L.L. Robinson, N. A. Sznajder, S. C. Riley, and R. A. Anderson Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human fetal testis and ovary Mol. Hum. Reprod., July 1, 2001; 7(7): 641 - 648. [Abstract] [Full Text] [PDF]

				D. K. Madtes, A. L. Elston, L. A. Kaback, and J. G. Clark Selective Induction of Tissue Inhibitor of Metalloproteinase-1 in Bleomycin-Induced Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., May 1, 2001; 24(5): 599 - 607. [Abstract] [Full Text]

				S. O. A. Koskinen, W. Wang, A. M. Ahtikoski, M. Kjar, X. Y. Han, J. Komulainen, V. Kovanen, and T. E. S. Takala Acute exercise induced changes in rat skeletal muscle mRNAs and proteins regulating type IV collagen content Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1292 - R1300. [Abstract] [Full Text] [PDF]

				L. Guedez, A. Mansoor, B. Birkedal-Hansen, M. S. Lim, P. Fukushima, D. Venzon, W. G. Stetler-Stevenson, and M. Stetler-Stevenson Tissue inhibitor of metalloproteinases 1 regulation of interleukin-10 in B-cell differentiation and lymphomagenesis Blood, March 15, 2001; 97(6): 1796 - 1802. [Abstract] [Full Text] [PDF]

				Y. Jiang, M. Wang, M. Y. Çeliker, Y. E. Liu, Q. X. Amy Sang, I. D. Goldberg, and Y. E. Shi Stimulation of Mammary Tumorigenesis by Systemic Tissue Inhibitor of Matrix Metalloproteinase 4 Gene Delivery Cancer Res., March 1, 2001; 61(6): 2365 - 2370. [Abstract] [Full Text]

				M. Selman, V. Ruiz, S. Cabrera, L. Segura, R. Ramirez, R. Barrios, and A. Pardo TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment? Am J Physiol Lung Cell Mol Physiol, September 1, 2000; 279(3): L562 - L574. [Abstract] [Full Text] [PDF]

				W. B. Nothnick Disruption of the Tissue Inhibitor of Metalloproteinase-1 Gene Results in Altered Reproductive Cyclicity and Uterine Morphology in Reproductive-Age Female Mice Biol Reprod, September 1, 2000; 63(3): 905 - 912. [Abstract] [Full Text]

				F. H. McCaffery, R. Leask, S. C. Riley, and E. E. Telfer Culture of Bovine Preantral Follicles in a Serum-Free System: Markers for Assessment of Growth and Development Biol Reprod, July 1, 2000; 63(1): 267 - 273. [Abstract] [Full Text]

				M. H. Kim, R. P. Kitson, P. Albertsson, U. Nannmark, P. H. Basse, P. J. K. Kuppen, M. E. Hokland, and R. H. Goldfarb Secreted and Membrane-Associated Matrix Metalloproteinases of IL-2-Activated NK Cells and Their Inhibitors J. Immunol., June 1, 2000; 164(11): 5883 - 5889. [Abstract] [Full Text] [PDF]

				C S SETHI, T A BAILEY, P J LUTHERT, and N H V CHONG Matrix metalloproteinase biology applied to vitreoretinal disorders Br. J. Ophthalmol., June 1, 2000; 84(6): 654 - 666. [Full Text]

				E. Maquoi, F. Frankenne, E. Baramova, C. Munaut, N. E. Sounni, A. Remacle, A. Noel, G. Murphy, and J.-M. Foidart Membrane Type 1 Matrix Metalloproteinase-associated Degradation of Tissue Inhibitor of Metalloproteinase 2 in Human Tumor Cell Lines J. Biol. Chem., April 6, 2000; 275(15): 11368 - 11378. [Abstract] [Full Text] [PDF]

				G. Li, R. Fridman, and H.-R. C. Kim Tissue Inhibitor of Metalloproteinase-1 Inhibits Apoptosis of Human Breast Epithelial Cells Cancer Res., December 1, 1999; 59(24): 6267 - 6275. [Abstract] [Full Text] [PDF]

				L. Badinga, F. J. Michel, and R. C.M. Simmen Uterine-Associated Serine Protease Inhibitors Stimulate Deoxyribonucleic Acid Synthesis in Porcine Endometrial Glandular Epithelial Cells of Pregnancy Biol Reprod, August 1, 1999; 61(2): 380 - 387. [Abstract] [Full Text]

				H. Nagase and J. F. Woessner Jr. Matrix Metalloproteinases J. Biol. Chem., July 30, 1999; 274(31): 21491 - 21494. [Full Text] [PDF]

				C. M. Dollery, S. E. Humphries, A. McClelland, D. S. Latchman, and J. R. McEwan Expression of Tissue Inhibitor of Matrix Metalloproteinases 1 by Use of an Adenoviral Vector Inhibits Smooth Muscle Cell Migration and Reduces Neointimal Hyperplasia in the Rat Model of Vascular Balloon Injury Circulation, June 22, 1999; 99(24): 3199 - 3205. [Abstract] [Full Text] [PDF]

				C. Vaillant, M. Didier-Bazes, A. Hutter, M.-F. Belin, and N. Thomasset Spatiotemporal Expression Patterns of Metalloproteinases and Their Inhibitors in the Postnatal Developing Rat Cerebellum J. Neurosci., June 15, 1999; 19(12): 4994 - 5004. [Abstract] [Full Text] [PDF]

				Q. Meng, V. Malinovskii, W. Huang, Y. Hu, L. Chung, H. Nagase, W. Bode, K. Maskos, and K. Brew Residue 2 of TIMP-1 Is a Major Determinant of Affinity and Specificity for Matrix Metalloproteinases but Effects of Substitutions Do Not Correlate with Those of the Corresponding P1' Residue of Substrate J. Biol. Chem., April 9, 1999; 274(15): 10184 - 10189. [Abstract] [Full Text] [PDF]

				S. C. Riley, R. Leask, T. Chard, N. C. Wathen, A. A. Calder, and D. C. Howe Secretion of matrix metalloproteinase-2, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases into the intrauterine compartments during early pregnancy Mol. Hum. Reprod., April 1, 1999; 5(4): 376 - 381. [Abstract] [Full Text] [PDF]

				A. Price, Q. Shi, D. Morris, M. E. Wilcox, P. M. A. Brasher, N. B. Rewcastle, D. Shalinsky, H. Zou, K. Appelt, R. N. Johnston, et al. Marked Inhibition of Tumor Growth in a Malignant Glioma Tumor Model by a Novel Synthetic Matrix MetalloproteinaseInhibitor AG3340 Clin. Cancer Res., April 1, 1999; 5(4): 845 - 854. [Abstract] [Full Text] [PDF]

				C. M. Dollery, J. R. McEwan, M. Wang, Q. A. Sang, Y. E. Liu, and Y. E. Shi TIMP-4 Is Regulated by Vascular Injury in Rats Circ. Res., March 19, 1999; 84(5): 498 - 504. [Abstract] [Full Text] [PDF]

				G Cox, W P Steward, and K J O'Byrne The plasmin cascade and matrix metalloproteinases in non-small cell lung cancer Thorax, February 1, 1999; 54(2): 169 - 179. [Full Text]

				R.K. Nuttall and T.G. Kennedy Gelatinases A and B and Tissue Inhibitors of Metalloproteinases 1, 2, and 3 during In Vivo and In Vitro Decidualization of Rat Endometrial Stromal Cells Biol Reprod, February 1, 1999; 60(2): 471 - 478. [Abstract] [Full Text] [PDF]

				W. Q. Liand and M. Zafarullah Oncostatin M Up-Regulates Tissue Inhibitor of Metalloproteinases-3 Gene Expression in Articular Chondrocytes via De Novo Transcription, Protein Synthesis, and Tyrosine Kinase- and Mitogen-Activated Protein Kinase-Dependent Mechanisms J. Immunol., November 1, 1998; 161(9): 5000 - 5007. [Abstract] [Full Text] [PDF]

				F. Aoudjit, E. F. Potworowski, T. A. Springer, and Y. St-Pierre Protection from Lymphoma Cell Metastasis in ICAM-1 Mutant Mice: A Posthoming Event J. Immunol., September 1, 1998; 161(5): 2333 - 2338. [Abstract] [Full Text] [PDF]

				K. Airola, M. Ahonen, N. Johansson, P. Heikkilä, J. Kere, V.-M. Kähäri, and U. K. Saarialho–Kere Human TIMP-3 Is Expressed During Fetal Development, Hair Growth Cycle, and Cancer Progression J. Histochem. Cytochem., April 1, 1998; 46(4): 437 - 448. [Abstract] [Full Text]

				S. Zucker, M. Drews, C. Conner, H. D. Foda, Y. A. DeClerck, K. E. Langley, W. F. Bahou, A. J. P. Docherty, and J. Cao Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) Binds to the Catalytic Domain of the Cell Surface Receptor, Membrane Type 1-Matrix Metalloproteinase 1 (MT1-MMP) J. Biol. Chem., January 9, 1998; 273(2): 1216 - 1222. [Abstract] [Full Text] [PDF]

				W. Zhao, H Li, K Yamashita, X. Guo, T Hoshino, S Yoshida, T Shinya, and T Hayakawa Cell cycle-associated accumulation of tissue inhibitor of metalloproteinases-1 (TIMP-1) in the nuclei of human gingival fibroblasts J. Cell Sci., January 5, 1998; 111(9): 1147 - 1153. [Abstract] [PDF]

				M. Iino, D. C. Foster, and W. Kisiel Quantification and Characterization of Human Endothelial Cell–Derived Tissue Factor Pathway Inhibitor-2 Arterioscler. Thromb. Vasc. Biol., January 1, 1998; 18(1): 40 - 46. [Abstract] [Full Text] [PDF]

				W. Huang, Q. Meng, K. Suzuki, H. Nagase, and K. Brew Mutational Study of the Amino-terminal Domain of Human Tissue Inhibitor of Metalloproteinases 1 (TIMP-1) Locates an Inhibitory Region for Matrix Metalloproteinases J. Biol. Chem., August 29, 1997; 272(35): 22086 - 22091. [Abstract] [Full Text] [PDF]

				Y. E. Liu, M. Wang, J. Greene, J. Su, S. Ullrich, H. Li, S. Sheng, P. Alexander, Q. A. Sang, and Y. E. Shi Preparation and Characterization of Recombinant Tissue Inhibitor of Metalloproteinase 4 (TIMP-4) J. Biol. Chem., August 15, 1997; 272(33): 20479 - 20483. [Abstract] [Full Text] [PDF]

				J. G. Pickering, C. M. Ford, B. Tang, and L. H. Chow Coordinated Effects of Fibroblast Growth Factor-2 on Expression of Fibrillar Collagens, Matrix Metalloproteinases, and Tissue Inhibitors of Matrix Metalloproteinases by Human Vascular Smooth Muscle Cells : Evidence for Repressed Collagen Production and Activated Degradative Capacity Arterioscler. Thromb. Vasc. Biol., March 1, 1997; 17(3): 475 - 482. [Abstract] [Full Text]

				M. Stetler-Stevenson, A. Mansoor, M. Lim, P. Fukushima, J. Kehrl, G. Marti, K. Ptaszynski, J. Wang, and W. G. Stetler-Stevenson Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Reactive and Neoplastic Lymphoid Cells Blood, March 1, 1997; 89(5): 1708 - 1715. [Abstract] [Full Text] [PDF]

				E. Ohuchi, K. Imai, Y. Fujii, H. Sato, M. Seiki, and Y. Okada Membrane Type 1Matrix Metalloproteinase Digests Interstitial Collagens and Other Extracellular Matrix Macromolecules J. Biol. Chem., January 24, 1997; 272(4): 2446 - 2451. [Abstract] [Full Text] [PDF]

				K. Hammani, A. Blakis, D. Morsette, A. M. Bowcock, C. Schmutte, P. Henriet, and Y. A. DeClerck Structure and Characterization of the Human Tissue Inhibitor of Metalloproteinases-2 Gene J. Biol. Chem., October 11, 1996; 271(41): 25498 - 25505. [Abstract] [Full Text] [PDF]