[en] Both invasion-promoting MT1-MMP and its physiological inhibitorTIMP-2 play a significant role in tumorigenesis and are identified in the most aggressive cancers. Despite its antiproteolytic effects in vitro, clinical data suggest that TIMP-2 expression is positively associated with tumor recurrence, thus emphasizing the wide-ranging role of TIMP-2 in malignancies. To shed light on this role of TIMP-2, we report that low concentrations of TIMP-2, by interacting with MT1-MMP (a specific membrane receptor of TIMP-2), induce the MEK/ERK signaling cascade in fibrosarcoma HT1080 cells which express MT1-MMP naturally. TIMP-2 binding with cell surface-associated MT1-MMP stimulates phosphorylation of MEK1/2, which is upstream of ERK1/2, and the ERK1/2 substrate p90RSK. Consistent with volumes of literature, we confirmed that the activation of ERK stimulated cell migration. Both the transcriptional silencing of MT1-MMP and the inhibition of MEK1/2 reversed the signaling effects of TIMP-2/MT1-MMP while the active site-targeting MMP inhibitor GM6001 did not. Our data suggest that both the interactions of TIMP-2 with MT1-MMP, which activate the pro-migratory ERK signaling cascade, and the conventional inhibition of MT1-MMP's catalytic activity by TIMP-2, play a role in the invasion-promoting function of MT1-MMP. The TIMP-2-induced stimulation of ERK signaling in cancer cells explains the direct, as opposed to the inverse, association of TIMP-2 expression with poor prognosis in cancer.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Sounni, Nor Eddine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Rozanov, D. V.
Remacle, A. G.
Golubkov, V. S.
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Strongin, A. Y.
Language :
English
Title :
TIMP-2 binding with cellular MT1-MMP stimulates invasion-promoting MEK/ERK signaling in cancer cells
Publication date :
2010
Journal title :
International Journal of Cancer
ISSN :
0020-7136
eISSN :
1097-0215
Publisher :
Wiley Liss, Inc., New York, United States - New York
Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002;2:161-74.
Seiki M. Membrane-type 1 matrix metalloproteinase: a key enzyme for tumor invasion. Cancer Lett 2003;194:1-11.
Strongin AY. Mislocalization and unconventional functions of cellular MMPs in cancer. Cancer Metastasis Rev 2006;25:87-98.
Zucker S, Pei D, Cao J, Lopez-Otin C. Membrane type-matrix metalloproteinases (MT-MMP). Curr Top Dev Biol 2003;54:1-74.
Golubkov VS, Chekanov AV, Savinov AY, Rozanov DV, Golubkova NV, Strongin AY. Membrane type-1 matrix metalloproteinase confers aneuploidy and tumorigenicity on mammary epithelial cells. Cancer Res 2006;66:10460-5.
Hotary KB, Allen ED, Brooks PC, Datta NS, Long MW, Weiss SJ. Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell 2003;114:33-45.
Sabeh F, Ota I, Holmbeck K, Birkedal-Hansen H, Soloway P, Balbin M, Lopez-Otin C, Shapiro S, Inada M, Krane S, Allen E, Chung D, et al. Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP. J Cell Biol 2004;167:769-81.
Golubkov VS, Chekanov AV, Shiryaev SA, Aleshin AE, Ratnikov BI, Gawlik K, Radichev I, Motamedchaboki K, Smith JW, Strongin AY. Proteolysis of the membrane type-1 matrix metalloproteinase prodomain: implications for a two-step proteolytic processing and activation. J Biol Chem 2007;282:36283-91.
Pei D, Weiss SJ. Furin-dependent intracellular activation of the human stromelysin-3 zymogen. Nature 1995;375:244-7.
Will H, Atkinson SJ, Butler GS, Smith B, Murphy G. The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation. Regulation by TIMP-2 and TIMP-3. J Biol Chem 1996;271:17119-23.
Murphy G, Knauper V, Lee MH, Amour A, Worley JR, Hutton M, Atkinson S, Rapti M, Williamson R. Role of TIMPs (tissue inhibitors of metalloproteinases) in pericellular proteolysis: the specificity is in the detail. Biochem Soc Symp 2003;70:65-80.
Worley JR, Thompkins PB, Lee MH, Hutton M, Soloway P, Edwards DR, Murphy G, Knauper V. Sequence motifs of tissue inhibitor of metalloproteinases 2 (TIMP-2) determining progelatinase A (proMMP-2) binding and activation by membrane-type metalloproteinase 1 (MT1-MMP). Biochem J 2003;372:799-809.
Strongin AY, Collier I, Bannikov G, Marmer BL, Grant GA, Goldberg GI. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem 1995;270:5331-8.
Willenbrock F, Crabbe T, Slocombe PM, Sutton CW, Docherty AJ, Cockett MI, O'shea M, Brocklehurst K, Phillips IR, Murphy G. The activity of the tissue inhibitors of metalloproteinases is regulated by C-terminal domain interactions: a kinetic analysis of the inhibition of gelatinase A. Biochemistry 1993;32:4330-7.
Rapti M, Knauper V, Murphy G, Williamson RA. Characterization of the AB loop region of TIMP-2. Involvement in pro-MMP-2 activation. J Biol Chem 2006;281:23386-94.
Belkin AM, Akimov SS, Zaritskaya LS, Ratnikov BI, Deryugina EI, Strongin AY. Matrix-dependent proteolysis of surface transglutaminase by membrane-type metalloproteinase regulates cancer cell adhesion and locomotion. J Biol Chem 2001;276:18415-22.
Mori H, Tomari T, Koshikawa N, Kajita M, Itoh Y, Sato H, Tojo H, Yana I, Seiki M. CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain. EMBO J 2002;21:3949-59.
Ratnikov BI, Rozanov DV, Postnova TI, Baciu PG, Zhang H, Discipio RG, Chestukhina GG, Smith JW, Deryugina EI, Strongin AY. An alternative processing of integrin alpha(v) subunit in tumor cells by membrane type-1 matrix metalloproteinase. J Biol Chem 2002;277: 7377-85.
Itoh Y, Takamura A, Ito N, Maru Y, Sato H, Suenaga N, Aoki T, Seiki M. Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion. EMBO J 2001;20:4782-93.
D'alessio S, Ferrari G, Cinnante K, Scheerer W, Galloway AC, Roses DF, Rozanov DV, Remacle AG, Oh ES, Shiryaev SA, Strongin AY, Pintucci G, 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 2008;283:87-99.
Dufour A, Sampson NS, Zucker S, Cao J. Role of the hemopexin domain of matrix metalloproteinases in cell migration. J Cell Physiol 2008;217:643-51.
Nishida Y, Miyamori H, Thompson EW, Takino T, Endo Y, Sato H. Activation of matrix metalloproteinase-2 (MMP-2) by membrane type 1 matrix metalloproteinase through an artificial receptor for proMMP-2 generates active MMP-2. Cancer Res 2008;68: 9096-104.
Ratnikov B, Deryugina E, Leng J, Marchenko G, Dembrow D, Strongin A. Determination of matrix metalloproteinase activity using biotinylated gelatin. Anal Biochem 2000;286:149-55.
Sounni NE, Devy L, Hajitou A, Frankenne F, Munaut C, Gilles C, Deroanne C, Thompson EW, Foidart JM, Noel A. MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression. FASEB J 2002;16:555-64.
Rozanov DV, Savinov AY, Williams R, Liu K, Golubkov VS, Krajewski S, Strongin AY. Molecular signature of MT1-MMP: transactivation of the downstream universal gene network in cancer. Cancer Res 2008;68:4086-96.
Deryugina EI, Bourdon MA, Luo GX, Reisfeld RA, Strongin A. Matrix metalloproteinase-2 activation modulates glioma cell migration. J Cell Sci 1997;110:2473-82.
Golubkov VS, Boyd S, Savinov AY, Chekanov AV, Osterman AL, Remacle A, Rozanov DV, Doxsey SJ, Strongin AY. Membranetype-1 matrix metalloproteinase (MT1-MMP) exhibits an important intracellular cleavage function and causes chromosome instability. J Biol Chem 2005;280:25079-86.
Golubkov VS, Chekanov AV, Doxsey SJ, Strongin AY. Centrosomal pericentrin is a direct cleavage target of membrane type-1 matrix metalloproteinase in humans but not in mice: potential implications for tumorigenesis. J Biol Chem 2005;280:42237-41.
Ueda J, Kajita M, Suenaga N, Fujii K, Seiki M. Sequencespecific silencing of MT1-MMP expression suppresses tumor cell migration and invasion: importance of MT1-MMP as a therapeutic target for invasive tumors. Oncogene 2003;22:8716-22.
Rozanov DV, Deryugina EI, Ratnikov BI, Monosov EZ, Marchenko GN, Quigley JP, Strongin AY. Mutation analysis of membrane type-1 matrix metalloproteinase (MT1-MMP). The role of the cytoplasmic tail Cys(574), the active site Glu(240), and furin cleavage motifs in oligomerization, processing, and self-proteolysis of MT1-MMP expressed in breast carcinoma cells. J Biol Chem 2001;276:25705-14.
Albini A, Melchiori A, Santi L, Liotta LA, Brown PD, Stetler-Stevenson WG. Tumor cell invasion inhibited by TIMP-2. J Natl Cancer Inst 1991;83:775-9.
Filippov S, Koenig GC, Chun TH, Hotary KB, Ota I, Bugge TH, Roberts JD, Fay WP, Birkedal-Hansen H, Holmbeck K, Sabeh F, Allen ED, et al. MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells. J Exp Med 2005;202:663-71.
Lehti K, Allen E, Birkedal-Hansen H, Holmbeck K, Miyake Y, Chun TH, Weiss SJ. An MT1-MMP-PDGF receptor-beta axis regulates mural cell investment of the microvasculature. Genes Dev 2005;19:979-91.
Maquoi E, Frankenne F, Noel A, Krell HW, Grams F, Foidart JM. Type IV collagen induces matrix metalloproteinase 2 activation in HT1080 fibrosarcoma cells. Exp Cell Res 2000;261:348-59.
Hernandez-Barrantes S, Toth M, Bernardo MM, Yurkova M, Gervasi DC, Raz Y, Sang QA, Fridman R. Binding of active (57 kDa) membrane type 1-matrix metalloproteinase (MT1-MMP) to tissue inhibitor of metalloproteinase (TIMP)-2 regulates MT1-MMP processing and pro-MMP-2 activation. J Biol Chem 2000;275:12080-9.
Friday BB, Adjei AA. Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res 2008;14:342-6.
Deryugina EI, Bourdon MA, Jungwirth K, Smith JW, Strongin AY. Functional activation of integrin alpha V beta 3 in tumor cells expressing membrane-type 1 matrix metalloproteinase. Int J Cancer 2000;86:15-23.
Roca F, Mauro LV, Morandi A, Bonadeo F, Vaccaro C, Quintana GO, Specterman S, De Kier Joffe EB, Pallotta MG, Puricelli LI, Lastiri J. Prognostic value of E-cadherin, beta-catenin, MMPs (7 and 9), and TIMPs (1 and 2) in patients with colorectal carcinoma. JSurg Oncol 2006;93:151-60.
Ruokolainen H, Paakko P, Turpeenniemi-Hujanen T. Tissue and circulating immunoreactive protein for MMP-2 and TIMP-2 in head and neck squamous cell carcinoma-tissue immunoreactivity predicts aggressive clinical course. Mod Pathol 2006;19: 208-17.
Swellam M, Arab LR, Bushnak HA. Clinical implications of HER-2/neu overexpression and proteolytic activity imbalance in breast cancer. IUBMB Life 2007;59:394-401.
Remacle A, Mccarthy K, Noel A, Maguire T, Mcdermott E, O'higgins N, Foidart JM, Duffy MJ. High levels of TIMP-2 correlate with adverse prognosis in breast cancer. Int J Cancer 2000;89: 118-21.
Grignon DJ, Sakr W, Toth M, Ravery V, Angulo J, Shamsa F, Pontes JE, Crissman JC, Fridman R. High levels of tissue inhibitor of metalloproteinase-2 (TIMP-2) expression are associated with poor outcome in invasive bladder cancer. Cancer Res 1996;56: 1654-9.
Visscher DW, Hoyhtya M, Ottosen SK, Liang CM, Sarkar FH, Crissman JD, Fridman R. Enhanced expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) in the stroma of breast carcinomas correlates with tumor recurrence. Int J Cancer 1994;59: 339-44.
Galm O, Suzuki H, Akiyama Y, Esteller M, Brock MV, Osieka R, Baylin SB, Herman JG. Inactivation of the tissue inhibitor of metalloproteinases-2 gene by promoter hypermethylation in lymphoid malignancies. Oncogene 2005;24:4799-805.
Ivanova T, Vinokurova S, Petrenko A, Eshilev E, Solovyova N, Kisseljov F, Kisseljova N. Frequent hypermethylation of 5′ flanking region of TIMP-2 gene in cervical cancer. Int J Cancer 2004;108:882-6.
Kubben FJ, Sier CF, Meijer MJ, Van Den Berg M, Van Der Reijden JJ, Griffioen G, Van De Velde CJ, Lamers CB, Verspaget HW. Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer. Br J Cancer 2006;95:744-51.
Pulukuri SM, Patibandla S, Patel J, Estes N, Rao JS. Epigenetic inactivation of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene in human prostate tumors. Oncogene 2007;26:5229-37.
Vairaktaris E, Yapijakis C, Yiannopoulos A, Vassiliou S, Serefoglou Z, Vylliotis A, Nkenke E, Derka S, Critselis E, Avgoustidis D, Neukam FW, Patsouris E. Strong association of the tissue inhibitor of metalloproteinase-2 polymorphism with an increased risk of oral squamous cell carcinoma in Europeans. Oncol Rep 2007;17: 963-8.
Jung KK, Liu XW, Chirco R, Fridman R, Kim HR. Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. EMBO J 2006;25:3934-42.
Stetler-Stevenson WG. Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signal 2008;1:re6.
Baker EA, Leaper DJ, Hayter JP, Dickenson AJ. The matrix metalloproteinase system in oral squamous cell carcinoma. Br J Oral Maxillofac Surg 2006;44:482-6.
Murawaki Y, Ikuta Y, Kawasaki H. Clinical usefulness of serum tissue inhibitor of metalloproteinases (TIMP)-2 assay in patients with chronic liver disease in comparison with serum TIMP-1. Clin Chim Acta 1999;281:109-20.
Pasieka Z, Stepien H, Czyz W, Pomorski L, Kuzdak K. Concentration of metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in the serum of patients with benign and malignant thyroid tumours treated surgically. Endocr Regul 2004; 38:57-63.
Ulrich D, Lichtenegger F, Eblenkamp M, Repper D, Pallua N. Matrix metalloproteinases, tissue inhibitors of metalloproteinases, aminoterminal propeptide of procollagen type III, and hyaluronan in sera and tissue of patients with capsular contracture after augmentation with Trilucent breast implants. Plast Reconstr Surg 2004;114:229-36.
Larsen MB, Stephens RW, Brunner N, Nielsen HJ, Engelholm LH, Christensen IJ, Stetler-Stevenson WG, Hoyer-Hansen G. Quantification of tissue inhibitor of metalloproteinases 2 in plasma from healthy donors and cancer patients. Scand J Immunol 2005;61:449-60.
Murphy G, Stanton H, Cowell S, Butler G, Knauper V, Atkinson S, Gavrilovic J. Mechanisms for pro matrix metalloproteinase activation. APMIS 1999;107:38-44.
Uekita T, Itoh Y, Yana I, Ohno H, Seiki M. Cytoplasmic tail-dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity. J Cell Biol 2001;155:1345-56.
Hackeng CM, Relou IA, Pladet MW, Gorter G, Van Rijn HJ, Akkerman JW. Early platelet activation by low density lipoprotein via p38MAP kinase. Thromb Haemost 1999;82:1749-56.
Hu K, Yang J, Tanaka S, Gonias SL, Mars WM, Liu Y. Tissue-type plasminogen activator acts as a cytokine that triggers intracellular signal transduction and induces matrix metalloproteinase-9 gene expression. J Biol Chem 2006;281:2120-7.
Ma Z, Thomas KS, Webb DJ, Moravec R, Salicioni AM, Mars WM, Gonias SL. Regulation of Rac1 activation by the low density lipoprotein receptor-related protein. J Cell Biol 2002;159:1061-70.
Mantuano E, Inoue G, Li X, Takahashi K, Gaultier A, Gonias SL, Campana WM. The hemopexin domain of matrix metalloproteinase-9 activates cell signaling and promotes migration of schwann cells by binding to low-density lipoprotein receptor-related protein. J Neurosci 2008;28:11571-82.
Webb DJ, Nguyen DH, Gonias SL. Extracellular signal-regulated kinase functions in the urokinase receptor-dependent pathway by which neutralization of low density lipoprotein receptor-related protein promotes fibrosarcoma cell migration and matrigel invasion. J Cell Sci 2000;113:123-34.
Seo DW, Li H, Guedez L, Wingfield PT, Diaz T, Salloum R, Wei BY, Stetler-Stevenson WG. TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell 2003;114:171-80.