Skip to main content

Advertisement

Log in

Functional disparities within the TIMP family in cancer: hints from molecular divergence

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

The members of the tissue inhibitor of metalloproteinase (TIMP) family (TIMP-1, 2, 3, 4) are prominently appreciated as natural inhibitors of cancer-promoting metalloproteinases. However, clinical and recent functional studies indicate that some of them correlate with bad prognosis and contribute to the progression of cancer and metastasis, pointing towards mechanisms beyond inhibition of cancer-promoting proteases. Indeed, it is increasingly recognized that TIMPs are multi-functional proteins mediating a variety of cellular effects including direct cell signaling. Our aim was to provide comprehensive information towards a better appreciation and understanding of the biological heterogeneity and complexity of the TIMPs in cancer. Comparison of all four members revealed distinct cancer-associated expression patterns and distinct prognostic impact including a clear correlation of TIMP-1 with bad prognosis for almost all cancer types. For the first time, we present the interactomes of all TIMPs regarding overlapping and non-overlapping interaction partners. Interestingly, the overlap was maximal for metalloproteinases (e.g., matrix metalloproteinase 1, 2, 3, 9) and decreased for non-protease molecules, especially cell surface receptors (e.g., CD63, overlapping only for TIMP-1 and 4; IGF-1R unique for TIMP-2; VEGFR2 unique for TIMP-3). Finally, we attempted to identify and summarize experimental evidence for common and unique structural traits of the four TIMPs on the basis of amino acid sequence and protein folding, which account for functional disparities. Altogether, the four TIMPs have to be appreciated as molecules with commonalities, but, more importantly, functional disparities, which need to be investigated further in the future, since those determine their distinct roles in cancer and metastasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Lambert, E., Dassé, E., Haye, B., & Petitfrère, E. (2004). TIMPs as multifacial proteins. Critical Reviews in Oncology/Hematology, 49(3), 187–198.

    Article  PubMed  Google Scholar 

  2. Lu, P., Takai, K., Weaver, V. M., & Werb, Z. (2011). Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harbor Perspectives in Biology, 3, a005058.

  3. Arpino, V., Brock, M., & Gill, S. E. (2015). The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix Biology: Journal of the International Society for Matrix Biology, 44-46, 247–254.

    Article  CAS  Google Scholar 

  4. Bonnans, C., Chou, J., & Werb, Z. (2014). Remodelling the extracellular matrix in development and disease. Nature Reviews Molecular Cell Biology, 15(12), 786–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Brand, K. (2002). Cancer gene therapy with tissue inhibitors of metalloproteinases (TIMPs). Current Gene Therapy, 2(2), 255–271.

    Article  CAS  PubMed  Google Scholar 

  6. Liotta, L. A., Tryggvason, K., Garbisa, S., Hart, I., Foltz, C. M., & Shafie, S. (1980). Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature, 284(5751), 67–68.

    Article  CAS  PubMed  Google Scholar 

  7. Köppel, P., Baici, A., Keist, R., Matzku, S., & Keller, R. (1984). Cathepsin B-like proteinase as a marker for metastatic tumor cell variants. Pathobiology: Journal of Immunopathology, Molecular and Cellular Biology, 52(5), 293–299.

    Article  Google Scholar 

  8. Thorgeirsson, U. P., Liotta, L., Kalebic, T., Thomas, K., Rios-Candelore, M., & Russo, R. G. (1982). Effect of natural protease inhibitors and a chemoattractant on tumor cell invasion in vitro. Journal of the National Cancer Institute, 69(5), 1049–1054.

    CAS  PubMed  Google Scholar 

  9. Joyce, J. A., Baruch, A., Chehade, K., Meyer-Morse, N., Giraudo, E., Tsai, F.-Y., Greenbaum, D. C., Hager, J. H., Bogyo, M., & Hanahan, D. (2004). Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Cancer Cell, 5(5), 443–453.

    Article  CAS  PubMed  Google Scholar 

  10. Albini, A., Melchiori, A., Santi, L., Liotta, L. A., Brown, P. D., & Stetler-Stevenson, W. G. (1991). Tumor cell invasion inhibited by TIMP-2. Journal of the National Cancer Institute, 83(11), 775–779.

    Article  CAS  PubMed  Google Scholar 

  11. Khokha, R. (1994). Suppression of the tumorigenic and metastatic abilities of murine B16-F10 melanoma cells in vivo by the overexpression of the tissue inhibitor of the metalloproteinases-1. Journal of the National Cancer Institute, 86(4), 299–304.

    Article  CAS  PubMed  Google Scholar 

  12. Rigg, A. S., & Lemoine, N. R. (2001). Adenoviral delivery of TIMP1 or TIMP2 can modify the invasive behavior of pancreatic cancer and can have a significant antitumor effect in vivo. Cancer Gene Therapy, 8(11), 869–878.

    Article  CAS  PubMed  Google Scholar 

  13. Jiang, Y., Goldberg, I. D., & Shi, Y. E. (2002). Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene, 21(14), 2245–2252.

    Article  CAS  PubMed  Google Scholar 

  14. Baker, A. H., George, S. J., Zaltsman, A. B., Murphy, G., & Newby, A. C. (1999). Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3. British Journal of Cancer, 79(9), 1347–1355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. McCarthy, K., Maguire, T., McGreal, G., McDermott, E., O’Higgins, N., & Duffy, M. J. (1999). High levels of tissue inhibitor of metalloproteinase-1 predict poor outcome in patients with breast cancer. International Journal of Cancer, 84(1), 44–48.

    Article  CAS  PubMed  Google Scholar 

  16. Remacle, A., McCarthy, K., Noël, A., Maguire, T., McDermott, E., O’Higgins, N., Foidart, J. M., & Duffy, M. J. (2000). High levels of TIMP-2 correlate with adverse prognosis in breast cancer. International Journal of Cancer, 89(2), 118–121.

    Article  CAS  PubMed  Google Scholar 

  17. Kopitz, C., Gerg, M., Bandapalli, O. R., Ister, D., Pennington, C. J., Hauser, S., Flechsig, C., Krell, H.-W., Antolovic, D., Brew, K., Nagase, H., Stangl, M., von Weyhern, C. W. H., Brücher, B. L. D. M., Brand, K., Coussens, L. M., Edwards, D. R., & Krüger, A. (2007). Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signaling. Cancer Research, 67(18), 8615–8623.

    Article  CAS  PubMed  Google Scholar 

  18. Schelter, F., Grandl, M., Seubert, B., Schaten, S., Hauser, S., Gerg, M., Boccaccio, C., Comoglio, P., & Krüger, A. (2011). Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met-signaling via inhibition of Adam-10. Clinical & Experimental Metastasis, 28(8), 793–802.

    Article  CAS  Google Scholar 

  19. Seubert, B., Grünwald, B., Kobuch, J., Cui, H., Schelter, F., Schaten, S., Siveke, J. T., Lim, N. H., Nagase, H., Simonavicius, N., Heikenwalder, M., Reinheckel, T., Sleeman, J. P., Janssen, K. P., Knolle, P. A., & Krüger, A. (2015). Tissue inhibitor of metalloproteinases (TIMP)-1 creates a premetastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice. Hepatology, 61(1), 238–248.

    Article  CAS  PubMed  Google Scholar 

  20. Cui, H., Seubert, B., Stahl, E., Dietz, H., Reuning, U., Moreno-Leon, L., Ilie, M., Hofman, P., Nagase, H., Mari, B., & Krüger, A. (2015). Tissue inhibitor of metalloproteinases-1 induces a pro-tumourigenic increase of miR-210 in lung adenocarcinoma cells and their exosomes. Oncogene, 34(28), 3640–3650.

    Article  CAS  PubMed  Google Scholar 

  21. Grünwald, B., Schoeps, B., & Krüger, A. (2019). Recognizing the molecular multifunctionality and interactome of TIMP-1. Trends in Cell Biology, 29(1), 6–19.

    Article  PubMed  CAS  Google Scholar 

  22. Ries, C. (2014). Cytokine functions of TIMP-1. Cellular and Molecular Life Sciences, 71(4), 659–672.

    Article  CAS  PubMed  Google Scholar 

  23. Chirco, R., Liu, X.-W., Jung, K.-K., & Kim, H.-R. C. (2006). Novel functions of TIMPs in cell signaling. Cancer Metastasis Reviews, 25(1), 99–113.

    Article  CAS  PubMed  Google Scholar 

  24. Mason, S. D., & Joyce, J. A. (2011). Proteolytic networks in cancer. Trends in Cell Biology, 21(4), 228–237.

    Article  CAS  PubMed  Google Scholar 

  25. Murthy, A., Cruz-Munoz, W., & Khokha, R. (2008). TIMPs: Extracellular modifiers in cancer development. In D. Edwards, G. Hoyer-Hansen, F. Blasi, & B. F. Sloane (Eds.), The cancer degradome (pp. 373–400). Springer.

  26. Murphy, G., Cawston, T. E., & Reynolds, J. J. (1981). An inhibitor of collagenase from human amniotic fluid. Purification, characterization and action on metalloproteinases. The Biochemical Journal, 195(1), 167–170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Docherty, A. J. P., Lyons, A., Smith, B. J., Wright, E. M., Stephens, P. E., Harris, T. J. R., Murphy, G., & Reynolds, J. J. (1985). Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature, 318(6041), 66–69.

    Article  CAS  PubMed  Google Scholar 

  28. Gasson, J. C., Golde, D. W., Kaufman, S. E., Westbrook, C. A., Hewick, R. M., Kaufman, R. J., Wong, G. G., Temple, P. A., Leary, A. C., Brown, E. L., Orr, E. C., & Clark, S. C. (1985). Molecular characterization and expression of the gene encoding human erythroid-potentiating activity. Nature, 315(6022), 768–771.

    Article  CAS  PubMed  Google Scholar 

  29. Cruz-Munoz, W., & Khokha, R. (2008). The role of tissue inhibitors of metalloproteinases in tumorigenesis and metastasis. Critical Reviews in Clinical Laboratory Sciences, 45(3), 291–338.

    Article  CAS  PubMed  Google Scholar 

  30. Goldberg, G. I., Marmer, B. L., Grant, G. A., Eisen, A. Z., Wilhelm, S., & He, C. S. (1989). Human 72-kilodalton type IV collagenase forms a complex with a tissue inhibitor of metalloproteases designated TIMP-2. Proceedings of the National Academy of Sciences of the United States of America, 86(21), 8207–8211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hamze, A. B., Wei, S., Bahudhanapati, H., Kota, S., Acharya, K. R., & Brew, K. (2007). Constraining specificity in the N-domain of tissue inhibitor of metalloproteinases-1; gelatinase-selective inhibitors. Protein Science, 16(9), 1905–1913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Stetler-Stevenson, W. G., Bersch, N., & Golde, D. W. (1992). Tissue inhibitor of metalloproteinase-2 (TIMP-2) has erythroid-potentiating activity. FEBS Letters, 296(2), 231–234.

    Article  CAS  PubMed  Google Scholar 

  33. Stetler-Stevenson, W. G., Brown, P. D., Onisto, M., Levy, A. T., & Liotta, L. A. (1990). Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues. The Journal of Biological Chemistry, 265(23), 13933–13938.

    CAS  PubMed  Google Scholar 

  34. Pavloff, N., Staskus, P. W., Kishnani, N. S., & Hawkes, S. P. (1992). A new inhibitor of metalloproteinases from chicken: ChIMP-3. A third member of the TIMP family. The Journal of Biological Chemistry, 267(24), 17321–17326.

    CAS  PubMed  Google Scholar 

  35. Greene, J., Wang, M., Liu, Y. E., Raymond, L. A., Rosen, C., & Shi, Y. E. (1996). Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. The Journal of Biological Chemistry, 271(48), 30375–30380.

    Article  CAS  PubMed  Google Scholar 

  36. Terpos, E., Dimopoulos, M. A., Shrivastava, V., Leitzel, K., Christoulas, D., Migkou, M., Gavriatopoulou, M., Anargyrou, K., Hamer, P., Kastritis, E., Carney, W., & Lipton, A. (2010). High levels of serum TIMP-1 correlate with advanced disease and predict for poor survival in patients with multiple myeloma treated with novel agents. Leukemia Research, 34(3), 399–402.

    Article  CAS  PubMed  Google Scholar 

  37. Fong, K. M., Kida, Y., Zimmerman, P. V., & Smith, P. J. (1996). TIMP1 and adverse prognosis in non-small cell lung cancer. Clinical Cancer Research, 2(8), 1369–1372.

    CAS  PubMed  Google Scholar 

  38. Honkavuori, M., Talvensaari-Mattila, A., Puistola, U., Turpeenniemi-Hujanen, T., & Santala, M. (2008). High serum TIMP-1 is associated with adverse prognosis in endometrial carcinoma. Anticancer Research, 28(5A), 2715–2719.

    PubMed  Google Scholar 

  39. Uhlén, M., Fagerberg, L., Hallström, B. M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, Å., Kampf, C., Sjöstedt, E., & Asplund, A. (2015). Tissue-based map of the human proteome. Science, 347(6220), 1260419.

    Article  PubMed  CAS  Google Scholar 

  40. Lichtinghagen, R., Musholt, P. B., Lein, M., Römer, A., Rudolph, B., Kristiansen, G., Hauptmann, S., Schnorr, D., Loening, S. A., & Jung, K. (2002). Different mRNA and protein expression of matrix metalloproteinases 2 and 9 and tissue inhibitor of metalloproteinases 1 in benign and malignant prostate tissue. European Urology, 42(4), 398–406.

    Article  CAS  PubMed  Google Scholar 

  41. Grünwald, B., Harant, V., Schaten, S., Frühschütz, M., Spallek, R., Höchst, B., Stutzer, K., Berchtold, S., Erkan, M., Prokopchuk, O., Martignoni, M., Esposito, I., Heikenwalder, M., Gupta, A., Siveke, J., Saftig, P., Knolle, P., Wohlleber, D., & Krüger, A. (2016). Pancreatic premalignant lesions secrete tissue inhibitor of metalloproteinases-1, which activates hepatic stellate cells via CD63 signaling to create a premetastatic niche in the liver. Gastroenterology, 151(5), 1011–1024.

    Article  PubMed  CAS  Google Scholar 

  42. Prokopchuk, O., Grünwald, B., Nitsche, U., Jäger, C., Prokopchuk, O. L., Schubert, E. C., Friess, H., Martignoni, M. E., & Krüger, A. (2018). Elevated systemic levels of the matrix metalloproteinase inhibitor TIMP-1 correlate with clinical markers of cachexia in patients with chronic pancreatitis and pancreatic cancer. BMC Cancer, 18(1), 128.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Laitinen, A., Hagström, J., Mustonen, H., Kokkola, A., Tervahartiala, T., Sorsa, T., Böckelman, C., & Haglund, C. (2018). Serum MMP-8 and TIMP-1 as prognostic biomarkers in gastric cancer. Tumour Biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine, 40(9), 1010428318799266.

    Article  CAS  Google Scholar 

  44. Wang, C.-S., Wu, T.-L., Tsao, K.-C., & Sun, C.-F. (2006). Serum TIMP-1 in gastric cancer patients: a potential prognostic biomarker. Annals of Clinical and Laboratory Science, 36(1), 23–30.

    PubMed  Google Scholar 

  45. Gouyer, V., Conti, M., Devos, P., Zerimech, F., Copin, M.-C., Créme, E., Wurtz, A., Porte, H., & Huet, G. (2005). Tissue inhibitor of metalloproteinase 1 is an independent predictor of prognosis in patients with nonsmall cell lung carcinoma who undergo resection with curative intent. Cancer, 103(8), 1676–1684.

    Article  CAS  PubMed  Google Scholar 

  46. Visscher, D. W., Höyhtyä, M., Ottosen, S. K., Liang, C.-M., Sarkar, F. H., Crissman, J. D., & Fridman, R. (1994). Enhanced expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) in the stroma of breast carcinomas correlates with tumor recurrence. International Journal of Cancer, 59(3), 339–344.

    Article  CAS  PubMed  Google Scholar 

  47. Ylisirniö, S., Höyhtyä, M., & Turpeenniemi-Hujanen, T. (2000). Serum matrix metalloproteinases-2,-9 and tissue inhibitors of metalloproteinases-1,-2 in lung cancer--TIMP-1 as a prognostic marker. Anticancer Research, 20(2B), 1311–1316.

    PubMed  Google Scholar 

  48. Drzewiecka-Jędrzejczyk, M., Wlazeł, R., Terlecka, M., & Jabłoński, S. (2017). Serum metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in lung carcinoma patients. Journal of Thoracic Disease, 9(12), 5306–5313.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Suemitsu, R., Yoshino, I., Tomiyasu, M., Fukuyama, S., Okamoto, T., & Maehara, Y. (2004). Serum tissue inhibitors of metalloproteinase-1 and -2 in patients with non-small cell lung cancer. Surgery Today, 34(11), 896–901.

    Article  CAS  PubMed  Google Scholar 

  50. Giannelli, G., Bergamini, C., Marinosci, F., Fransvea, E., Quaranta, M., Lupo, L., Schiraldi, O., & Antonaci, S. (2002). Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma. International Journal of Cancer, 97(4), 425–431.

    Article  CAS  PubMed  Google Scholar 

  51. Bachman, K. E., Herman, J. G., Corn, P. G., Merlo, A., Costello, J. F., Cavenee, W. K., Baylin, S. B., & Graff, J. R. (1999). Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggests a suppressor role in kidney, brain, and other human cancers. Cancer Research, 59(4), 798–802.

    CAS  PubMed  Google Scholar 

  52. Cymbaluk-Płoska, A., Chudecka-Głaz, A., Pius-Sadowska, E., Machaliński, B., Menkiszak, J., & Sompolska-Rzechuła, A. (2018). Suitability assessment of baseline concentration of MMP3, TIMP3, HE4 and CA125 in the serum of patients with ovarian cancer. Journal of Ovarian Research, 11(1), 1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Gu, X., Fu, M., Ding, Y., Ni, H., Zhang, W., Zhu, Y., Tang, X., Xiong, L., Li, J., Qiu, L., Xu, J., & Zhu, J. (2014). TIMP-3 expression associates with malignant behaviors and predicts favorable survival in HCC. PLoS One, 9(8), e106161.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Sounni, N. E., Rozanov, D. V., Remacle, A. G., Golubkov, V. S., Noel, A., & Strongin, A. Y. (2010). Timp-2 binding with cellular MT1-MMP stimulates invasion-promoting MEK/ERK signaling in cancer cells. International Journal of Cancer, 126(5), 1067–1078.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Valacca, C., Tassone, E., & Mignatti, P. (2015). TIMP-2 interaction with MT1-MMP activates the AKT pathway and protects tumor cells from apoptosis. PLoS One, 10(9), e0136797.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Valente, P., Fassina, G., Melchiori, A., Masiello, L., Cilli, M., Vacca, A., Onisto, M., Santi, L., Stetler-Stevenson, W. G., & Albini, A. (1998). TIMP-2 over-expression reduces invasion and angiogenesis and protects B16F10 melanoma cells from apoptosis. International Journal of Cancer, 75(2), 246–253.

    Article  CAS  PubMed  Google Scholar 

  57. Forte, D., Salvestrini, V., Corradi, G., Rossi, L., Catani, L., Lemoli, R. M., Cavo, M., & Curti, A. (2017). The tissue inhibitor of metalloproteinases-1 (TIMP-1) promotes survival and migration of acute myeloid leukemia cells through CD63/PI3K/Akt/p21 signaling. Oncotarget, 8(2), 2261.

    Article  PubMed  Google Scholar 

  58. Jiang, Y., Wang, M., Celiker, M. Y., Liu, Y. E., Sang, Q. X., Goldberg, I. D., & Shi, Y. E. (2001). Stimulation of mammary tumorigenesis by systemic tissue inhibitor of matrix metalloproteinase 4 gene delivery. Cancer Research, 61(6), 2365–2370.

    CAS  PubMed  Google Scholar 

  59. Scilabra, S. D., Troeberg, L., Yamamoto, K., Emonard, H., Thøgersen, I., Enghild, J. J., Strickland, D. K., & Nagase, H. (2013). Differential regulation of extracellular tissue inhibitor of metalloproteinases-3 levels by cell membrane-bound and shed low density lipoprotein receptor-related protein 1. The Journal of Biological Chemistry, 288(1), 332–342.

    Article  CAS  PubMed  Google Scholar 

  60. Emonard, H., Bellon, G., Troeberg, L., Berton, A., Robinet, A., Henriet, P., Marbaix, E., Kirkegaard, K., Patthy, L., Eeckhout, Y., Nagase, H., Hornebeck, W., & Courtoy, P. J. (2004). Low density lipoprotein receptor-related protein mediates endocytic clearance of pro-MMP-2. TIMP-2 complex through a thrombospondin-independent mechanism. The Journal of Biological Chemistry, 279(52), 54944–54951.

    Article  CAS  PubMed  Google Scholar 

  61. Hahn-Dantona, E., Ruiz, J. F., Bornstein, P., & Strickland, D. K. (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, 276(18), 15498–15503.

    Article  CAS  PubMed  Google Scholar 

  62. Jackson, H. W., Defamie, V., Waterhouse, P., & Khokha, R. (2017). TIMPs: versatile extracellular regulators in cancer. Nature Reviews Cancer, 17(1), 38–53.

    Article  CAS  PubMed  Google Scholar 

  63. Murphy, G. (2011). Tissue inhibitors of metalloproteinases. Genome Biology, 12(11), 233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Brew, K., & Nagase, H. (2010). The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochimica et Biophysica Acta, 1803(1), 55–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lambert, E., Bridoux, L., Devy, J., Dassé, E., Sowa, M.-L., Duca, L., Hornebeck, W., Martiny, L., & Petitfrère-Charpentier, E. (2009). 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(5), 1102–1115.

    Article  CAS  Google Scholar 

  66. Tsagaraki, I., Tsilibary, E. C., & Tzinia, A. K. (2010). TIMP-1 interaction with αvβ3 integrin confers resistance to human osteosarcoma cell line MG-63 against TNF-α-induced apoptosis. Cell and Tissue Research, 342(1), 87–96.

    Article  CAS  PubMed  Google Scholar 

  67. Zhang, J., Wu, T., Zhan, S., Qiao, N., Zhang, X., Zhu, Y., Yang, N., Sun, Y., Zhang, X. A., Bleich, D., & Han, X. (2017). TIMP-1 and CD82, a promising combined evaluation marker for PDAC. Oncotarget, 8(4), 6496–6512.

    PubMed  Google Scholar 

  68. Jung, K.-K., Liu, X.-W., Chirco, R., Fridman, R., & Kim, H.-R. C. (2006). Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. The EMBO Journal, 25(17), 3934–3942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Pols, M. S., & Klumperman, J. (2009). Trafficking and function of the tetraspanin CD63. Experimental Cell Research, 315(9), 1584–1592.

    Article  CAS  PubMed  Google Scholar 

  70. Groft, L. L., Muzik, H., Rewcastle, N. B., Johnston, R. N., Knäuper, V., Lafleur, M. A., Forsyth, P. A., & Edwards, D. R. (2001). Differential expression and localization of TIMP-1 and TIMP-4 in human gliomas. British Journal of Cancer, 85(1), 55–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rorive, S., Lopez, X. M., Maris, C., Trepant, A.-L., Sauvage, S., Sadeghi, N., Roland, I., Decaestecker, C., & Salmon, I. (2010). TIMP-4 and CD63: new prognostic biomarkers in human astrocytomas. Modern Pathology, 23(10), 1418–1428.

    Article  CAS  PubMed  Google Scholar 

  72. Ahonen, M., Baker, A. H., & Kähäri, V.-M. (1998). Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells. Cancer Research, 58(11), 2310–2315.

    CAS  PubMed  Google Scholar 

  73. Zhang, H., Wang, Y.-S., Han, G., & Shi, Y. (2007). TIMP-3 gene transfection suppresses invasive and metastatic capacity of human hepatocarcinoma cell line HCC-7721. Hepatobiliary & Pancreatic Diseases International: HBPD INT, 6(5), 487–491.

    Article  CAS  Google Scholar 

  74. Amour, A., Knight, C. G., Webster, A., Slocombe, P. M., Stephens, P. E., Knäuper, V., Docherty, A. J. P., & Murphy, G. (2000). The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS Letters, 473(3), 275–279.

    Article  CAS  PubMed  Google Scholar 

  75. Kashiwagi, M., Tortorella, M., Nagase, H., & Brew, K. (2001). TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). The Journal of Biological Chemistry, 276(16), 12501–12504.

    Article  CAS  PubMed  Google Scholar 

  76. Wang, W.-M., Ge, G., Lim, N. H., Nagase, H., & Greenspan, D. S. (2006). TIMP-3 inhibits the procollagen N-proteinase ADAMTS-2. The Biochemical Journal, 398(3), 515–519.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Qi, J. H., Ebrahem, Q., Moore, N., Murphy, G., Claesson-Welsh, L., Bond, M., Baker, A., & Anand-Apte, B. (2003). A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nature Medicine, 9(4), 407–415.

    Article  CAS  PubMed  Google Scholar 

  78. Kang, K.-H., Park, S.-Y., Rho, S. B., & Lee, J.-H. (2008). Tissue inhibitor of metalloproteinases-3 interacts with angiotensin II type 2 receptor and additively inhibits angiogenesis. Cardiovascular Research, 79(1), 150–160.

    Article  CAS  PubMed  Google Scholar 

  79. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674.

    Article  CAS  PubMed  Google Scholar 

  80. Klenotic, P. A., Munier, F. L., Marmorstein, L. Y., & Anand-Apte, B. (2004). Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a binding partner of epithelial growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1). Implications for macular degenerations. The Journal of Biological Chemistry, 279(29), 30469–30473.

    Article  CAS  PubMed  Google Scholar 

  81. Yu, W.-H., Shuan-su, C. Y., Meng, Q., Brew, K., & Woessner, J. F. (2000). TIMP-3 binds to sulfated glycosaminoglycans of the extracellular matrix. The Journal of Biological Chemistry, 275(40), 31226–31232.

    Article  CAS  PubMed  Google Scholar 

  82. Hayakawa, T., Yamashita, K., Ohuchi, E., & Shinagawa, A. (1994). Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2). Journal of Cell Science, 107(Pt 9), 2373–2379.

    CAS  PubMed  Google Scholar 

  83. Hoegy, S. E., Oh, H.-R., Corcoran, M. L., & Stetler-Stevenson, W. G. (2001). Tissue inhibitor of metalloproteinases-2 (TIMP-2) suppresses TKR-growth factor signaling independent of metalloproteinase inhibition. The Journal of Biological Chemistry, 276(5), 3203–3214.

    Article  CAS  PubMed  Google Scholar 

  84. Oh, J., Diaz, T., Wei, B., Chang, H., Noda, M., & Stetler-Stevenson, W. G. (2006). TIMP-2 upregulates RECK expression via dephosphorylation of paxillin tyrosine residues 31 and 118. Oncogene, 25(30), 4230–4234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Seo, D.-W., Li, H., Qu, C.-K., Oh, J., Kim, Y.-S., Diaz, T., Wei, B., Han, J.-W., & Stetler-Stevenson, W. G. (2006). Shp-1 mediates the antiproliferative activity of tissue inhibitor of metalloproteinase-2 in human microvascular endothelial cells. The Journal of Biological Chemistry, 281(6), 3711–3721.

    Article  CAS  PubMed  Google Scholar 

  86. Fernandez, C. A., Roy, R., Lee, S., Yang, J., Panigrahy, D., van Vliet, K. J., & Moses, M. A. (2010). The anti-angiogenic peptide, loop 6, binds insulin-like growth factor-1 receptor. The Journal of Biological Chemistry, 285(53), 41886–41895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. D’Alessio, S., Ferrari, G., Cinnante, K., Scheerer, W., Galloway, A. C., Roses, D. F., Rozanov, D. V., Remacle, A. G., Oh, E.-S., & Shiryaev, S. A. (2008). Tissue inhibitor of metalloproteinases-2 binding to membrane-type 1 matrix metalloproteinase induces MAPK activation and cell growth by a non-proteolytic mechanism. The Journal of Biological Chemistry, 283(1), 87–99.

    Article  PubMed  CAS  Google Scholar 

  88. López-Otín, C., & Overall, C. M. (2002). Protease degradomics: a new challenge for proteomics. Nature Reviews Molecular Cell Biology, 3(7), 509–519.

    Article  PubMed  CAS  Google Scholar 

  89. Gomez, D. E., Alonso, D. F., Yoshiji, H., & Thorgeirsson, U. P. (1997). Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. European Journal of Cell Biology, 74(2), 111–122.

    CAS  PubMed  Google Scholar 

  90. Bode, W., & Maskos, K. (2003). Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases. Biological Chemistry, 384(6), 863–872.

    Article  CAS  PubMed  Google Scholar 

  91. Nagase, H., Visse, R., & Murphy, G. (2006). Structure and function of matrix metalloproteinases and TIMPs. Cardiovascular Research, 69(3), 562–573.

    Article  CAS  PubMed  Google Scholar 

  92. Maskos, K., & Bode, W. (2003). Structural basis of matrix metalloproteinases and tissue inhibitors of metalloproteinases. Molecular Biotechnology, 25(3), 241–266.

    Article  CAS  PubMed  Google Scholar 

  93. Tuuttila, A., Morgunova, E., Bergmann, U., Lindqvist, Y., Maskos, K., Fernandez-Catalan, C., Bode, W., Tryggvason, K., & Schneider, G. (1998). Three-dimensional structure of human tissue inhibitor of metalloproteinases-2 at 2.1 Å resolution. Journal of Molecular Biology, 284(4), 1133–1140.

    Article  CAS  PubMed  Google Scholar 

  94. Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF Chimera—a visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25(13), 1605–1612.

    Article  CAS  PubMed  Google Scholar 

  95. Gomis-R, F.-X., Maskos, K., Betz, M., Bergner, A., Huber, R., Suzuki, K., Yoshida, N., Nagase, H., Brew, K., & Bourenkov, G. P. (1997). Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1. Nature, 389(6646), 77–81.

    Article  Google Scholar 

  96. Kumar, S., Stecher, G., & Tamura, K. (2016). MEGA7: molecular evolutionary genetics analysis version 7.0 for bigger datasets. Molecular Biology and Evolution, 33(7), 1870–1874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Wisniewska, M., Goettig, P., Maskos, K., Belouski, E., Winters, D., Hecht, R., Black, R., & Bode, W. (2008). Structural determinants of the ADAM inhibition by TIMP-3: crystal structure of the TACE-N-TIMP-3 complex. Journal of Molecular Biology, 381(5), 1307–1319.

    Article  CAS  PubMed  Google Scholar 

  98. Meng, Q., Malinovskii, V., Huang, W., Hu, Y., Chung, L., Nagase, H., Bode, W., Maskos, K., & Brew, K. (1999). 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. The Journal of Biological Chemistry, 274(15), 10184–10189.

    Article  CAS  PubMed  Google Scholar 

  99. Wei, S., Chen, Y., Chung, L., Nagase, H., & Brew, K. (2003). Protein engineering of the tissue inhibitor of metalloproteinase 1 (TIMP-1) inhibitory domain. In search of selective matrix metalloproteinase inhibitors. The Journal of Biological Chemistry, 278(11), 9831–9834.

    Article  CAS  PubMed  Google Scholar 

  100. Lee, M.-H., Rapti, M., Knäuper, V., & Murphy, G. (2004). Threonine 98, the pivotal residue of tissue inhibitor of metalloproteinases (TIMP)-1 in metalloproteinase recognition. The Journal of Biological Chemistry, 279(17), 17562–17569.

    Article  CAS  PubMed  Google Scholar 

  101. Rapti, M., Knäuper, V., Murphy, G., & Williamson, R. A. (2006). Characterization of the AB loop region of TIMP-2 involvement in pro-MMP-2 activation. The Journal of Biological Chemistry, 281(33), 23386–23394.

    Article  CAS  PubMed  Google Scholar 

  102. Fernandez-Catalan, C., Bode, W., Huber, R., Turk, D., Calvete, J. J., Lichte, A., Tschesche, H., & Maskos, K. (1998). Crystal structure of the complex formed by the membrane type 1-matrix metalloproteinase with the tissue inhibitor of metalloproteinases-2, the soluble progelatinase A receptor. The EMBO Journal, 17(17), 5238–5248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Nagase, H., & Brew, K. (2003). Designing TIMP (tissue inhibitor of metalloproteinases) variants that are selective metalloproteinase inhibitors. Biochemical Society Symposium, 70, 201–212.

    CAS  Google Scholar 

  104. Batra, J., Soares, A. S., Mehner, C., & Radisky, E. S. (2013). Matrix metalloproteinase-10/TIMP-2 structure and analyses define conserved core interactions and diverse exosite interactions in MMP/TIMP complexes. PLoS One, 8(9), e75836.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lee, M.-H., Rapti, M., & Murphy, G. (2005). Total conversion of tissue inhibitor of metalloproteinase (TIMP) for specific metalloproteinase targeting: fine-tuning TIMP-4 for optimal inhibition of tumor necrosis factor-{alpha}-converting enzyme. The Journal of Biological Chemistry, 280(16), 15967–15975.

    Article  CAS  PubMed  Google Scholar 

  106. Nagase, H., & Murphy, G. (2008). Tailoring TIMPs for selective metalloproteinase inhibition. In D. Edwards, G. Hoyer-Hansen, F. Blasi, & B. F. Sloane (Eds.), The Cancer Degradome (pp. 787–810). Springer.

  107. Rapti, M., Atkinson, S. J., Lee, M.-H., Trim, A., Moss, M., & Murphy, G. (2008). The isolated N-terminal domains of TIMP-1 and TIMP-3 are insufficient for ADAM10 inhibition. The Biochemical Journal, 411(2), 433–439.

    Article  CAS  PubMed  Google Scholar 

  108. Morgunova, E., Tuuttila, A., Bergmann, U., & Tryggvason, K. (2002). Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2. Proceedings of the National Academy of Sciences of the United States of America, 99(11), 7414–7419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kobuch, J., Cui, H., Grünwald, B., Saftig, P., Knolle, P. A., & Krüger, A. (2015). TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice. Haematologica, 100(8), 1005–1013.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Cui, H., Grosso, S., Schelter, F., Mari, B., & Krüger, A. (2012). On the pro-metastatic stress response to cancer therapies: evidence for a positive co-operation between TIMP-1, HIF-1α, and miR-210. Frontiers in Pharmacology, 3, 134.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Warner, R. B. (2013). Analysis of the structure and function of a TIMP-1/CD63 complex and its relationship to an MT1-MMP/CD63 complex. Wayne State University Dissertations. Paper 864, http://digitalcommons.wayne.edu/oa_dissertations. Accessed 10 Sep 2019.

  112. Mittal, S., & Saluja, D. (2015). Protein post-translational modifications: role in protein structure, function and stability. In Proteostasis and Chaperone Surveillance (pp. 25–37). Springer.

  113. Xin, F., & Radivojac, P. (2012). Post-translational modifications induce significant yet not extreme changes to protein structure. Bioinformatics (Oxford, England), 28(22), 2905–2913.

    Article  CAS  Google Scholar 

  114. Darling, A. L., & Uversky, V. N. (2018). Intrinsic disorder and posttranslational modifications: the darker side of the biological dark matter. Frontiers in Genetics, 9, 158. https://doi.org/10.3389/fgene.2018.00158.

  115. Khoury, G. A., Baliban, R. C., & Floudas, C. A. (2011). Proteome-wide post-translational modification statistics: frequency analysis and curation of the swiss-prot database. Scientific Reports, 1, 90.

    Article  CAS  PubMed Central  Google Scholar 

  116. Hart, G. W. (1992). Glycosylation. Current Opinion in Cell Biology, 4(6), 1017–1023.

    Article  CAS  PubMed  Google Scholar 

  117. Okada, Y., Watanabe, S., Nakanishi, I., Kishi, J.-I., Hayakawa, T., Watorek, W., Travis, J., & Nagase, H. (1988). Inactivation of tissue inhibitor of metalloproteinases by neutrophil elastase and other serine proteinases. FEBS Letters, 229(1), 157–160.

    Article  CAS  PubMed  Google Scholar 

  118. Nagase, H., Suzuki, K., Cawston, T. E., & Brew, K. (1997). Involvement of a region near valine-69 of tissue inhibitor of metalloproteinases (TIMP)-1 in the interaction with matrix metalloproteinase 3 (stromelysin 1). The Biochemical Journal, 325(1), 163–167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Jackson, P. L., Xu, X., Wilson, L., Weathington, N. M., Clancy, J. P., Blalock, J. E., & Gaggar, A. (2010). Human neutrophil elastase-mediated cleavage sites of MMP-9 and TIMP-1: implications to cystic fibrosis proteolytic dysfunction. Molecular Medicine (Cambridge, Mass.), 16(5-6), 159–166.

    CAS  Google Scholar 

  120. Itoh, Y., & Nagase, H. (1995). Preferential inactivation of tissue inhibitor of metalloproteinases-1 that is bound to the precursor of matrix metalloproteinase 9 (progelatinase B) by human neutrophil elastase. The Journal of Biological Chemistry, 270(28), 16518–16521.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Molecular graphics and analyses were performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, USA, with support from NIH P41-GM103311.

Funding

This work was supported by grants to A.K. from the Deutsche Forschungsgemeinschaft, Bonn, Germany (KR2047/1-3, and KR2047/8-1), and the Wilhelm-Sander-Stiftung, Munich, Germany (2016.124.1).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Achim Krüger.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 120 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eckfeld, C., Häußler, D., Schoeps, B. et al. Functional disparities within the TIMP family in cancer: hints from molecular divergence. Cancer Metastasis Rev 38, 469–481 (2019). https://doi.org/10.1007/s10555-019-09812-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-019-09812-6

Keywords

Navigation