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RECK: A novel suppressor of malignancy linking oncogenic signaling to extracellular matrix remodeling

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Abstract

RECK was first isolated as a transformation suppressor gene by cDNA expression cloning in a mouse fibroblast cell line transformed by an activated RAS oncogene. Subsequently, reduced expression of RECK in transformed cells and cancer cells were demonstrated. Moreover, in several types of tumors, positive correlation between RECK expression and survival of patients have been noted. RECK encodes a GPI-anchored glycoprotein harboring three protease inhibitor-like domains. The RECK protein regulates at least three members of the matrix metalloproteinase (MMP) family, MMP-2, MMP-9, and MT1-MMP, in vitro or in cultured cells. Restored expression of RECK in cancer cell lines results in strong suppression of invasion, metastasis, and tumor angiogenesis. Mice lacking RECK die in utero with reduced integrity of blood vessels, the neural tube, and mesenchymal tissues. In these mice, MMP activity is elevated, and the amount of collagen type I greatly reduced. The RECK null phenotype is partially rescued (half day delay of death and marked recovery of tissue integrity) by MMP-2 null mutation, demonstrating functional interaction between RECK and MMP-2 in vivo and involvement of other target(s) for RECK in the lethal phenotype. These findings indicate that (i) RECK is an important regulator of extracellular matrix remodeling and that (ii) down-regulation of RECK by oncogenic signaling leads to the excessive activation of MMPs thereby promoting malignant behavior of cancer cells such as invasion, metastasis, and angiogenesis.

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References

  1. Noda M, Kitayama H, Matsuzaki T, Sugimoto Y, Okayama H, Bassin RH, Ikawa Y: Detection of genes with a potential for suppressing the transformed phenotype associated with activated ras genes. Proc Natl Acad Sci USA 86: 162–166, 1989

    Google Scholar 

  2. Noda M: Expression cloning of tumor suppressor genes: A guide for optimists. Mol Carcinogenesis 3: 251–253, 1990

    Google Scholar 

  3. Kitayama H, Sugimoto Y, Matsuzaki T, Ikawa Y, Noda M: A ras-related gene with transformation suppressor activity. Cell 56: 77–84, 1989

    Google Scholar 

  4. Noda M: Structures and functions of the Krev-1 transformation suppressor gene and its relatives. Biochim Biophys Acta 1155: 97–109, 1993

    Google Scholar 

  5. Takahashi C, Akiyama N, Matsuzaki T, Takai S, Kitayama H, Noda M: Characterization of a human MSX-2 cDNA and its fragment isolated as a transformation suppressor gene against v-Ki-ras oncogene. Oncogene 12: 2137–2146, 1996

    Google Scholar 

  6. Izumi H, Takahashi C, Oh J, Noda M: Tissue factor pathway inhibitor-2 suppresses the production of active matrix metalloproteinase-2 and is down-regulated in cells harboring ativated ras oncogenes. FEBS Lett 481: 31–36, 2000

    Google Scholar 

  7. Takahashi C, Sheng Z, Horan TP, Kitayama H, Maki M, Hitomi K, Kitaura Y, Takai S, Sasahara RM, Horimoto A, Ikawa Y, Ratzkin B, Arakawa T, Noda M: Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK. Proc Natl Acad Sci USA 95: 13221–13226, 1998

    Google Scholar 

  8. Bos JL, de Rooij J, Reedquist KA: Rap1 signaling: adhering to new models. Nat Rev Mol Cell Biol 2: 369–377, 2001

    Google Scholar 

  9. Welm J, Mott B, Werb Z: Developmental biology: Vasculogenesis is a wreck without RECK. Current Biol 12: R209-R211, 2002.

    Google Scholar 

  10. Weaver V: Membrane-associated MMP regulators: Novel cell adhesion tumor suppressor proteins? Developmental Cell 2: 6–7, 2001

    Google Scholar 

  11. Gullberg D: Importance of ECM remodeling clarified. Trends Cell Biol 12: 110, 2002

    Google Scholar 

  12. Rhee JS, Coussens LM: RECKing MMP function: Implication for cancer development. Trends Cell Biol 12: 209–211, 2002

    Google Scholar 

  13. Baker AH, Edwards DR, Murphy G: Metalloproteinase inhibitors: Biological actions and therapeutic opportunities. J Cell Sci 115: 3719–3727, 2002

    Google Scholar 

  14. Sasahara RM, Takahashi C, Noda M: Involvement of the Sp1 site in ras-mediated downregulation of the RECK metastasis suppressor gene. Biochem Biophys Res Commun 264: 668–675, 1999

    Google Scholar 

  15. Furumoto K, Arii S, Mori A, Furuyama H, Gorrin Rivas MJ, Nakao T, Isobe N, Murata T, Takahashi C, Noda M, Imamura M: RECK gene expression in hepatocellular carcinoma, Correlation with invasion-related clinicopathological factors and its clinical significance. Hepatology 33: 189–195, 2001

    Google Scholar 

  16. Laskowski M Jr, Kato I: Protein inhibitors of proteinases. Annu Rev Biochem 49: 593–626, 1980

    Google Scholar 

  17. Werb Z: ECM and cell surface proteolysis, regulating cellular ecology. Cell 91: 439–442, 1997

    Google Scholar 

  18. Nagase H, Woessner JF Jr: Matrix metalloproteinases. J Biol Chem 274: 21491–21494, 1999

    Google Scholar 

  19. Vu TH, Werb Z: Matrix metalloproteinases, effectors of development and normal physiology. Genes Dev 14: 2123–2133, 2000

    Google Scholar 

  20. Egeblad M, Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nature Rev Cancer 2: 161–174, 2002

    Google Scholar 

  21. Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M: A matrix metalloproteinase expression on the surface of invasive tumor cells. Nature 370: 61–65, 1994

    Google Scholar 

  22. Sato H, Kinoshita T, Takino T, Nakayama K, Seiki M: Activation of a recombinant membrane type 1-matrix metalloproteinase (MT1-MMP) by furin and its interaction with tissue inhibitor of metalloproteinases (TIMP)-2. FEBS Lett 393: 101–104, 1996

    Google Scholar 

  23. Atkinson SJ, Crabbe T, Cowell S, Ward RV, Butler MJ, Sato H, Seiki, M, Reynolds JJ, Murphy G: Intermolecular autolytic cleavage can contribute to the activation of progelatinase A by cell membranes. J Biol Chem 270: 30479–30485, 1995

    Google Scholar 

  24. Wilhelm SM, Pentland AP, Marmer BL, Grant GA, Eisen AZ, Goldberg GI: Tissue cooperation in a proteolytic cascade activating human interstitial collagenase. Proc Natl Acad Sci USA 86: 2632–2636, 1989

    Google Scholar 

  25. Ogata Y, Enghild JJ, Nagase H: Matrix metalloproteinase 3 (stromelysin) activates the precursor for the human matrix metalloproteinase 9. J Biol Chem 267: 3581–3584, 1992

    Google Scholar 

  26. Oh J, Takahashi R, Kondo S, Mizoguchi A, Adachi E, Sasahara RM, Nishimura S, Imamura Y, Kitayama H, Alexander DB, Ide C, Horan TP, Arakawa T, Yoshida H, Nishikawa S, Itoh Y, Seiki M, Itohara S, Takahashi C, Noda M: The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell 107: 789–800, 2001

    Google Scholar 

  27. Brew K, Dinakarpandian D, Nagase H: Tissue inhibitors of metalloproteinases, evolution, structure and function. Biochim Biophys Acta 1477: 267–283, 2000

    Google Scholar 

  28. Hatcher VB, Wertheim MS, Rhee CY, Tsien G, Burk PG: Relationship between cell surface protease activity and doubling time in various normal and transformed cells. Biochim Biophys Acta 451: 499–510, 1976

    Google Scholar 

  29. Rohrlich ST, Rifkin DB: Patterns of plasminogen activator production in cultured normal embryonic cells. J Cell Biol 75: 31–42, 1977

    Google Scholar 

  30. Adams SL, Sobel ME, Howard BH, Olden K, Yamada KM, de Crombrugghe B, Pastan I: Levels of translatable mRNAs for cell surface protein, collagen precursors, and two membrane proteins are altered in Rous sarcoma virustransformed chick embryo fibroblasts. Proc Natl Acad Sci USA 74: 3399–3403, 1977

    Google Scholar 

  31. Olden K, Yamada KM: Mechanism of the decrease in the major cell surface protein of chick embryo fibroblasts after transformation. Cell 11: 957–969, 1977

    Google Scholar 

  32. Yamada KM: Cell surface marker for malignancy. Nature 273: 335–336, 1978

    Google Scholar 

  33. Plantefaber LC, Hynes RO: Changes in integrin receptors on oncogenically transformed cells. Cell 56: 281–290, 1989

    Google Scholar 

  34. Stetler-Stevenson WG: Matrix metalloproteinases in angiogenesis: A moving target for therapeutic intervention. Clin Invest 103: 1237–1241, 1999

    Google Scholar 

  35. Deryugina EI, Soroceanu L, Strongin AY: Up-regulation of vascular endothelial growth factor by membrane-type 1 matrix metalloproteinase stimulates human glioma xenograft growth and angiogenesis. Cancer Res 62: 580–588, 2002

    Google Scholar 

  36. Fang J, Shing Y, Wiederschain D, Yan L, Butterfield C, Jackson G, Harper J, Tamvakopoulos G, Moses MA: Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model. Proc Natl Acad Sci USA 97: 3884–3889, 2000

    Google Scholar 

  37. Haas TL, Milkiewicz M, Davis SJ, Zhou AL, Egginton S, Brown MD, Madri JA, Hudlicka O: Matrix metalloproteinase activity is required for activity-induced angiogenesis in rat skeletal muscle. Am J Physiol Heart Circ Physiol 279: H1540-H1547, 2000

    Google Scholar 

  38. Itoh T, Ikeda T, Gomi H, Nakao S, Suzuki T, Itohara S: Unaltered secretion of b-amyloid precursor protein in gelatinase A (Matrix Metalloproteinase 2)-deficient mice. J Biol Chem 272: 22389–22392, 1997

    Google Scholar 

  39. Itoh T, Tomioka M, Yoshida H, Yoshioka T, Nishimoto H, Itohara S: Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res 58: 1048–1051, 1998

    Google Scholar 

  40. Kato T, Kure T, Chang J, Gabison EE, Itoh T, Itohara S, Azar DT: Diminished corneal angiogenesis in gelatinase A-deficient mice. FEBS Lett 508: 187–190, 2001

    Google Scholar 

  41. Holmbeck K, Bianco P, Caterina J, Yamada S, Kromer M, Kuznetsov SA, Mankani M, Robey PG, Poole AR, Pidoux I, Ward JM, Birkedal-Hansen H: MT1-MMPdeficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99: 81–92, 1999.

    Google Scholar 

  42. Zhou Z, Apte SS, Soininen R, Cao R, Baaklini GY, Rauser RW, Wang J, Cao Y, Tryggvason K: Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc Natl Acad Sci USA 97: 4052–4057, 2000.

    Google Scholar 

  43. Caterina JJ, Yamada S, Caterina NCM, Longenecker G, Holmback K, Shi J, Yermovsky AE, Engler JA, Birkeda-Hansen H: Inactivating mutation of the mouse tissue inhibitor of metalloproteinase-2 (Timp-2) gene alters proMMP-2 activation. J Biol Chem 275: 26416–26422, 2000

    Google Scholar 

  44. Nothnick WB, Soloway P, Curry TE Jr: Assessment of the role of tissue inhibitor of metalloproteinase-1 (TIMP-1) during the periovulatory period in female mice lacking a functional TIMP-1 gene. Biol Reprod 56: 1181–1188, 1997

    Google Scholar 

  45. Wang Z, Juttermann R, Soloway PD: TIMP-2 is required for efficient activation of proMMP-2 in vivo. J Biol Chem 275: 26411–26415, 2000

    Google Scholar 

  46. Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos G: Requisite role of angiopoietin-1, a ligand for TIE2 receptor during embryonic angiogenesis. Cell 87: 1171–1180, 1996

    Google Scholar 

  47. Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M, Gridley T, Wolburg H, Risau W, Qin Y: Distinct roles of the receptor tyrosine kinase Tie-1 and Tie-2 in blood vessel formation. Nature 376: 70–74, 1995

    Google Scholar 

  48. Risau W: Mechanisms of angiogenesis. Nature 386: 671–674, 1997

    Google Scholar 

  49. Hanahan D: Signaling vascular morphogenesis and maintenance. Science 277: 48–50, 1997

    Google Scholar 

  50. Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353–364, 1996

    Google Scholar 

  51. Lohler J, Timpl R, Jaenisch R: Embryonic lethal mutation in mouse collagen I gene causes rupture of blood vessels and is associated with erythropoietic and mesechymal cell death. Cell 38: 597–607, 1984

    Google Scholar 

  52. Henkemeyer M, Rossi DJ, Holmyard DP, Puri MC, Mbanalu G, Harpal K, Shih TS, Jacks T, Pawson T: Vascular sytem defects and neuronal apoptosis in mice lacking Ras GTPase-activating protein. Nature 377: 695–701, 1995

    Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Makoto Noda, Rei Takahashi, Shunya Kondo, Hitoshi Kitayama & Chiaki Takahashi

  2. Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Junseo Oh

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  1. Makoto Noda
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  2. Junseo Oh
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  4. Shunya Kondo
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  5. Hitoshi Kitayama
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  6. Chiaki Takahashi
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Correspondence to Makoto Noda.

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Noda, M., Oh, J., Takahashi, R. et al. RECK: A novel suppressor of malignancy linking oncogenic signaling to extracellular matrix remodeling. Cancer Metastasis Rev 22, 167–175 (2003). https://doi.org/10.1023/A:1023043315031

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