The Membrane-Anchored MMP Inhibitor RECK Is a Key Regulator of Extracellular Matrix Integrity and Angiogenesis

Matrix metalloproteinases (MMPs) are essential for proper extracellular matrix remodeling. We previously found that a membrane-anchored glycoprotein, RECK, negatively regulates MMP-9 and inhibits tumor invasion and metastasis. Here we show that RECK regulates two other MMPs, MMP-2 and MT1-MMP, known to be involved in cancer progression, that mice lacking a functional RECK gene die around E10.5 with defects in collagen fibrils, the basal lamina, and vascular development, and that this phenotype is partially suppressed by MMP-2 null mutation. Also, vascular sprouting is dramatically suppressed in tumors derived from RECK-expressing fibrosarcoma cells grown in nude mice. These results support a role for RECK in the regulation of MMP-2 in vivo and implicate RECK downregulation in tumor angiogenesis.

[1]  I. Thesleff,et al.  Molecular cloning of murine 72-kDa type IV collagenase and its expression during mouse development. , 1992, The Journal of biological chemistry.

[2]  S. Itohara,et al.  Mice devoid of the glial fibrillary acidic protein develop normally and are susceptible to scrapie prions , 1995, Neuron.

[3]  H. Birkedal‐Hansen,et al.  Inactivating Mutation of the Mouse Tissue Inhibitor of Metalloproteinases-2(Timp-2) Gene Alters ProMMP-2 Activation* , 2000, The Journal of Biological Chemistry.

[4]  Motoharu Seiki,et al.  A matrix metalloproteinase expressed on the surface of invasive tumour cells , 1994, Nature.

[5]  M. Noda,et al.  Involvement of the Sp1 site in ras-mediated downregulation of the RECK metastasis suppressor gene. , 1999, Biochemical and biophysical research communications.

[6]  J. Folkman,et al.  Blood Vessel Formation: What Is Its Molecular Basis? , 1996, Cell.

[7]  Thiennu H. Vu,et al.  Matrix metalloproteinases: effectors of development and normal physiology. , 2000, Genes & development.

[8]  L. Liotta,et al.  Differential expression of membrane-type matrix metalloproteinase and its correlation with gelatinase A activation in human malignant brain tumors in vivo and in vitro. , 1996, Cancer research.

[9]  K. Brew,et al.  Tissue inhibitors of metalloproteinases: evolution, structure and function. , 2000, Biochimica et biophysica acta.

[10]  S. Arii,et al.  RECK gene expression in hepatocellular carcinoma: Correlation with invasion‐related clinicopathological factors and its clinical significance , 2001, Hepatology.

[11]  W. Risau,et al.  Mechanisms of angiogenesis , 1997, Nature.

[12]  S. Itohara,et al.  Unaltered Secretion of β-Amyloid Precursor Protein in Gelatinase A (Matrix Metalloproteinase 2)-deficient Mice* , 1997, The Journal of Biological Chemistry.

[13]  M. Dardenne.  Role of thymic peptides as transmitters between the neuroendocrine and immune systems. , 1999, Annals of medicine.

[14]  F. Kikkawa,et al.  c‐Ras is required for the activation of the matrix metalloproteinases by concanavalin A in 3Y1 cells , 1997, FEBS letters.

[15]  W. Stetler-Stevenson,et al.  Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. , 1999, The Journal of clinical investigation.

[16]  Y. Tamura,et al.  Inhibition of gelatinolytic activity in tumor tissues by synthetic matrix metalloproteinase inhibitor: application of film in situ zymography. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[17]  H. Niwa,et al.  Efficient selection for high-expression transfectants with a novel eukaryotic vector. , 1991, Gene.

[18]  S. Weiss,et al.  Transmembrane-deletion Mutants of the Membrane-type Matrix Metalloproteinase-1 Process Progelatinase A and Express Intrinsic Matrix-degrading Activity (*) , 1996, The Journal of Biological Chemistry.

[19]  P. Soloway,et al.  TIMP-2 Is Required for Efficient Activation of proMMP-2 in Vivo * , 2000, The Journal of Biological Chemistry.

[20]  D. Hanahan,et al.  MMP-9 Supplied by Bone Marrow–Derived Cells Contributes to Skin Carcinogenesis , 2000, Cell.

[21]  H. Kitayama,et al.  Characterization of a human MSX-2 cDNA and its fragment isolated as a transformation suppressor gene against v-Ki-ras oncogene. , 1996, Oncogene.

[22]  T. Yagi,et al.  Homologous recombination at c-fyn locus of mouse embryonic stem cells with use of diphtheria toxin A-fragment gene in negative selection. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[23]  I. Pastan,et al.  Decreased levels of collagen mRNA in rous sarcoma virus-transformed chick embryo fibroblasts. , 1978, The Journal of biological chemistry.

[24]  T. Sugiyama,et al.  Preservation of pathological tissue specimens by freeze‐drying for immunohistochemical staining and various molecular biological analyses , 1999, Pathology international.

[25]  Y. Okada,et al.  TIMP-2 Promotes Activation of Progelatinase A by Membrane-type 1 Matrix Metalloproteinase Immobilized on Agarose Beads* , 1998, The Journal of Biological Chemistry.

[26]  Z. Werb.  ECM and Cell Surface Proteolysis: Regulating Cellular Ecology , 1997, Cell.

[27]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.

[28]  L. Liotta,et al.  Secretion of type IV collagenolytic protease and metastatic phenotype: induction by transfection with c-Ha-ras but not c-Ha-ras plus Ad2-E1a. , 1987, Cancer research.

[29]  H. Birkedal‐Hansen.  Proteolytic remodeling of extracellular matrix. , 1995, Current opinion in cell biology.

[30]  Douglas Hanahan,et al.  Signaling Vascular Morphogenesis and Maintenance , 1997, Science.

[31]  G Murphy,et al.  A novel coumarin‐labelled peptide for sensitive continuous assays of the matrix metalloproteinases , 1992, FEBS letters.

[32]  M. Stack,et al.  Membrane associated matrix metalloproteinases in metastasis. , 1999, BioEssays : news and reviews in molecular, cellular and developmental biology.

[33]  R. Hynes,et al.  Changes in integrin receptors on oncogenically transformed cells , 1989, Cell.

[34]  I. Pastan,et al.  Effects of transformation on fibronectin gene expression using cloned fibronectin cDNA. , 1981, The Journal of biological chemistry.

[35]  R. Muschel,et al.  Developmental expression of MMP‐9 (gelatinase B) mRNA in mouse embryos , 1995, Developmental dynamics : an official publication of the American Association of Anatomists.

[36]  H. Kitayama,et al.  A ras-related gene with transformation suppressor activity , 1989, Cell.

[37]  Yamamura Ken-ichi,et al.  Efficient selection for high-expression transfectants with a novel eukaryotic vector , 1991 .

[38]  Y. Fujiwara,et al.  Vascular endothelial cell lineage-specific promoter in transgenic mice. , 1995, Development.

[39]  Y. Hiraoka,et al.  Nedd5, a mammalian septin, is a novel cytoskeletal component interacting with actin-based structures. , 1997, Genes & development.

[40]  R. Jaenisch,et al.  Embryonic lethal mutation in mouse collagen I gene causes rupture of blood vessels and is associated with erythropoietic and mesenchymal cell death , 1984, Cell.

[41]  A. Hanby,et al.  Levels of matrix metalloproteases in bladder cancer correlate with tumor grade and invasion. , 1993, Cancer research.

[42]  M. Hidalgo,et al.  Development of matrix metalloproteinase inhibitors in cancer therapy. , 2001, Journal of the National Cancer Institute.

[43]  P. Soloway,et al.  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. , 1997, Biology of reproduction.

[44]  H. Kitayama,et al.  Detection of genes with a potential for suppressing the transformed phenotype associated with activated ras genes. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Y Ikawa,et al.  Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Y. Okada,et al.  Membrane Type 1 Matrix Metalloproteinase Digests Interstitial Collagens and Other Extracellular Matrix Macromolecules* , 1997, The Journal of Biological Chemistry.

[47]  Stanley J. Wiegand,et al.  Vascular-specific growth factors and blood vessel formation , 2000, Nature.

[48]  C. Marshall,et al.  Mechanism of activation of an N‐ras gene in the human fibrosarcoma cell line HT1080. , 1984, The EMBO journal.