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Roles of hepatocyte growth factor activator (HGFA) and its inhibitor HAI-1 in the regeneration of injured gastrointestinal mucosa

  • Positioning of treatment for IBD by repairing mucosa
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Abstract

Hepatocyte growth factor (HGF)/scatter factor (SF) is thought to play an important role in the regeneration of injured gastrointestinal mucosa by promoting the proliferation and migration of epithelial cells. HGF/SF is secreted by stromal cells as an inactive precursor form, and is specifically activated by HGF activator (HGFA) to the active form. HGFA is also produced as a precursor form and activated by thrombin in injured tissues. The activity of HGFA is regulated by two recently identified Kunitz-type serine proteinase inhibitors, namely HGFA inhibitor type 1 (HAI-1) and type 2 (HAI-2). Although the activation of HGF/SF is a critical limiting step in the HGF/SF-induced signaling pathway, little is known about the regulation of HGF/SF activation in injured gastrointestinal mucosa. Immunohistochemically, all these proteins have been detected in gastrointestinal epithelial cells, and HAI-1 was upregulated in regenerative epithelium relative to normal epithelium. During the course of acetic acid-induced murine experimental colitis, HAI-1, but not HAI-2, was indeed upregulated in the recovery phase. In vitro study revealed that HAI-1 is not only an inhibitor, but also a specific cell-surface binding protein, of active HGFA, and acts as a reservoir of this enzyme on the cell surface. Active HGFA/HAI-1 complexes were quickly released from the cell surface by treatment with IL-1β accompanying significant recovery of HGFA activity in the culture supernatant. These results suggest that HAI-1 is a cell-surface acceptor of activated HGFA in regenerative epithelial cells, and functions on the cell surface to localize the active HGFA that is going to enter the repair process. This concentrated HGFA activity would ensure the efficient pericellular activation of HGF in the injured gastrointestinal mucosa, and promote the proliferation and migration of gastrointestinal epithelial cells.

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References

  1. Gordon JI. Intestinal epithelial differentiation: new insights from chimeric and transgenic mice. J Cell Biol 1989;108:1187–94.

    Article  PubMed  CAS  Google Scholar 

  2. Beck PL, Wallace JL. Cytokines in inflammatory bowel disease. Mediators Inflamm 1997;6:95–103.

    Article  PubMed  CAS  Google Scholar 

  3. Efstathiou JA, Pignatelli M. Modulation of epithelial cell adhesion in gastrointestinal homeostasis. Am J Pathol 1998;153:341–7.

    Article  PubMed  CAS  Google Scholar 

  4. Wright NA. Aspects of the biology of regeneration and repair in the human gastrointestinal tract. Phil Trans R Soc Lond B 1998;353:925–33.

    Article  CAS  Google Scholar 

  5. Matsumoto K, Nakamura T. Emerging multipotent aspects of hepatocyte growth factor. J Biochem 1996;119:591–600.

    Article  PubMed  CAS  Google Scholar 

  6. Boros P, Miller CM. Hepatocyte growth factor: a multifunctional cytokine. Lancet 1995;345:293–5.

    Article  PubMed  CAS  Google Scholar 

  7. Gohda E, Tsubouchi H, Nakayama H, Hirono S, Sakiyama O, Takahashi K, et al. Purification and partial characterization of hepatocyte growth factor from plasma of a patient with fulminant hepatic failure. J Clin Invest 1988;81:414–9.

    Article  PubMed  CAS  Google Scholar 

  8. Nakayama T, Nama K, Ichihara A, Kaise N, Nishino T. Purification and subunit structure of hepatocyte growth factor from rat platelets. FEBS Lett 1987;224:311–6.

    Article  Google Scholar 

  9. Stoker M, Gherardi E, Perryman M, Gray J. Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature 1987;327:239–42.

    Article  PubMed  CAS  Google Scholar 

  10. Weidner KM, Arakaki N, Hartmann G, Vandekerckhove J, Weingart S, Reider H, et al. Evidence for the identity of human scatter factor and human hepatocyte growth factor. Proc Natl Acad Sci USA 1991;88:7001–5.

    Article  PubMed  CAS  Google Scholar 

  11. Naldini L, Weidner KM, Vigna E, Gaudino G, Bardelli A, Ponzetto C, et al. Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. EMBO J 1991; 10:2867–78.

    PubMed  CAS  Google Scholar 

  12. Kinoshita Y, Nakata H, Sazzad H, Asahara M, Kawanami C, Matsushima Y, et al. Gene expression of keratinocyte and hepatocyte growth factor during the healing of rat gastric mucosal lesions. Gastroenterology 1995; 109:1068–77.

    Article  PubMed  CAS  Google Scholar 

  13. Schmassmann A, Stettler C, Poulsom R, Tarasova N, Hirschi C, Flogerzi B, et al. Roles of hepatocyte growth factor and its receptor met during gastric ulcer healing in rats. Gastroenterology 1997;113:1858–72.

    Article  PubMed  CAS  Google Scholar 

  14. Dignass AU, Lynch-Devaney K, Podolsky DK. Hepatocyte growth factor/scatter factor modulates intestinal epithelial cell proliferation and migration. Biochem Biophys Res Commun 1994;202:701–9.

    Article  PubMed  CAS  Google Scholar 

  15. Watanabe S, Hirose M, Wang XE, Maehiro K, Kobayashi O, Nagahara A, et al. Hepatocyte growth factor accelerates the wound repair of cultured gastric mucosal cells. Biochem Biophys Res Commun 1994;199:1453–60.

    Article  PubMed  CAS  Google Scholar 

  16. Naldini L, Tamagnone L, Vigna E, Sachs M, Hartmann G, Birchmeier W, et al. Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor. EMBO J 1992;11:4825–33.

    PubMed  CAS  Google Scholar 

  17. Naka D, Ishii T, Yoshiyama Y, Miyazawa K, Hara H, Hishida T, et al. Activation of hepatocyte growth factor by proteolytic conversion of a single chain form to a heterodimer. J Biol Chem 1992;267:20114–9.

    PubMed  CAS  Google Scholar 

  18. Birchmeier C, Gherardi E. Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. Trends Cell Biol 1998;10:404–10.

    Article  Google Scholar 

  19. Mars WM, Zarnegar R, Michalopoulos GK. Activation of hepatocyte growth factor by the plasminogen activators uPA and tPA. Am J Pathol 1993;143:949–58.

    PubMed  CAS  Google Scholar 

  20. Naldini L, Vigna E, Bardelli A, Follenzi A, Galimi F, Comoglio PM, et al. Biological activation of pro-HGF (hepatocyte growth factor) by urokinase is controlled by a stoichiometric reaction. J Biol Chem 1995;270:603–11.

    Article  PubMed  CAS  Google Scholar 

  21. Shimomura T, Ochiai M, Kondo J, Morimoto Y. A novel protease obtained from FBS-containing culture supernatant, that processes single-chain form hepatocyte growth factor to two-chain form in serum-free culture. Cytotechnology 1992;8:219–29.

    Article  PubMed  CAS  Google Scholar 

  22. Miyazawa K, Shimomura T, Kitamura A, Kondo J, Morimoto Y, Kitamura N. Molecular cloning and sequence analysis of the cDNA for a human serine protease responsible for activation of hepatocyte growth factor. J Biol Chem 1993;268:10024–8.

    PubMed  CAS  Google Scholar 

  23. Shimomura T, Miyazawa K, Komiyama Y, Hiraoka H, Naka D, Morimoto Y, et al. Activation of hepatocyte growth factor by two homologous proteases, blood-coagulation factor Xlla and hepatocyte growth factor activator. Eur J Biochem 1995;229:257–61.

    Article  PubMed  CAS  Google Scholar 

  24. Mizuno K, Takehara T, Nakamura T. Proteolytic activation of a single-chain precursor of hepatocyte growth factor by extracellular serine protease. Biochem Biophys Res Commun 1992;189: 1631–8.

    Article  PubMed  CAS  Google Scholar 

  25. Lee SL, Dickson RB, Lin CY. Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase, and epithelial membrane serine protease. J Biol Chem 2000;275: 36720–5.

    Article  PubMed  CAS  Google Scholar 

  26. Kataoka H, Hamasuna R, Itoh H, Kitamura N, Koono M. Activation of hepatocyte growth factor/scatter factor in colorectal carcinoma. Cancer Res2000;60:6148–59.

    PubMed  CAS  Google Scholar 

  27. Kinoshita Y, Kishi K, Asahara M, Matsushima Y, Wang HY. Production and activation of hepatocyte growth factor during the healing of rat gastric ulcers. Digestion 1996;58:225–31.

    Article  Google Scholar 

  28. Itoh H, Hamasuna R, Kataoka H, Yamauchi M, Miyazawa K, Kitamura N, et al. Mouse hepatocyte growth factor activator gene: its expression not only in the liver but also in the gastrointestinal tract. Biochim Biophys Acta 2000;1491:295–302.

    Article  PubMed  CAS  Google Scholar 

  29. Matsubara Y, Ichinose M, Yahagi N, Tukada S, Oka M, Miki K, et al. Hepatocyte growth factor activator: a possible regulator of morphogenesis during fetal development of the rat gastrointestinal tract. Biochem Biophys Res Commun 1998;253:477–84.

    Article  PubMed  CAS  Google Scholar 

  30. Miyazawa K, Wang Y, Minoshima S, Shimizu N, Kitamura N. Structural organization and chromosomal localization of the human hepatocyte growth factor activator gene: phylogenetic and functional relationship with blood coagulation factor XII, uroki-nase, and tissue-type plasminogen activator. Eur J Biochem 1998;258:355–61.

    Article  PubMed  CAS  Google Scholar 

  31. Shimomura T, Kondo J, Ochiai M, Naka D, Miyazawa K, Morimoto K, et al. Activation of the zymogen of hepatocyte growth factor activator by thrombin. J Biol Chem 1993;268:22927–32.

    PubMed  CAS  Google Scholar 

  32. Miyazawa K, Shimomura T, Naka D, Kitamura N. Proteolytic activation of hepatocyte growth factor in response to tissue injury. J Biol Chem 1994;269:8966–70.

    PubMed  CAS  Google Scholar 

  33. Miyazawa K, Shimomura T, Kitamura N. Activation of hepatocyte growth factor in the injured tissues is mediated by hepatocyte growth factor activator. J Biol Chem 1996;271:3615–18.

    Article  PubMed  CAS  Google Scholar 

  34. Shimomura T, Denda K, Kitamura A, Kawaguchi T, Kito M, Kondo J, et al. Hepatocyte growth factor activator inhibitor, a novel Kunitz-type serine protease inhibitor. J Biol Chem 1997; 272:6370–6.

    Article  PubMed  CAS  Google Scholar 

  35. Kawaguchi T, Qin L, Shimomura T, Kondo J, Matsumoto K, Denda K, et al. Purification and cloning of hepatocyte growth factor activator inhibitor type 2, a Kunitz-type serine protease inhibitor. J Biol Chem 1997;272:27558–64.

    Article  PubMed  CAS  Google Scholar 

  36. Marlor CW, Delaria KA, Davis G, Muller DK, Greve JM, Tamburini PP. Identification and cloning of human placental bikunin, a novel serine protease inhibitor containing two Kunitz domains. J Biol Chem 1997;272:12202–8.

    Article  PubMed  CAS  Google Scholar 

  37. Delaria KA, Muller DK, Marlor CW, Brown JE, Das RC, Roczniak SO, et al. Characterization of placental bikunin, a novel human serine proteinase inhibitor. J Biol Chem 1997;272:12209–14.

    Article  PubMed  CAS  Google Scholar 

  38. Kataoka H, Suganuma T, Shimomura T, Itoh H, Kitamura N, Nabeshima K. Distribution of hepatocyte growth factor activator inhibitor type 1 (HAI-1) in human tissues: cellular surface localization of HAI-1 in simple columnar epithelium and its modulated expression in injured and regenerative tissues. J Histochem Cytochem 1999;47:673–82.

    Article  PubMed  CAS  Google Scholar 

  39. Itoh H, Yamauchi M, Kataoka H, Hamasuna R, Kitamura N, Koono M. Genomic structure and chromosomal localization of the human hepatocyte growth factor activator inhibitor type 1 and 2 genes. Eur J Biochem 2000;267:3351–9.

    Article  PubMed  CAS  Google Scholar 

  40. Itoh H, Kataoka H, Hamasuna R, Kitamura N, Koono M. Hepatocyte growth factor activator inhibitor type 2 lacking the first Kunitz-type serine proteinase inhibitor domain is a predominant product in mouse but not in human. Biochem Biophys Res Commun 1999;255:740–8.

    Article  PubMed  CAS  Google Scholar 

  41. Itoh H, Kataoka H, Yamauchi M, Naganuma S, Akiyama Y, Nuki Y, et al. Identification of hepatocyte growth factor activator inhibitor type 2 (HAI-2)-related small peptide (H2RSP): its nuclear localization and generation of chimeric mRNA transcribed from both HAI-2 and H2RSP genes. Biochem Biophys Res Commun 2001;288:390–9.

    Article  PubMed  CAS  Google Scholar 

  42. Qin L, Denda K, Shimomura T, Kawaguchi T, Kitamura N. Functional characterization of Kunitz domains in hepatocyte growth factor activator inhibitor type 2. FEBS Lett 1998;436:111–4.

    Article  PubMed  CAS  Google Scholar 

  43. Kataoka H, Itoh H, Nuki Y, Hamasuna R, Naganuma S, Kitamura N, et al. Mouse hepatocyte growth factor (HGF) activator inhibitor type 2 lacking the first Kunitz domain potently inhibits the HGF activator. Biochem Biophys Res Commun 2002;290: 1096–100.

    Article  PubMed  CAS  Google Scholar 

  44. Lin CY, Anders J, Johnson M, Dickson RB. Purification and characterization of a complex containing matriptase and a Kunitz-type serine protease inhibitor from human milk. J Biol Chem 1999;274:18237–42.

    Article  PubMed  CAS  Google Scholar 

  45. Shimomura T, Denda K, Kawaguchi T, Matsumoto K, Miyazawa K, Kitamura N. Multiple sites of proteolytic cleavage to release soluble forms of hepatocyte growth factor activator inhibitor type 1 from a transmembrane form. J Biochem 1999;126: 821–8.

    Article  PubMed  CAS  Google Scholar 

  46. Kataoka H, Shimomura T, Kawaguchi T, Hamasuna R, Itoh H, Kitamura N, et al. Hepatocyte growth factor activator inhibitor type 1 is a specific cell surface binding protein of hepatocyte growth factor activator (HGFA) and regulates HGFA activity in pericellular microenvironments. J Biol Chem 2000;275:40453–62.

    Article  PubMed  CAS  Google Scholar 

  47. Itoh H, Kataoka H, Tomita M, Hamasuna R, Nawa Y, Kitamura N, et al. Up-regulation of hepatocyte growth factor activator inhibitor type-1 but not type-2 along with regeneration of intestinal mucosa. Am J Phys 2000;278:G635–43.

    CAS  Google Scholar 

  48. Itoh H, Kataoka H, Meng JY, Hamasuna R, Kitamura N, Koono M. Mouse hepatocyte growth factor activator inhibitor type 1 (HAI-1) and type 2 (HAI-2)/placental bikunin genes and their promoters. Biochim Biophys Acta 2001:1519:92–5.

    Article  PubMed  CAS  Google Scholar 

  49. Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, et al. Scatter factor/hepatocyte growth factor is essential for liver development. Nature 1995;373:699–702.

    Article  PubMed  CAS  Google Scholar 

  50. Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T, et al. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature 1995;373:702–5.

    Article  PubMed  CAS  Google Scholar 

  51. Denda K, Shimomura T, Kawaguchi T, Miyazawa K, Kitamura N. Functional characterization of Kunitz domains in hepatocyte growth factor activator inhibitor type 1. J Biol Chem 2002;277: 14053–9.

    Article  PubMed  CAS  Google Scholar 

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  1. Second Department of Pathology, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan

    Hiroshi Itoh & Hiroaki Kataoka

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  1. Hiroshi Itoh
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Itoh, H., Kataoka, H. Roles of hepatocyte growth factor activator (HGFA) and its inhibitor HAI-1 in the regeneration of injured gastrointestinal mucosa. J Gastroenterol 37 (Suppl 14), 15–21 (2002). https://doi.org/10.1007/BF03326408

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