Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

HGF (Hepatocyte Growth Factor)

  • Hiroki Sato
  • Shunsuke Aoki
  • Takashi Kato
  • Kunio MatsumotoEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101701


Historical Background

In 1984, hepatocyte growth factor (HGF) was first reported as a potent mitogen of rat hepatocytes in a primary culture. The primary structure of HGF became evident with cDNA cloning in 1989, and HGF was simultaneously identified as a novel growth factor (Nakamura et al. 1989; Miyazawa et al. 1989). Meanwhile, scatter factor was identified from fibroblast-cultured media as a scattering-inducible factor toward epithelial cells. The biological activities of HGF and scatter factor seemed unrelated, but subsequent biochemical analysis has revealed that HGF and scatter factor are identical.

Initially, a transforming Met fusion protein, translocated promoter region (TPR)–Met, was discovered in a human osteosarcoma cell line as an active oncogene (Cooper et al. 1984). The proto-oncogene c-Met was later found to encode the transmembrane protein with intracellular tyrosine...

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


  1. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4:915–25.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Bladt F, Riethmacher D, Isenmann S, Aguzzi A, Birchmeier C. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature. 1995;376:768–71.PubMedCrossRefGoogle Scholar
  3. Bottaro DP, Rubin JS, Faletto DL, Chan AM-L, Kmiecik TE, Vande Woude GF, Aaronson SA. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991;251:802–4.PubMedCrossRefGoogle Scholar
  4. Cecchi F, Rabe DC, Bottaro DP. Targeting the HGF/Met signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:553–72.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Chirgadze DY, Hepple JP, Zhou H, Byrd RA, Blundell TL, Gherardi E. Crystal structure of the NK1 fragment of HGF/SF suggests a novel mode for growth factor dimerization and receptor binding. Nat Struct Biol. 1999;6:72–9.PubMedCrossRefGoogle Scholar
  6. Cooper CS, Park M, Blair DG, Tainsky MA, Huebner K, Croce CM, Vande Woude GF. Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature. 1984;311:29–33.PubMedCrossRefGoogle Scholar
  7. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale C-M, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Jänne PA. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–43.PubMedCrossRefGoogle Scholar
  8. Gherardi E, Birchmeier W, Birchmeier C, Vande Woude GF. Targeting MET in cancer: rationale and progress. Nat Rev Cancer. 2012;12:89–103.PubMedCrossRefGoogle Scholar
  9. Ito K, Sakai K, Suzuki Y, Ozawa N, Hatta T, Natsume T, Matsumoto K, Suga H. Artificial human Met agonists based on macrocycle scaffolds. Nat Commun. 2015;6:6373.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Kawaguchi M, Kataoka H. Mechanisms of hepatocyte growth factor activation in cancer tissues. Cancer. 2014;6:1890–904.CrossRefGoogle Scholar
  11. Matsumoto K, Funakoshi H, Takahashi H, Sakai K. HGF-Met pathway in regeneration and drug discovery. Biomedicine. 2014;2:275–300.CrossRefGoogle Scholar
  12. Miyazawa K, Tsubouchi H, Naka D, Takahashi K, Okigaki M, Arakaki N, Nakayama H, Hirono S, Sakiyama O, Takahashi K, Gohda E, Daikuhara Y, Kitamura N. Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. Biochem Biophys Res Commun. 1989;163:967–73.PubMedCrossRefGoogle Scholar
  13. Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, Tashiro K, Shimizu S. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989;342:440–3.PubMedCrossRefGoogle Scholar
  14. Sakai K, Aoki S, Matsumoto K. Hepatocyte growth factor and Met in drug discovery. J Biochem. 2015;157:271–84.PubMedCrossRefGoogle Scholar
  15. Schiering N, Knapp S, Marconi M, Flocco MM, Cui J, Perego R, Rusconi L, Cristiani C. Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met and its complex with the microbial alkaloid K-252a. Proc Natl Acad Sci U S A. 2003;100:12654–9.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E, Birchmeier C. Scatter factor/hepatocyte growth factor is essential for liver development. Nature. 1995;373:699–702.PubMedCrossRefGoogle Scholar
  17. Stamos J, Lazarus RA, Yao X, Kirchhofer D, Wiesmann C. Crystal structure of the HGF β-chain in complex with the Sema domain of the Met receptor. EMBO J. 2004;23:2325–35.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Trusolino L, Bertotti A, Comoglio PM. MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol. 2010;11:834–48.PubMedCrossRefGoogle Scholar
  19. Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T, Kitamura N. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature. 1995;373:702–5.PubMedCrossRefGoogle Scholar
  20. Wang W, Marimuthu A, Tsai J, Kumar A, Krupka HI, Zhang C, Powell B, Suzuki Y, Nguyen H, Tabrizizad M, Luu C, West BL. Structural characterization of autoinhibited c-Met kinase produced by coexpression in bacteria with phosphatase. Proc Natl Acad Sci U S A. 2006;103:3563–8.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Hiroki Sato
    • 1
  • Shunsuke Aoki
    • 2
  • Takashi Kato
    • 3
  • Kunio Matsumoto
    • 1
    Email author
  1. 1.Division of Tumor Dynamics and Regulation, Cancer Research InstituteKanazawa UniversityKanazawaJapan
  2. 2.Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems EngineeringKyushu Institute of TechnologyIizuka-shiJapan
  3. 3.Department of Pharmacology, Faculty of MedicineKinki UniversitySayamaJapan