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Gene Review

HGF  -  hepatocyte growth factor (hepapoietin A;...

Canis lupus familiaris

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High impact information on HGF

  • MDCK cells were then stimulated with scatter factor/hepatocyte growth factor (SF/HGF) to initiate invasion and tubulogenesis atop either type I collagen or interstitial stroma to determine the ability of MMPs to accelerate, modify, or disrupt morphogenic responses [1].
  • Although HGF/SF secreting cells can mimic signals from Hensen's node that maintain L5 expression, they cannot rescue the ability of the node to induce anterior structures (which is normally lost after stage 4) [2].
  • We therefore show that activation of the tyrosine kinase activity of HGF-R/Met via an autocrine HGF loop is directly responsible for pseudopodial protrusion, thereby explaining the motile and invasive potential of this model epithelium-derived tumor cell line [3].
  • The scattering of Madin-Darby canine kidney (MDCK) epithelial cells by scatter factor/hepatocyte growth factor (SF/HGF) is associated with transcriptional induction of the urokinase gene, which occurs essentially through activation of an EBS/AP1 response element [4].
  • We found that SF/HGF induces rapid and sustained phosphorylation of the extracellular signal-regulated kinase (ERK) MAPK while stimulating weakly and then repressing phosphorylation of the JUN N-terminal kinase (JNK) MAPK for several hours [4].

Biological context of HGF

  • Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional cytokine that induces mitogenesis, motility, invasion, and morphogenesis of several epithelial and endothelial cell lines in culture [5].
  • The met proto-oncogene is a receptor tyrosine kinase for hepatocyte growth factor/scatter factor (HGF/SF) [6].
  • This sequence of events provides a model for efficient cell scattering by SF/HGF at low cell density [4].
  • Despite structural similarities between MSP and HGF, the primary receptor binding site is located on the alpha chain of HGF/SF but on the beta chain of MSP [7].
  • Moreover, both the HGF- and TPA-induced disruption of the cadherin-based cell-cell adhesion and the subsequent cell migration were inhibited in both sMDCK-Cdc42HsDA and -G25KDA cells [8].

Anatomical context of HGF

  • The blebbing response was dependent on autocrine HGF (hepatocyte growth factor) activation of c-Met and prevented by inhibition of RhoA, ROCK and p38 MAPK (p38 mitogen-activated protein kinase), but not ERK (extracellular-signal-regulated kinase) or PI3K (phosphoinositide 3-kinase) [9].
  • Hepatocyte growth factor/scatter factor (HGF/SF) stimulates the motility of epithelial cells, initially inducing centrifugal spreading of colonies followed by disruption of cell-cell junctions and subsequent cell scattering [10].
  • Conversely, expression of mutants of Vav2 that increased stress fiber formation inhibited HGF/SF-induced cell scattering [11].
  • HGF/SF is a multifunctional cytokine that stimulates mitogenesis, motility, invasion, and tubulogenesis of a spectrum of epithelial and endothelial cells in culture [6].
  • These results indicate that activation of both MAP kinase and PI 3-kinase by Ras is required for adherens junction disassembly and that this is essential for the motile response to HGF/SF [10].

Associations of HGF with chemical compounds

  • The receptor for HGF/SF has been identified as the Met tyrosine kinase [5].
  • The release of arachidonic acid by MDCK cells following HGF/SF stimulation is establishing this fatty acid and its metabolites as major components involved in the transduction of MET-driven signals and at the same time in the amplification of such signals [12].
  • LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, inhibits HGF-induced PAK4 kinase activation, relocalisation, and cell rounding [13].
  • Hepatocyte growth factor/scatter factor (HGF/SF) is a mesenchymally derived glycoprotein with a strong scattering effect on epithelial cells [14].
  • Addition of ChTX (50 nM), IbTX (100 nM), Stk (100 nM) or CLT (1 microM) inhibited the HGF/SF-stimulated MDCK II cell migration [15].

Regulatory relationships of HGF


Other interactions of HGF

  • Macrophage-stimulating protein (MSP) and hepatocyte growth factor/scatter factor (HGF/SF) are plasminogen-related growth and motility factors that interact with cell-surface protein tyrosine kinase receptors [7].
  • Membrane-associated HB-EGF modulates HGF-induced cellular responses in MDCK cells [17].
  • Whereas enhancement of DNA synthesis and induction of cell flattening by SF/HGF were independent of substratum composition (i.e. occurred on both fibronectin and vitronectin surfaces), colony dispersion as a result of cell separation fails to occur or is markedly reduced on surfaces where vitronectin is the major adhesive ligand [18].
  • We identified repression of JNK as a signaling target of HGF/SF for protection against TNF-alpha-induced cell death [16].

Analytical, diagnostic and therapeutic context of HGF

  • HGF titration followed by a subsequent washout of the antibodies led to renewed pseudopodial protrusion and cellular movement [3].
  • Immunodepletion of MAP kinase via electroporation of an anti-MAP kinase antibody, did not significantly decrease arachidonic acid release in HGF/SF-stimulated MDCK cells [12].
  • Moreover, the HGF/SF protein was detected by Western blotting in the MDCK(LT)-conditioned medium [19].
  • When compared with the unstimulated cells, the inhibition of cell adhesion promoted by HGF/SF correlated with an increased stability of the newly synthesized soluble E-cadherin and Pg and an altered phosphorylation pattern of E-cadherin, as determined by partial proteolytic peptide mapping [14].
  • Cell migration induced by HGF/SF consisted of two distinct phases, initial cell spreading between 2 and 9 h after the start of treatment, and the scattering phase which started approximately 12 h after treatment [20].


  1. Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3. Hotary, K., Allen, E., Punturieri, A., Yana, I., Weiss, S.J. J. Cell Biol. (2000) [Pubmed]
  2. Preventing the loss of competence for neural induction: HGF/SF, L5 and Sox-2. Streit, A., Sockanathan, S., Pérez, L., Rex, M., Scotting, P.J., Sharpe, P.T., Lovell-Badge, R., Stern, C.D. Development (1997) [Pubmed]
  3. Autocrine activation of the hepatocyte growth factor receptor/met tyrosine kinase induces tumor cell motility by regulating pseudopodial protrusion. Vadnais, J., Nault, G., Daher, Z., Amraei, M., Dodier, Y., Nabi, I.R., Noël, J. J. Biol. Chem. (2002) [Pubmed]
  4. Sequential activation of ERK and repression of JNK by scatter factor/hepatocyte growth factor in madin-darby canine kidney epithelial cells. Paumelle, R., Tulasne, D., Leroy, C., Coll, J., Vandenbunder, B., Fafeur, V. Mol. Biol. Cell (2000) [Pubmed]
  5. Hepatocyte growth factor-induced scatter of Madin-Darby canine kidney cells requires phosphatidylinositol 3-kinase. Royal, I., Park, M. J. Biol. Chem. (1995) [Pubmed]
  6. Tyrosine 1356 in the carboxyl-terminal tail of the HGF/SF receptor is essential for the transduction of signals for cell motility and morphogenesis. Zhu, H., Naujokas, M.A., Fixman, E.D., Torossian, K., Park, M. J. Biol. Chem. (1994) [Pubmed]
  7. Interaction of macrophage-stimulating protein with its receptor. Residues critical for beta chain binding and evidence for independent alpha chain binding. Danilkovitch, A., Miller, M., Leonard, E.J. J. Biol. Chem. (1999) [Pubmed]
  8. Involvement of Cdc42 small G protein in cell-cell adhesion, migration and morphology of MDCK cells. Kodama, A., Takaishi, K., Nakano, K., Nishioka, H., Takai, Y. Oncogene (1999) [Pubmed]
  9. Rho/ROCK-dependent pseudopodial protrusion and cellular blebbing are regulated by p38 MAPK in tumour cells exhibiting autocrine c-Met activation. Jia, Z., Vadnais, J., Lu, M.L., Noël, J., Nabi, I.R. Biol. Cell (2006) [Pubmed]
  10. Activation of both MAP kinase and phosphatidylinositide 3-kinase by Ras is required for hepatocyte growth factor/scatter factor-induced adherens junction disassembly. Potempa, S., Ridley, A.J. Mol. Biol. Cell (1998) [Pubmed]
  11. Involvement of an SHP-2-Rho small G protein pathway in hepatocyte growth factor/scatter factor-induced cell scattering. Kodama, A., Matozaki, T., Fukuhara, A., Kikyo, M., Ichihashi, M., Takai, Y. Mol. Biol. Cell (2000) [Pubmed]
  12. Cytosolic phospholipase A2 is activated by the hepatocyte growth factor receptor-kinase in Madin Darby canine kidney cells. Skouteris, G.G., Schröder, C.H. J. Cell. Sci. (1997) [Pubmed]
  13. PAK4 is activated via PI3K in HGF-stimulated epithelial cells. Wells, C.M., Abo, A., Ridley, A.J. J. Cell. Sci. (2002) [Pubmed]
  14. Inhibition of junction assembly in cultured epithelial cells by hepatocyte growth factor/scatter factor is concomitant with increased stability and altered phosphorylation of the soluble junctional molecules. Pasdar, M., Li, Z., Marreli, M., Nguyen, B.T., Park, M., Wong, K. Cell Growth Differ. (1997) [Pubmed]
  15. Hepatocyte growth factor/scatter factor stimulates Ca2+-activated membrane K+ current and migration of MDCK II cells. Jin, M., Defoe, D.M., Wondergem, R. J. Membr. Biol. (2003) [Pubmed]
  16. Inhibition of JNK by HGF/SF prevents apoptosis induced by TNF-alpha. Reveneau, S., Paumelle, R., Deheuninck, J., Leroy, C., De Launoit, Y., Fafeur, V. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
  17. Membrane-associated HB-EGF modulates HGF-induced cellular responses in MDCK cells. Singh, A.B., Tsukada, T., Zent, R., Harris, R.C. J. Cell. Sci. (2004) [Pubmed]
  18. Modulation of scatter factor/hepatocyte growth factor activity by cell-substratum adhesion. Clark, P. J. Cell. Sci. (1994) [Pubmed]
  19. Inactivation of retinoblastoma family proteins by SV40 T antigen results in creation of a hepatocyte growth factor/scatter factor autocrine loop associated with an epithelial-fibroblastoid conversion and invasiveness. Martel, C., Harper, F., Cereghini, S., Noë, V., Mareel, M., Crémisi, C. Cell Growth Differ. (1997) [Pubmed]
  20. HGF/SF-induced spreading of MDCK cells correlates with disappearance of barmotin/7H6, a tight junction-associated protein, from the cell membrane. Muto, S., Sato, Y., Umeki, Y., Yoshida, K., Yoshioka, T., Nishikawa, Y., Nakamura, T., Mori, M., Koyama, K., Enomoto, K. Cell Biol. Int. (2000) [Pubmed]
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