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Gene Review

EGF  -  epidermal growth factor

Canis lupus familiaris

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Disease relevance of EGF

  • RESULTS: EGF dose dependently inhibited carbachol-stimulated aminopyrine uptake in a pertussis toxin-insensitive, genistein (tyrosine kinase inhibitor)--sensitive manner, with a maximal inhibitory effect (37.5% +/- 6.8%) achieved at 10(-7) mol/L [1].
  • One candidate was found to be the second EGF-like domain residue, Arg94, which is also associated with severe hemophilia B when mutated [2].
  • This suggests that EGF may be a useful therapeutic agent in the healing of gastric ulcers [3].
  • In addition, glioma cells were stimulated to migrate in a dose-dependant manner in response to epidermal growth factor (EGF) coincident with the reduction of Cx43 levels and increased serine phosphorylation [4].
  • EGF has no effect on proliferation of CTE cells on plastic but induces hyperplasia of CTE cells on collagen matrices [5].

High impact information on EGF

  • Disruption of GRB2 interactions by microinjection of a peptide corresponding to the GRB2 SH2 domain or its phosphopeptide ligand blocked EGF receptor endocytosis; other SH2 domains that bind EGF receptors or antibodies that neutralize RAS did not [6].
  • EGF stimulation of canine epithelial cells induced a rapid and transient association of the SH3-SH2-SH3 protein GRB2 with dynamin, a guanosine triphosphatase that regulates endocytosis [6].
  • EGF/TGF alpha and IGF-I are potential factors directly regulating proliferation of fundic mucosal cells [7].
  • CONCLUSIONS: The inhibitory action of EGF on carbachol-stimulated parietal cell activity seems to involve protein kinase C [1].
  • BACKGROUND & AIMS: Epidermal growth factor (EGF) inhibits secretagogue-stimulated gastric acid secretion via an EGF receptor located on parietal cells [1].

Biological context of EGF

  • Expression of SrcK- did not alter EGF-evoked Shc tyrosine phosphorylation, Shc-Grb2 complex formation and MAPK activation, three elements of the Ras pathway [8].
  • We reported that incubation of purified canine parietal cells with epidermal growth factor (EGF) for 6-16 h, stimulates H(+)/K(+)-ATPase alpha-subunit gene expression through the activation of Akt [9].
  • Here we demonstrate that transforming growth factor beta(1) (TGFbeta(1)) selectively inhibits the cAMP-dependent cell cycle in mid-G1 and various cell cycle regulatory events, but it weakly affects the stimulation of DNA synthesis by epidermal growth factor (EGF), hepatocyte growth factor, serum, and phorbol esters [10].
  • This EGF response element (ERE) conferred EGF inducibility when linked to homologous and heterologous promoters [11].
  • Transfection of the cells with dominant negative Akt inhibited EGF, but not Shh stimulation of H(+)/K(+)-ATPase-luciferase activity [9].

Anatomical context of EGF

  • Since tyrosine phosphorylation of cytoskeleton-associated proteins pp125FAK and cortactin were abolished in EGF-stimulated SrcK- cells, we concluded that, in contrast to Ras, Src kinases may control epithelial cell dispersion in the absence of gene expression and by directly regulating the organization of the cortical cytoskeleton [8].
  • This treatment led to the internalization of nonactivated EGF-EGFR complexes into endosomes [12].
  • Additionally they suggest that complex interactions occur between the mechanisms of action of EGF and of phorbol esters in the thyroid cell [13].
  • This finding correlates with the ability of CrkII to promote the breakdown of adherens junctions in stable cell lines and the ability of EGF to stimulate enhanced Rac activity in cells overexpressing CrkII [14].
  • After TPA and EGF, the time courses of stimulation of c-fos and c-myc were the same as those for mitogenically stimulated fibroblasts [15].

Associations of EGF with chemical compounds

  • Most highly conserved between EMR2 and CD97 is the fourth EGF domain, which mediates binding to chondroitin sulfate, a ligand specificity shared by both receptors [16].
  • The protein kinase C inhibitors H-7 and staurosporine dose dependently reversed the inhibitory action of EGF, whereas H-89 (protein kinase A inhibitor) failed to alter the effect of EGF [1].
  • The differences in the protein phosphorylation patterns in response to TSH, EGF, and TPA suggested that the newly emerging cyclic AMP-mediated mitogenic pathway is distinct from the better known growth factor- and tumor promoter-induced pathways [17].
  • We treated cells with EGF in the presence of AG-1478, a specific EGFR tyrosine kinase inhibitor, and monensin, which blocks the recycling of EGFR [12].
  • Moreover like EGF, phorbol esters strongly inhibited in 2 days the morphological effects of TSH and basal and TSH-stimulated iodide transport capacity and thyroglobulin messenger RNA accumulation, two markers of thyroid differentiation [13].

Physical interactions of EGF


Regulatory relationships of EGF

  • Both apical and basolateral EGF activated tyrosine phosphorylation of EGF receptors (EGFR), beta-catenin, and cellular substrate as evident on confocal microscopy [19].
  • The dog thyrocyte I- trapping activity and the expression of the genes coding for dog thyrocyte thyroglobulin or thyroid peroxidase are enhanced by TSH through the cAMP cascade and reduced by mitogens such as epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol 13-acetate (TPA) [20].

Other interactions of EGF

  • These findings provide evidence that TGF-beta, EGF, PDGF-AA, PDGF-BB, IGF, bFGF and VEGF are all expressed at 10 days after tendon injury but by different cell types and in different locations [21].
  • Membrane-associated HB-EGF modulates HGF-induced cellular responses in MDCK cells [22].
  • Regulation of TSH receptor (TSHr) mRNA accumulation has been investigated in canine thyrocytes in primary culture by in situ hybridization experiments; the effects of the mitogenic thyrotropin (TSH), epidermal growth factor (EGF), and phorbol ester TPA (12-O-tetradecanoylphorbol-13-acetate) have been compared [23].
  • EGF, like glucagon, was still growth stimulatory to the PGE1-independent cells [24].

Analytical, diagnostic and therapeutic context of EGF


  1. Epidermal growth factor inhibits carbachol-stimulated canine parietal cell function via protein kinase C. Wang, L., Wilson, E.J., Osburn, J., DelValle, J. Gastroenterology (1996) [Pubmed]
  2. Blood coagulation factor IX residues Glu78 and Arg94 provide a link between both epidermal growth factor-like domains that is crucial in the interaction with factor VIII light chain. Christophe, O.D., Lenting, P.J., Kolkman, J.A., Brownlee, G.G., Mertens, K. J. Biol. Chem. (1998) [Pubmed]
  3. Epidermal growth factor receptors in the canine antrum. Zimmerman, R.P., Gates, T.S., Boehmer, C.G., Mantyh, P.W. Peptides (1988) [Pubmed]
  4. Gap junction intercellular communication in gliomas is inversely related to cell motility. McDonough, W.S., Johansson, A., Joffee, H., Giese, A., Berens, M.E. Int. J. Dev. Neurosci. (1999) [Pubmed]
  5. Effect of hormones on growth and function of cultured canine tracheal epithelial cells. Van Scott, M.R., Lee, N.P., Yankaskas, J.R., Boucher, R.C. Am. J. Physiol. (1988) [Pubmed]
  6. Requirement for the adapter protein GRB2 in EGF receptor endocytosis. Wang, Z., Moran, M.F. Science (1996) [Pubmed]
  7. Mitogenic response of canine fundic epithelial cells in short-term culture to transforming growth factor alpha and insulinlike growth factor I. Chen, M.C., Lee, A.T., Soll, A.H. J. Clin. Invest. (1991) [Pubmed]
  8. Src and Ras are involved in separate pathways in epithelial cell scattering. Boyer, B., Roche, S., Denoyelle, M., Thiery, J.P. EMBO J. (1997) [Pubmed]
  9. Regulation and function of the sonic hedgehog signal transduction pathway in isolated gastric parietal cells. Stepan, V., Ramamoorthy, S., Nitsche, H., Zavros, Y., Merchant, J.L., Todisco, A. J. Biol. Chem. (2005) [Pubmed]
  10. Transforming growth factor beta(1) selectively inhibits the cyclic AMP-dependent proliferation of primary thyroid epithelial cells by preventing the association of cyclin D3-cdk4 with nuclear p27(kip1). Depoortere, F., Pirson, I., Bartek, J., Dumont, J.E., Roger, P.P. Mol. Biol. Cell (2000) [Pubmed]
  11. Epidermal growth factor induces H+,K+-ATPase alpha-subunit gene expression through an element homologous to the 3' half-site of the c-fos serum response element. Kaise, M., Muraoka, A., Yamada, J., Yamada, T. J. Biol. Chem. (1995) [Pubmed]
  12. Endosomal signaling of epidermal growth factor receptor stimulates signal transduction pathways leading to cell survival. Wang, Y., Pennock, S., Chen, X., Wang, Z. Mol. Cell. Biol. (2002) [Pubmed]
  13. Stimulation of cell proliferation and inhibition of differentiation expression by tumor-promoting phorbol esters in dog thyroid cells in primary culture. Roger, P.P., Reuse, S., Servais, P., Van Heuverswyn, B., Dumont, J.E. Cancer Res. (1986) [Pubmed]
  14. Crk synergizes with epidermal growth factor for epithelial invasion and morphogenesis and is required for the met morphogenic program. Lamorte, L., Rodrigues, S., Naujokas, M., Park, M. J. Biol. Chem. (2002) [Pubmed]
  15. Regulation of protooncogenes c-fos and c-myc expressions by protein tyrosine kinase, protein kinase C, and cyclic AMP mitogenic pathways in dog primary thyrocytes: a positive and negative control by cyclic AMP on c-myc expression. Reuse, S., Maenhaut, C., Dumont, J.E. Exp. Cell Res. (1990) [Pubmed]
  16. An unusual mode of concerted evolution of the EGF-TM7 receptor chimera EMR2. Kwakkenbos, M.J., Matmati, M., Madsen, O., Pouwels, W., Wang, Y., Bontrop, R.E., Heidt, P.J., Hoek, R.M., Hamann, J. FASEB J. (2006) [Pubmed]
  17. Differential protein phosphorylation in induction of thyroid cell proliferation by thyrotropin, epidermal growth factor, or phorbol ester. Contor, L., Lamy, F., Lecocq, R., Roger, P.P., Dumont, J.E. Mol. Cell. Biol. (1988) [Pubmed]
  18. Elevated epidermal growth factor receptor binding in plutonium-induced lung tumors from dogs. Leung, F.C., Bohn, L.R., Dagle, G.E. Proc. Soc. Exp. Biol. Med. (1991) [Pubmed]
  19. Apical and basolateral EGF receptors regulate gastric mucosal paracellular permeability. Chen, M.C., Goliger, J., Bunnett, N., Soll, A.H. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  20. Tonic modulation of dog thyrocyte H2O2 generation and I- uptake by thyrotropin through the cyclic adenosine 3',5'-monophosphate cascade. Raspé, E., Dumont, J.E. Endocrinology (1995) [Pubmed]
  21. Expression of growth factors in canine flexor tendon after laceration in vivo. Tsubone, T., Moran, S.L., Amadio, P.C., Zhao, C., An, K.N. Annals of plastic surgery. (2004) [Pubmed]
  22. 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]
  23. Differential regulation of thyrotropin receptor and thyroglobulin mRNA accumulation at the cellular level: an in situ hybridization study. Pohl, V., Maenhaut, C., Gérard, C., Vassart, G., Dumont, J.E. Exp. Cell Res. (1992) [Pubmed]
  24. PGE1-independent MDCK cells have elevated intracellular cyclic AMP but retain the growth stimulatory effects of glucagon and epidermal growth factor in serum-free medium. Taub, M., Devis, P.E., Grohol, S.H. J. Cell. Physiol. (1984) [Pubmed]
  25. Association of p120 ras GAP with endocytic components and colocalization with epidermal growth factor (EGF) receptor in response to EGF stimulation. Wang, Z., Tung, P.S., Moran, M.F. Cell Growth Differ. (1996) [Pubmed]
  26. Differential protein synthesis in the induction of thyroid cell proliferation by thyrotropin, epidermal growth factor or serum. Lamy, F., Roger, P.P., Lecocq, R., Dumont, J.E. Eur. J. Biochem. (1986) [Pubmed]
  27. Nanoparticle tethered antioxidant response element as a biosensor for oxygen induced toxicity in retinal endothelial cells. Prow, T., Grebe, R., Merges, C., Smith, J.N., McLeod, D.S., Leary, J.F., Lutty, G.A. Mol. Vis. (2006) [Pubmed]
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