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Gene Review

HBEGF  -  heparin-binding EGF-like growth factor

Homo sapiens

Synonyms: DTR, DTS, DTSF, HEGFL, Proheparin-binding EGF-like growth factor
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Disease relevance of HBEGF


Psychiatry related information on HBEGF


High impact information on HBEGF

  • HB-EGF is also expressed in cultured human macrophages and may be involved in macrophage-mediated cellular proliferation [8].
  • HBEGF in the complex has the typical EGF-like fold and packs its principal beta hairpin against the face of a beta sheet in the receptor-binding domain of DT [9].
  • We describe the crystal structure at 2.65 A resolution of diphtheria toxin (DT) complexed 1:1 with a fragment of its cell-surface receptor, the precursor of heparin-binding epidermal-growth-factor-like growth factor (HBEGF) [9].
  • This was achieved by rapidly killing peptide-pulsed DCs carrying a diphtheria toxin receptor transgene with timed injections of diphtheria toxin without altering the course of an accompanying infection [10].
  • This appears to be secondary to visceral obesity and the metabolic syndrome, with increased levels of output of free fatty acids and heparin-binding EGF-like growth factor from the adipose tissue of the mice [11].

Chemical compound and disease context of HBEGF


Biological context of HBEGF


Anatomical context of HBEGF


Associations of HBEGF with chemical compounds

  • Heparin-binding epidermal growth factor (HBEGF) binds to EGFRs with high affinity and to heparan sulfate proteoglycans, resulting in increased mitogenic potential compared to other EGF family members [2].
  • A construct with a 22-amino-acid flexible linker (L22) between the HBEGF and SAP moieties exhibited an affinity for the EGFR that was comparable to that of HBEGF [2].
  • Factors relevant to the biology of leukemic growth, such as tumor necrosis factor-alpha (TNF-alpha), 1alpha,25-(OH)2D3, and especially all-trans retinoic acid (ATRA), upregulated HB-EGF mRNA in HL-60 or ML-3 cells [4].
  • It was concluded that HB-EGF TM, which is synthesized exclusively in the luminal epithelium at the site of blastocyst apposition, and which is a juxtacrine adhesion factor for blastocysts, could be one of the mediators of blastocyst adhesion to the uterus in the process of implantation [22].
  • Concurrent treatment with HB-EGF and cycloheximide resulted in superinduction of HB-EGF and AR, suggesting that these peptides are immediate early genes in RIE-1 cells [23].

Physical interactions of HBEGF


Co-localisations of HBEGF

  • In epiretinal membranes of patients with PVR, HB-EGF immunoreactivity partially colocalized with GFAP [29].
  • HB-EGF colocalized with HER-1 and HER-4 in HPMCs and induced their adhesion to collagen type I, expression of beta 1 integrins, and migration [30].

Regulatory relationships of HBEGF

  • Signal transduction by the EGF receptor tyrosine kinase as evidenced by receptor autophosphorylation is induced by HB-EGF only in the presence of heparin, in contrast to EGF-induced receptor autophosphorylation, which is independent of heparin [21].
  • Granulocyte-macrophage colony-stimulating factor (GM-CSF) induced HB-EGF mRNA and acquisition of sensitivity to DT in one previously HB-EGF-negative leukemia case [4].
  • In addition, because effects of BAG-1 on regulated secretion of soluble HB-EGF were also identified, this interaction has the potential to alter the signaling capabilities of both the membrane-anchored and the diffusible forms of the growth factor [26].
  • Heparin-binding epidermal growth factor-like growth factor (HB-EGF) mRNA and protein expression is induced by EGF in MCF-10A nontransformed and Ha-ras transfected human mammary epithelial cells [31].
  • The binding of HB-EGF to tumour cells is blocked by mAbs which act as EGF and TGF alpha antagonists [32].

Other interactions of HBEGF


Analytical, diagnostic and therapeutic context of HBEGF


  1. Human trophoblast survival at low oxygen concentrations requires metalloproteinase-mediated shedding of heparin-binding EGF-like growth factor. Armant, D.R., Kilburn, B.A., Petkova, A., Edwin, S.S., Duniec-Dmuchowski, Z.M., Edwards, H.J., Romero, R., Leach, R.E. Development (2006) [Pubmed]
  2. Targeting tumor cells via EGF receptors: selective toxicity of an HBEGF-toxin fusion protein. Chandler, L.A., Sosnowski, B.A., McDonald, J.R., Price, J.E., Aukerman, S.L., Baird, A., Pierce, G.F., Houston, L.L. Int. J. Cancer (1998) [Pubmed]
  3. Isolation and characterization of heparin-binding growth factors in human leiomyomas and normal myometrium. Mangrulkar, R.S., Ono, M., Ishikawa, M., Takashima, S., Klagsbrun, M., Nowak, R.A. Biol. Reprod. (1995) [Pubmed]
  4. Heparin-binding epidermal growth factor-like growth factor/diphtheria toxin receptor expression by acute myeloid leukemia cells. Vinante, F., Rigo, A., Papini, E., Cassatella, M.A., Pizzolo, G. Blood (1999) [Pubmed]
  5. Heparin-binding EGF-like growth factor interacts with mouse blastocysts independently of ErbB1: a possible role for heparan sulfate proteoglycans and ErbB4 in blastocyst implantation. Paria, B.C., Elenius, K., Klagsbrun, M., Dey, S.K. Development (1999) [Pubmed]
  6. Distress tolerance in the eating disorders. Corstorphine, E., Mountford, V., Tomlinson, S., Waller, G., Meyer, C. Eating behaviors (2007) [Pubmed]
  7. The Chinese version of the Davidson Trauma Scale: a practice test for validation. Chen, C.H., Lin, S.K., Tang, H.S., Shen, W.W., Lu, M.L. Psychiatry and clinical neurosciences. (2001) [Pubmed]
  8. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Higashiyama, S., Abraham, J.A., Miller, J., Fiddes, J.C., Klagsbrun, M. Science (1991) [Pubmed]
  9. Crystal structure of the complex of diphtheria toxin with an extracellular fragment of its receptor. Louie, G.V., Yang, W., Bowman, M.E., Choe, S. Mol. Cell (1997) [Pubmed]
  10. Duration of the initial TCR stimulus controls the magnitude but not functionality of the CD8+ T cell response. Prlic, M., Hernandez-Hoyos, G., Bevan, M.J. J. Exp. Med. (2006) [Pubmed]
  11. CEACAM1 modulates epidermal growth factor receptor--mediated cell proliferation. Abou-Rjaily, G.A., Lee, S.J., May, D., Al-Share, Q.Y., Deangelis, A.M., Ruch, R.J., Neumaier, M., Kalthoff, H., Lin, S.H., Najjar, S.M. J. Clin. Invest. (2004) [Pubmed]
  12. Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells. Johnson, F.M., Saigal, B., Donato, N.J. J. Cell. Physiol. (2005) [Pubmed]
  13. A central role of EGF receptor transactivation in angiotensin II -induced cardiac hypertrophy. Shah, B.H., Catt, K.J. Trends Pharmacol. Sci. (2003) [Pubmed]
  14. Heparin-binding EGF-like growth factor is a promising target for ovarian cancer therapy. Miyamoto, S., Hirata, M., Yamazaki, A., Kageyama, T., Hasuwa, H., Mizushima, H., Tanaka, Y., Yagi, H., Sonoda, K., Kai, M., Kanoh, H., Nakano, H., Mekada, E. Cancer Res. (2004) [Pubmed]
  15. Heparin-binding transforming growth factor alpha-Pseudomonas exotoxin A. A heparan sulfate-modulated recombinant toxin cytotoxic to cancer cells and proliferating smooth muscle cells. Mesri, E.A., Kreitman, R.J., Fu, Y.M., Epstein, S.E., Pastan, I. J. Biol. Chem. (1993) [Pubmed]
  16. Neuropeptide-induced transactivation of a neuronal epidermal growth factor receptor is mediated by metalloprotease-dependent formation of heparin-binding epidermal growth factor. Shah, B.H., Farshori, M.P., Catt, K.J. J. Biol. Chem. (2004) [Pubmed]
  17. Canonical WNT signaling pathway and human AREG. Katoh, Y., Katoh, M. Int. J. Mol. Med. (2006) [Pubmed]
  18. Cytotoxic effects of basic FGF and heparin binding EGF conjugated with cytotoxin saporin on vascular cell cultures. Chen, C., Li, J., Micko, C.J., Pierce, G.F., Cunningham, M.R., Lumsden, A.B. J. Surg. Res. (1998) [Pubmed]
  19. Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation. Elenius, K., Paul, S., Allison, G., Sun, J., Klagsbrun, M. EMBO J. (1997) [Pubmed]
  20. Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate epoxygenase metabolites in epithelial cells. Chen, J.K., Capdevila, J., Harris, R.C. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  21. Heparin-dependent binding and autophosphorylation of epidermal growth factor (EGF) receptor by heparin-binding EGF-like growth factor but not by EGF. Aviezer, D., Yayon, A. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  22. Mouse preimplantation blastocysts adhere to cells expressing the transmembrane form of heparin-binding EGF-like growth factor. Raab, G., Kover, K., Paria, B.C., Dey, S.K., Ezzell, R.M., Klagsbrun, M. Development (1996) [Pubmed]
  23. Auto- and cross-induction within the mammalian epidermal growth factor-related peptide family. Barnard, J.A., Graves-Deal, R., Pittelkow, M.R., DuBois, R., Cook, P., Ramsey, G.W., Bishop, P.R., Damstrup, L., Coffey, R.J. J. Biol. Chem. (1994) [Pubmed]
  24. Purification of heparin-binding epidermal growth factor-like growth factor from pig uterine luminal flushings, and its production by endometrial tissues. Kim, G.Y., Besner, G.E., Steffen, C.L., McCarthy, D.W., Downing, M.T., Luquette, M.H., Abad, M.S., Brigstock, D.R. Biol. Reprod. (1995) [Pubmed]
  25. Heparin-like molecules on the cell surface potentiate binding of diphtheria toxin to the diphtheria toxin receptor/membrane-anchored heparin-binding epidermal growth factor-like growth factor. Shishido, Y., Sharma, K.D., Higashiyama, S., Klagsbrun, M., Mekada, E. J. Biol. Chem. (1995) [Pubmed]
  26. BAG-1 is a novel cytoplasmic binding partner of the membrane form of heparin-binding EGF-like growth factor: a unique role for proHB-EGF in cell survival regulation. Lin, J., Hutchinson, L., Gaston, S.M., Raab, G., Freeman, M.R. J. Biol. Chem. (2001) [Pubmed]
  27. Angiopoietin-regulated recruitment of vascular smooth muscle cells by endothelial-derived heparin binding EGF-like growth factor. Iivanainen, E., Nelimarkka, L., Elenius, V., Heikkinen, S.M., Junttila, T.T., Sihombing, L., Sundvall, M., Maatta, J.A., Laine, V.J., Yla-Herttuala, S., Higashiyama, S., Alitalo, K., Elenius, K. FASEB J. (2003) [Pubmed]
  28. CD9 antigen interacts with heparin-binding EGF-like growth factor through its heparin-binding domain. Sakuma, T., Higashiyama, S., Hosoe, S., Hayashi, S., Taniguchi, N. J. Biochem. (1997) [Pubmed]
  29. Changes in retinal gene expression in proliferative vitreoretinopathy: glial cell expression of HB-EGF. Hollborn, M., Tenckhoff, S., Jahn, K., Iandiev, I., Biedermann, B., Schnurrbusch, U.E., Limb, G.A., Reichenbach, A., Wolf, S., Wiedemann, P., Kohen, L., Bringmann, A. Mol. Vis. (2005) [Pubmed]
  30. HB-EGF is produced in the peritoneal cavity and enhances mesothelial cell adhesion and migration. Faull, R.J., Stanley, J.M., Fraser, S., Power, D.A., Leavesley, D.I. Kidney Int. (2001) [Pubmed]
  31. Regulation of heparin-binding EGF-like growth factor expression in Ha-ras transformed human mammary epithelial cells. Martínez-Lacaci, I., De Santis, M., Kannan, S., Bianco, C., Kim, N., Wallace-Jones, B., Wechselberger, C., Ebert, A.D., Salomon, D.S. J. Cell. Physiol. (2001) [Pubmed]
  32. The binding of HB-EGF to tumour cells is blocked by mAbs which act as EGF and TGF alpha antagonists. Modjtahedi, H., Dean, C. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  33. GPI-anchored diphtheria toxin receptor allows membrane translocation of the toxin without detectable ion channel activity. Lanzrein, M., Sand, O., Olsnes, S. EMBO J. (1996) [Pubmed]
  34. Heparin-binding EGF-like growth factor, which acts as the diphtheria toxin receptor, forms a complex with membrane protein DRAP27/CD9, which up-regulates functional receptors and diphtheria toxin sensitivity. Iwamoto, R., Higashiyama, S., Mitamura, T., Taniguchi, N., Klagsbrun, M., Mekada, E. EMBO J. (1994) [Pubmed]
  35. Co-expression of heparin-binding EGF-like growth factor and related peptides in human gastric carcinoma. Naef, M., Yokoyama, M., Friess, H., Büchler, M.W., Korc, M. Int. J. Cancer (1996) [Pubmed]
  36. ADAM19 expression in human nephrogenesis and renal disease: Associations with clinical and structural deterioration. Melenhorst, W.B., van den Heuvel, M.C., Timmer, A., Huitema, S., Bulthuis, M., Timens, W., van Goor, H. Kidney Int. (2006) [Pubmed]
  37. Expression of betacellulin, heparin-binding epidermal growth factor and epiregulin in human malignant fibrous histiocytoma. Yamamoto, T., Akisue, T., Marui, T., Nakatani, T., Kawamoto, T., Hitora, T., Nagira, K., Fujita, I., Matsumoto, K., Kurosaka, M. Anticancer Res. (2004) [Pubmed]
  38. Epidermal growth factor receptor mediates stress-induced expression of its ligands in rat gastric epithelial cells. Miyazaki, Y., Hiraoka, S., Tsutsui, S., Kitamura, S., Shinomura, Y., Matsuzawa, Y. Gastroenterology (2001) [Pubmed]
  39. Structure-function analysis of the diphtheria toxin receptor toxin binding site by site-directed mutagenesis. Mitamura, T., Umata, T., Nakano, F., Shishido, Y., Toyoda, T., Itai, A., Kimura, H., Mekada, E. J. Biol. Chem. (1997) [Pubmed]
  40. Structure of heparin-binding EGF-like growth factor. Multiple forms, primary structure, and glycosylation of the mature protein. Higashiyama, S., Lau, K., Besner, G.E., Abraham, J.A., Klagsbrun, M. J. Biol. Chem. (1992) [Pubmed]
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