Skip to main content
SpringerLink
Log in

HB-EGF (Heparin-Binding EGF-Like Growth Factor)

  • Living reference work entry
  • First Online:
Encyclopedia of Signaling Molecules

  • 242 Accesses

Synonyms

Diphtheria toxin receptor; DTR; DTS; DTSF; HBEGF; Heparin-binding epidermal growth factor-like growth factor

Historical Background

Since the discovery of epidermal growth factor (EGF) in 1962, a total of seven mammalian ligands that bind the EGF receptor (EGFR/ErbB1) have been identified, including transforming growth factor-α (TGFα), amphiregulin (ARG), betacellulin (BTC), epiregulin (ERG), epigen (EPG), and heparin-binding EGF-like growth factor (HB-EGF) (Harris et al. 2003). Historically, HB-EGF was the fourth growth factor to be identified among EGFR-ligands. Major findings regarding HB-EGF are:

  • Discovery of HB-EGF (Higashiyama et al. 1991)

  • Identification of HB-EGF as the diphtheria toxin receptor (DTR) (Naglich et al. 1992; Iwamoto et al. 1994)

  • Identification of HB-EGF’s major role in EGFR transactivation (Prenzel et al. 1999)

  • Establishment of HB-EGF-null mouse lines (Iwamoto et al. 2003; Jackson et al. 2003)

  • Proof of the physiological significance of HB-EGF shedding...

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

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Asakura M, Kitakaze M, Takashima S, Liao Y, Ishikura F, Yoshinaka T, et al. Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nat Med. 2002;8:35–40. doi:10.1038/nm0102-35.

    Article  CAS  PubMed  Google Scholar 

  • Blobel CP. ADAMs: key components in EGFR signaling and development. Nat Rev Mol Cell Biol. 2005;6:32–43. doi:10.1038/nrm1548.

    Article  CAS  PubMed  Google Scholar 

  • Bollee G, Flamant M, Schordan S, Fligny C, Rumpel E, Milon M, et al. Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis. Nat Med. 2011;17:1242–50. doi:10.1038/nm.2491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diaz B, Yuen A, Iizuka S, Higashiyama S, Courneidge SA. Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia. J Cell Biol. 2013;201:279–92. doi:10.1083/jcb.201209151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hao L, Du M, Lopez-Campistrous A, Fernandez-Parton C. Agonist-induced activation of matrix metalloproteinase-7 promotes vasoconstriction through the epidermal growth factor-receptor pathway. Circ Res. 2004;94:68–76. doi:10.1161/01.RES.0000109413.57726.91.

    Article  CAS  PubMed  Google Scholar 

  • Harris RC, Chung E, Coffey RJ. EGF receptor ligands. Exp Cell Res. 2003;284:2–13. doi:10.1016/S0014-4827(02)00105-2.

    Article  CAS  PubMed  Google Scholar 

  • Higashiyama S, Abraham JA, Miller J, Fiddes JC, Klagsbrun M. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science. 1991;251:936–9. doi:10.1126/science.1840698.

    Article  CAS  PubMed  Google Scholar 

  • Higashiyama S, Iwabuki H, Morimoto C, Hieda M, Inoue H, Matsushita N. Membrane-anchored growth factors, the epidermal growth factor family: beyond receptor ligands. Cancer Sci. 2008;99:214–20. doi:10.1111/j.1349-7006.2007.00676.x.

    Article  CAS  PubMed  Google Scholar 

  • Ichise T, Adachi S, Ohishi M, Ikawa M, Okabe M, Iwamoto R, et al. Humanized gene replacement in mice reveals the contribution of cancer stroma-derived HB-EGF to tumor growth. Cell Struct Funct. 2010;35:3–13. doi:10.1247/csf.09025.

    Article  CAS  PubMed  Google Scholar 

  • Iwamoto R, Higashiyama S, Mitamura T, Taniguchi N, Klagsbrun M, Mekada E. 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. EMBO J. 1994;13:2322–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Iwamoto R, Mekada E. Heparin-binding EGF-like growth factor: a juxtacrine growth factor. Cytokine Growth Factor Rev. 2000;11:335–44. doi:10.1016/S1359-6101(00)00013-7.

    Article  CAS  PubMed  Google Scholar 

  • Iwamoto R, Yamazaki S, Asakura M, Takashima S, Hasuwa H, Miyado K, et al. Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc Natl Acad Sci USA. 2003;100:3221–6. doi:10.1073/pnas.0537588100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iwamoto R, Mine N, Kawaguchi T, Minami S, Saeki K, Mekada E. HB-EGF function in cardiac valve development requires interaction with heparan sulfate proteoglycans. Development. 2010;137:2205–14. doi:10.1242/dev.048926.

    Article  CAS  PubMed  Google Scholar 

  • Jackson LF, Qiu TH, Sunnarborg SW, Chang A, Zhang C, Patterson C, et al. Defective valvulogenesis in HB-EGF and TACE-null mice is associated with aberrant BMP signaling. EMBO J. 2003;22:2704–16. doi:10.1093/emboj/cdg264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kawakami A, Yoshida M. Remnant lipoproteins and atherogenesis. J Atheroscler Thromb. 2005;12:73–6. doi:10.5551/jat.12.73.

    Article  CAS  PubMed  Google Scholar 

  • Kimura R, Iwamoto R, Mekada E. Soluble form of heparin-binding EGF-like growth factor contributes to retinoic acid-induced epidermal hyperplasia. Cell Struct Funct. 2005;30:35–42. doi:10.1247/csf.30.35.

    Article  CAS  PubMed  Google Scholar 

  • Koshikawa N, Mizushima H, Minegishi T, Iwamoto R, Mekada E, Seiki M. Membrane type 1-matrix metalloproteinase cleaves off the NH2-terminal portion of heparin-binding epidermal growth factor and converts it into a heparin-independent growth factor. Cancer Res. 2010;70:6093–103. doi:10.1158/0008-5472.CAN-10-0346.

    Article  CAS  PubMed  Google Scholar 

  • Lemjabbar H, Basbaum C. Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. Nat Med. 2002;8:41–6. doi:10.1038/nm0102-41.

    Article  CAS  PubMed  Google Scholar 

  • Mekada E, Iwamoto R. HB-EGF. UCSD-Nature Molecule Pages. 2008. doi:10.1038/mp.a002932.01.

    Google Scholar 

  • Minami S, Iwamoto R, Mekada E. HB-EGF decelerates cell proliferation synergistically with TGFα in perinatal distal lung development. Dev Dyn. 2008;237:247–58. doi:10.1002/dvdy.21398.

    Article  CAS  PubMed  Google Scholar 

  • Mine N, Iwamoto R, Mekada E. HB-EGF promotes epithelial cell migration in eyelid development. Development. 2005;132:4317–26. doi:10.1242/dev.02030.

    Article  CAS  PubMed  Google Scholar 

  • Miyamoto S, Hirata M, Yamazaki A, Kageyama T, Hasuwa H, Mizushima H, et al. Heparin-binding EGF-like growth factor is a promising target for ovarian cancer therapy. Cancer Res. 2004;64:5720–7. doi:10.1158/0008-5472.CAN-04-0811.

    Article  CAS  PubMed  Google Scholar 

  • Miyamoto S, Yagi H, Yotsumoto F, Kawarabayashi T, Mekada E. Heparin-binding epidermal growth factor-like growth factor as a novel targeting molecule for cancer therapy. Cancer Sci. 2006;97:341–7. doi:10.1111/j.1349-7006.2006.00188.x.

    Article  CAS  PubMed  Google Scholar 

  • Murata T, Mizushima H, Chinen I, Moribe H, Yagi S, Hoffman RM, et al. HB-EGF and PDGF mediate reciprocal interactions of carcinoma cells with cancer-associated fibroblasts to support progression of uterine cervical cancers. Cancer Res. 2011;71:6632–42. doi:10.1158/0008-5472.CAN-11-0034.

    Article  Google Scholar 

  • Naglich JG, Metherall JE, Russell DW, Eidels L. Expression cloning of a diphtheria toxin receptor: identity with a heparin-binding EGF-like growth factor precursor. Cell. 1992;69:1051–61. doi:10.1016/0092-8674(92)90623-K.

    Article  CAS  PubMed  Google Scholar 

  • Nanba D, Mammoto A, Hashimoto K, Higashiyama S. Proteolytic release of the carboxy-terminal fragment of proHB-EGF causes nuclear export of PLZF. J Cell Biol. 2003;163:489–502. doi:10.1083/jcb.200303017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohtsu H, Dempsey PJ, Eguchi S. ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors. Am J Physiol Cell Physiol. 2006;291:1–10. doi:10.1152/ajpcell.00620.2005.

    Article  Google Scholar 

  • Oyagi A, Morimoto N, Hamanaka J, Ishiguro M, Tsuruma K, Shimazawa M, et al. Forebrain-specific heparin-binding epidermal growth factor-like growth factor knockout mice show exacerbated ischemia and reperfusion injury. Neuroscience. 2011;185:116–24. doi:10.1016/j.neuroscience.2011.04.034.

    Article  CAS  PubMed  Google Scholar 

  • Prenzel N, Zwick E, Daub H, Leserer M, Abraham R, Wallasch C, et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature. 1999;402:884–8. doi:10.1038/47260.

    CAS  PubMed  Google Scholar 

  • Prince RN, Schreiter ER, Zou P, Wiley HS, Ting AY, Lee RT, et al. The heparin-binding domain of HB-EGF mediates localization to sites of cell-cell contact and prevents HB-EGF proteolytic release. J Cell Sci. 2010;123:2308–18. doi:10.1242/jcs.058321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shirakata Y, Kimura R, Nanba D, Iwamoto R, Tokumaru S, Morimoto C, et al. Heparin-binding EGF-like growth factor accelerates keratinocyte migration and skin wound healing. J Cell Sci. 2005;118:2363–70. doi:10.1242/jcs.02346.

    Article  CAS  PubMed  Google Scholar 

  • Svensson KJ, Kucharzewska P, Christianson HC, Skold S, Lofstedt T, Johansson MC, et al. Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells. Proc Natl Acad Sci USA. 2011;108:13147–52. doi:10.1073/pnas.1104261108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takemura T, Yoshida Y, Kiso S, Saji Y, Ezaki H, Hamano M, et al. Conditional knockout of heparin-binding epidermal growth factor-like growth factor in the liver accelerates carbon tetrachloride-induced liver injury in mice. Hepatol Res. 2013a;43:384–93. doi:10.1111/j.1872-034X.2012.01074.x.

    Article  CAS  PubMed  Google Scholar 

  • Takemura T, Yoshida Y, Kiso S, Kizu T, Furuta K, Ezaki H, et al. Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice. Biochem Biophys Res Commun. 2013b;437:185–91. doi:10.1016/j.bbrc.2013.05.097.

    Article  CAS  PubMed  Google Scholar 

  • Wan J, Ramachandran R, Goldman D. HB-EGF is necessary and sufficient for Muller glia dedifferentiation and retina regeneration. Dev Cell. 2012;22:334–47. doi:10.1016/j.devcel.2011.11.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie H, Wang H, Tranguch S, Iwamoto R, Mekada E, DeMayo FJ, et al. Maternal heparin-binding-EGF deficiency limits pregnancy success in mice. Proc Natl Acad Sci USA. 2007;104:18315–20. doi:10.1073/pnas.0707909104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamazaki S, Iwamoto R, Saeki K, Asakura M, Takashima S, Yamazaki A, et al. Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities. J Cell Biol. 2003;163:469–75. doi:10.1083/jcb.200307035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan

    Ryo Iwamoto & Eisuke Mekada

Authors
  1. Ryo Iwamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eisuke Mekada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eisuke Mekada .

Editor information

Editors and Affiliations

  1. Dept. Biological Science, Department of Molecular Science and Tech College of Natural Science, Suwon, Korea (Republic of)

    Sangdun Choi

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media LLC

About this entry

Cite this entry

Iwamoto, R., Mekada, E. (2016). HB-EGF (Heparin-Binding EGF-Like Growth Factor). In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6438-9_127-1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-6438-9_127-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, New York, NY

  • Online ISBN: 978-1-4614-6438-9

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation