Heparin-binding EGF-like growth factor explained

Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of proteins that in humans is encoded by the HBEGF gene.

HB-EGF-like growth factor is synthesized as a membrane-anchored mitogenic and chemotactic glycoprotein. An epidermal growth factor produced by monocytes and macrophages, due to an affinity for heparin is termed HB-EGF. It has been shown to play a role in wound healing, cardiac hypertrophy, and heart development and function.^[1] First identified in the conditioned media of human macrophage-like cells, HB-EGF is an 87-amino acid glycoprotein that displays highly regulated gene expression.^[2] Ectodomain shedding results in the soluble mature form of HB-EGF, which influences the mitogenicity and chemotactic factors for smooth muscle cells and fibroblasts. The transmembrane form of HB-EGF is the unique receptor for diphtheria toxin and functions in juxtacrine signaling in cells. Both forms of HB-EGF participate in normal physiological processes and in pathological processes including tumor progression and metastasis, organ hyperplasia, and atherosclerotic disease.^[3] HB-EGF can bind two locations on cell surfaces: heparan sulfate proteoglycans and EGF-receptors effecting cell-to-cell interactions.^[4]

Interactions

Heparin-binding EGF-like growth factor has been shown to interact with NRD1,^[5] Zinc finger and BTB domain-containing protein 16^{[6] [7]} and BAG1.^[8]

HB-EGF biological activities with these genes influence cell cycle progression, molecular chaperone regulation, cell survival, cellular functions, adhesion, and mediation of cell migration. The NRD1 gene codes for the protein nardilysin, an HB-EGF modulator.^[9] Zinc finger and BTB domain-containing protein 16 and BAG family molecular chaperone regulator function as co-chaperone proteins in processes involving HB-EGF.

Role in cancer

Recent studies indicate significant HB-EGF gene expression elevation in a number of human cancers as well as cancer-derived cell lines. Evidence indicates that HB-EGF plays a significant role in the development of malignant phenotypes contributing to the metastatic and invasive behaviors of tumors.^[10] The proliferative and chemotactic effects of HB-EGF results from the target influence on particular cells including fibroblasts, smooth muscles cells, and keratinocytes. For numerous cell types such as breast and ovarian tumor cells, human epithelial cells and keratinocytes HB-EGF is a potent mitogen resulting in evidenced upregulation of HB-EGF in such specimens.^[11] Both in vivo and in vitro studies of tumor formation in cancer derived cell lines indicate that expression of HB-EGF is essential for tumor development. As a result, studies implementing the use of specific HB-EGF inhibitors and monoclonal antibodies against HB-EGF show the potential for the development of novel therapies for treating cancers by targeting HB-EGF expression.^[12]

Role in cardiac development and vasculature

HB-EGF binding and activation of EGF receptors plays a critical role during cardiac valve tissue development and the maintenance of normal heart function in adults. During valve tissue development the interaction of HB-EGF with EGF receptors and heparan sulfate proteoglycans is essential for the prevention of malformation of valves due to enlargement.^[13] In the vascular system areas of disturbed flow show upregulation of HB-EGF with promotion of vascular lesions, atherogenesis, and hyperplasia of intimal tissue in vessels. The flow disturbance remodeling of the vascular tissues due to HB-EGF expression contributes to aortic valve disease, peripheral vascular disease, and conduit stenosis.^[14]

Role in wound healing

HB-EGF is the predominant growth factor in the epithelialization required for cutaneous wound healing. The mitogenic and migratory effects of HB-EGF on keratinocytes and fibroblasts promotes dermal repair and angiogenesis necessary for wound healing and is a major component of wound fluids.^[15] HB-EGF displays target cell specificity during the early stages of wound healing being released by macrophages, monocytes, and keratinocytes. HB-EGF cell surface binding to heparan sulfate proteoglycans enhances mitogen promoting capabilities increasing the rate of skin wound healing, decreasing human skin graft healing times, and promotes rapid healing of ulcers, burns, and epidermal split thickness wounds.^[16]

Role in other physiological processes

HB-EGF is recognized as an important component for the modulation of cell activity in various biological interactions. Found widely distributed in cerebral neurons and neuroglia, HB-EGF induced by brain hypoxia and or ischemia subsequently stimulates neurogenesis. Interactions between uterine HB-EGF and epidermal growth factor receptors of blastocysts influence embryo-uterine interactions and implantation.^[17] Studies show HB-EGF protects intestinal stem cells and intestinal epithelial cells in necrotizing enterocolitis, a disease affecting premature newborns. Associated with a breakdown in gut barrier function, necrotizing enterocolitis may be mediated by HB-EGF effects on intestinal mucosa.^[18] HB-EGF expressed during skeletal muscle contraction facilitates peripheral glucose removal, glucose tolerance and uptake. The upregulation of HB-EGF with exercise may explain the molecular basis for the decrease in metabolic disorders such as obesity and type 2 diabetes with regular exercise.^[19]

Further reading

• Higashiyama S, Lau K, Besner GE, etal . Structure of heparin-binding EGF-like growth factor. Multiple forms, primary structure, and glycosylation of the mature protein . J. Biol. Chem. . 267 . 9 . 6205–12 . 1992 . 10.1016/S0021-9258(18)42682-8 . 1556128 . free .
• Yoshizumi M, Kourembanas S, Temizer DH, etal . Tumor necrosis factor increases transcription of the heparin-binding epidermal growth factor-like growth factor gene in vascular endothelial cells . J. Biol. Chem. . 267 . 14 . 9467–9 . 1992 . 10.1016/S0021-9258(19)50112-0 . 1577791 . free .
• Higashiyama S, Abraham JA, Miller J, etal . A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF . Science . 251 . 4996 . 936–9 . 1991 . 1840698 . 10.1126/science.1840698 . 1991Sci...251..936H . 23639487 .
• Iwamoto R, Senoh H, Okada Y, etal . An antibody that inhibits the binding of diphtheria toxin to cells revealed the association of a 27-kDa membrane protein with the diphtheria toxin receptor . J. Biol. Chem. . 266 . 30 . 20463–9 . 1991 . 10.1016/S0021-9258(18)54947-4 . 1939101 . free .
• Hayes H, Kaneda Y, Uchida T, Okada Y . Regional assignment of the gene for diphtheria toxin sensitivity using subchromosomal fragments in microcell hybrids . Chromosoma . 96 . 1 . 26–32 . 1988 . 3436221 . 10.1007/BF00285879 . 35349033 .
• Bennett KL, Jackson DG, Simon JC, etal . CD44 isoforms containing exon V3 are responsible for the presentation of heparin-binding growth factor . J. Cell Biol. . 128 . 4 . 687–98 . 1995 . 7532176 . 10.1083/jcb.128.4.687 . 2199889 .
• Pathak BG, Gilbert DJ, Harrison CA, etal . Mouse chromosomal location of three EGF receptor ligands: amphiregulin (Areg), betacellulin (Btc), and heparin-binding EGF (Hegfl) . Genomics . 28 . 1 . 116–8 . 1995 . 7590736 . 10.1006/geno.1995.1116 .
• Mitamura T, Higashiyama S, Taniguchi N, etal . Diphtheria toxin binds to the epidermal growth factor (EGF)-like domain of human heparin-binding EGF-like growth factor/diphtheria toxin receptor and inhibits specifically its mitogenic activity . J. Biol. Chem. . 270 . 3 . 1015–9 . 1995 . 7836353 . 10.1074/jbc.270.3.1015 . free .
• Hashimoto K, Higashiyama S, Asada H, etal . Heparin-binding epidermal growth factor-like growth factor is an autocrine growth factor for human keratinocytes . J. Biol. Chem. . 269 . 31 . 20060–6 . 1994 . 10.1016/S0021-9258(17)32127-0 . 8051092 . free .
• Kobrin MS, Funatomi H, Friess H, etal . Induction and expression of heparin-binding EGF-like growth factor in human pancreatic cancer . Biochem. Biophys. Res. Commun. . 202 . 3 . 1705–9 . 1994 . 8060360 . 10.1006/bbrc.1994.2131 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Thompson SA, Higashiyama S, Wood K, etal . Characterization of sequences within heparin-binding EGF-like growth factor that mediate interaction with heparin . J. Biol. Chem. . 269 . 4 . 2541–9 . 1994 . 10.1016/S0021-9258(17)41979-X . 8300582 . free .
• Fen Z, Dhadly MS, Yoshizumi M, etal . Structural organization and chromosomal assignment of the gene encoding the human heparin-binding epidermal growth factor-like growth factor/diphtheria toxin receptor . Biochemistry . 32 . 31 . 7932–8 . 1993 . 8347598 . 10.1021/bi00082a014 .
• Elenius K, Paul S, Allison G, etal . Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation . EMBO J. . 16 . 6 . 1268–78 . 1997 . 9135143 . 10.1093/emboj/16.6.1268 . 1169725 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, etal . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Louie GV, Yang W, Bowman ME, Choe S . Crystal structure of the complex of diphtheria toxin with an extracellular fragment of its receptor . Mol. Cell . 1 . 1 . 67–78 . 1998 . 9659904 . 10.1016/S1097-2765(00)80008-8 . free .
• Borer JG, Park JM, Atala A, etal . Heparin-binding EGF-like growth factor expression increases selectively in bladder smooth muscle in response to lower urinary tract obstruction . Lab. Invest. . 79 . 11 . 1335–45 . 1999 . 10576204 .
• Nakamura K, Mitamura T, Takahashi T, etal . Importance of the major extracellular domain of CD9 and the epidermal growth factor (EGF)-like domain of heparin-binding EGF-like growth factor for up-regulation of binding and activity . J. Biol. Chem. . 275 . 24 . 18284–90 . 2000 . 10749879 . 10.1074/jbc.M907971199 . free .
• Duque JL, Adam RM, Mullen JS, etal . Heparin-binding epidermal growth factor-like growth factor is an autocrine mediator of human prostate stromal cell growth in vitro . J. Urol. . 165 . 1 . 284–8 . 2001 . 11125426 . 10.1097/00005392-200101000-00080 .
• Lin J, Hutchinson L, Gaston SM, etal . 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 . J. Biol. Chem. . 276 . 32 . 30127–32 . 2001 . 11340068 . 10.1074/jbc.M010237200 . free .

Notes and References

1. Nanba D, Higashiyama S . Dual intracellular signaling by proteolytic cleavage of membrane-anchored heparin-binding EGF-like growth factor . Cytokine Growth Factor Rev. . 15 . 1 . 13–9 . February 2004 . 14746810 . 10.1016/j.cytogfr.2003.10.002 .
2. Jin K, Mao XO, Sun Y, Xie L, Jin L, Nishi E, Klagsbrun M, Greenberg DA . Heparin-binding epidermal growth factor-like growth factor: hypoxia-inducible expression in vitro and stimulation of neurogenesis in vitro and in vivo . J. Neurosci. . 22 . 13 . 5365–73 . July 2002 . 12097488 . 10.1523/JNEUROSCI.22-13-05365.2002. free . 6758221 .
3. Raab G, Klagsbrun M . Heparin-binding EGF-like growth factor . Biochim. Biophys. Acta . 1333 . 3 . F179–99 . December 1997 . 9426203 . 10.1016/S0304-419X(97)00024-3.
4. Das SK, Wang XN, Paria BC, Damm D, Abraham JA, Klagsbrun M, Andrews GK, Dey SK . Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation . Development . 120 . 5 . 1071–83 . May 1994 . 10.1242/dev.120.5.1071 . 8026321 .
5. Nishi E, Prat A, Hospital V, Elenius K, Klagsbrun M . N-arginine dibasic convertase is a specific receptor for heparin-binding EGF-like growth factor that mediates cell migration . EMBO J. . 20 . 13 . 3342–50 . July 2001 . 11432822 . 125525 . 10.1093/emboj/20.13.3342 .
6. 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. . 163 . 3 . 489–502 . November 2003 . 14597771 . 2173632 . 10.1083/jcb.200303017 .
7. Nanba D, Toki F, Higashiyama S . Roles of charged amino acid residues in the cytoplasmic domain of proHB-EGF . Biochem. Biophys. Res. Commun. . 320 . 2 . 376–82 . July 2004 . 15219838 . 10.1016/j.bbrc.2004.05.176 .
8. Lin J, Hutchinson L, Gaston SM, Raab G, Freeman MR . 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 . J. Biol. Chem. . 276 . 32 . 30127–32 . August 2001 . 11340068 . 10.1074/jbc.M010237200 . free .
9. Hospital V, Prat A . Nardilysin, a basic residues specific metallopeptidase that mediates cell migration and proliferation . Protein Pept. Lett. . 11 . 5 . 501–8 . October 2004 . 15544571 . 10.2174/0929866043406508 .
10. 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. . 97 . 5 . 341–7 . May 2006 . 16630129 . 10.1111/j.1349-7006.2006.00188.x . 32160328 . 11159358 .
11. Nolan TM, Di Girolamo N, Coroneo MT, Wakefield D . Proliferative effects of heparin-binding epidermal growth factor-like growth factor on pterygium epithelial cells and fibroblasts . Invest. Ophthalmol. Vis. Sci. . 45 . 1 . 110–3 . January 2004 . 14691161 . 10.1167/iovs.03-0046 .
12. Miyazono K . Ectodomain shedding of HB-EGF: a potential target for cancer therapy . J. Biochem. . 151 . 1 . 1–3 . January 2012 . 21976708 . 10.1093/jb/mvr120 . free .
13. Iwamoto R, Mekada E . ErbB and HB-EGF signaling in heart development and function . Cell Struct. Funct. . 31 . 1 . 1–14 . 2006 . 16508205 . 10.1247/csf.31.1. free .
14. Zhang H, Sunnarborg SW, McNaughton KK, Johns TG, Lee DC, Faber JE . Heparin-binding epidermal growth factor-like growth factor signaling in flow-induced arterial remodeling . Circ. Res. . 102 . 10 . 1275–85 . May 2008 . 18436796 . 2752633 . 10.1161/CIRCRESAHA.108.171728 .
15. Shirakata Y, Kimura R, Nanba D, Iwamoto R, Tokumaru S, Morimoto C, Yokota K, Nakamura M, Sayama K, Mekada E, Higashiyama S, Hashimoto K . Heparin-binding EGF-like growth factor accelerates keratinocyte migration and skin wound healing . J. Cell Sci. . 118 . Pt 11 . 2363–70 . June 2005 . 15923649 . 10.1242/jcs.02346 . 17496049 .
16. Marikovsky M, Breuing K, Liu PY, Eriksson E, Higashiyama S, Farber P, Abraham J, Klagsbrun M . Appearance of heparin-binding EGF-like growth factor in wound fluid as a response to injury . Proc. Natl. Acad. Sci. U.S.A. . 90 . 9 . 3889–93 . May 1993 . 8483908 . 46411 . 10.1073/pnas.90.9.3889. 1993PNAS...90.3889M . free .
17. Leach RE, Khalifa R, Armant DR, Brudney A, Das SK, Dey SK, Fazleabas AT . Heparin-binding EGF-like growth factor modulation by antiprogestin and CG in the baboon (Papio anubis) . J. Clin. Endocrinol. Metab. . 86 . 9 . 4520–8 . September 2001 . 11549702 . 10.1210/jcem.86.9.7835. free .
18. Chen CL, Yu X, James IO, Zhang HY, Yang J, Radulescu A, Zhou Y, Besner GE . Heparin-binding EGF-like growth factor protects intestinal stem cells from injury in a rat model of necrotizing enterocolitis . Lab. Invest. . 92 . 3 . 331–44 . March 2012 . 22157721 . 10.1038/labinvest.2011.167 . 3289750.
19. Fukatsu Y, Noguchi T, Hosooka T, Ogura T, Kotani K, Abe T, Shibakusa T, Inoue K, Sakai M, Tobimatsu K, Inagaki K, Yoshioka T, Matsuo M, Nakae J, Matsuki Y, Hiramatsu R, Kaku K, Okamura H, Fushiki T, Kasuga M . Muscle-specific overexpression of heparin-binding epidermal growth factor-like growth factor increases peripheral glucose disposal and insulin sensitivity . Endocrinology . 150 . 6 . 2683–91 . June 2009 . 19264873 . 10.1210/en.2008-1647 . free .