Heparin-binding EGF-like growth factor

HBEGF
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1XDT, 2M8S
Identifiers
Aliases	HBEGF , DTR, DTS, DTSF, HEGFL, heparin binding EGF like growth factor
External IDs	OMIM: 126150; MGI: 96070; HomoloGene: 1466; GeneCards: HBEGF; OMA:HBEGF - orthologs
Gene location (Human) Chr. Chromosome 5 (human) [1] Band 5q31.3 Start 140,332,843 bp [1] End 140,346,603 bp [1]
Gene location (Mouse) Chr. Chromosome 18 (mouse) [2] Band 18 B2|18 19.46 cM Start 36,637,980 bp [2] End 36,648,858 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in synovial joint gallbladder mucosa of urinary bladder lower lobe of lung synovial membrane upper lobe of left lung Skeletal muscle tissue of rectus abdominis pericardium skin of thigh apex of heart Top expressed in ankle ankle joint decidua muscle of thigh sciatic nerve triceps brachii muscle endothelial cell of lymphatic vessel lumbar subsegment of spinal cord epithelium of lens right lung More reference expression data BioGPS More reference expression data
Gene ontology Molecular function growth factor activity heparin binding protein tyrosine kinase activity phosphatidylinositol-4,5-bisphosphate 3-kinase activity epidermal growth factor receptor binding Cellular component extracellular region endocytic vesicle membrane integral component of membrane membrane cell surface plasma membrane clathrin-coated endocytic vesicle membrane integral component of plasma membrane extracellular space clathrin-coated vesicle membrane Biological process positive regulation of keratinocyte migration cell chemotaxis MAPK cascade signal transduction wound healing, spreading of epidermal cells positive regulation of cell migration positive regulation of cell growth muscle organ development positive regulation of smooth muscle cell proliferation regulation of heart contraction negative regulation of elastin biosynthetic process cell migration positive regulation of wound healing epidermal growth factor receptor signaling pathway ERBB2 signaling pathway phosphatidylinositol phosphate biosynthetic process peptidyl-tyrosine phosphorylation regulation of cell motility positive regulation of cell population proliferation positive regulation of peptidyl-tyrosine phosphorylation regulation of signaling receptor activity positive regulation of protein kinase B signaling negative regulation of epidermal growth factor receptor signaling pathway membrane organization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1839 15200 Ensembl ENSG00000113070 ENSMUSG00000024486 UniProt Q99075 Q06186 RefSeq (mRNA) NM_001945 NM_010415 RefSeq (protein) NP_001936 NP_034545 Location (UCSC) Chr 5: 140.33 – 140.35 Mb Chr 18: 36.64 – 36.65 Mb PubMed search [3] [4]
Wikidata
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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. ^[5] 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. ^[6] 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. ^[7] HB-EGF can bind two locations on cell surfaces: heparan sulfate proteoglycans and EGF-receptors effecting cell-to-cell interactions. ^[8]

Interactions

Heparin-binding EGF-like growth factor has been shown to interact with NRD1, ^[9] Zinc finger and BTB domain-containing protein 16 ^{[10] [11]} and BAG1. ^[12]

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. ^[13] 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. ^[14] 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. ^[15] 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. ^[16]

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. ^[17] 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. ^[18]

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. ^[19] 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. ^[20]

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. ^[6] Interactions between uterine HB-EGF and epidermal growth factor receptors of blastocysts influence embryo-uterine interactions and implantation. ^[21] 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. ^[22] 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. ^[23]

References

1. GRCh38: Ensembl release 89: ENSG00000113070 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024486 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Nanba D, Higashiyama S (February 2004). "Dual intracellular signaling by proteolytic cleavage of membrane-anchored heparin-binding EGF-like growth factor". Cytokine Growth Factor Rev. 15 (1): 13–9. doi:10.1016/j.cytogfr.2003.10.002. PMID   14746810.
6. Jin K, Mao XO, Sun Y, Xie L, Jin L, Nishi E, Klagsbrun M, Greenberg DA (July 2002). "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. doi: 10.1523/JNEUROSCI.22-13-05365.2002 . PMC   6758221 . PMID   12097488.
7. Raab G, Klagsbrun M (December 1997). "Heparin-binding EGF-like growth factor". Biochim. Biophys. Acta. 1333 (3): F179–99. doi:10.1016/S0304-419X(97)00024-3. PMID   9426203.
8. Das SK, Wang XN, Paria BC, Damm D, Abraham JA, Klagsbrun M, Andrews GK, Dey SK (May 1994). "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. doi:10.1242/dev.120.5.1071. PMID   8026321.
9. Nishi E, Prat A, Hospital V, Elenius K, Klagsbrun M (July 2001). "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. doi:10.1093/emboj/20.13.3342. PMC   125525 . PMID   11432822.
10. Nanba D, Mammoto A, Hashimoto K, Higashiyama S (November 2003). "Proteolytic release of the carboxy-terminal fragment of proHB-EGF causes nuclear export of PLZF". J. Cell Biol. 163 (3): 489–502. doi:10.1083/jcb.200303017. PMC   2173632 . PMID   14597771.
11. Nanba D, Toki F, Higashiyama S (July 2004). "Roles of charged amino acid residues in the cytoplasmic domain of proHB-EGF". Biochem. Biophys. Res. Commun. 320 (2): 376–82. doi:10.1016/j.bbrc.2004.05.176. PMID   15219838.
12. Lin J, Hutchinson L, Gaston SM, Raab G, Freeman MR (August 2001). "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. doi: 10.1074/jbc.M010237200 . PMID   11340068.
13. Hospital V, Prat A (October 2004). "Nardilysin, a basic residues specific metallopeptidase that mediates cell migration and proliferation". Protein Pept. Lett. 11 (5): 501–8. doi:10.2174/0929866043406508. PMID   15544571.
14. Miyamoto S, Yagi H, Yotsumoto F, Kawarabayashi T, Mekada E (May 2006). "Heparin-binding epidermal growth factor-like growth factor as a novel targeting molecule for cancer therapy". Cancer Sci. 97 (5): 341–7. doi:10.1111/j.1349-7006.2006.00188.x. PMC   11159358 . PMID   16630129. S2CID   32160328.
15. Nolan TM, Di Girolamo N, Coroneo MT, Wakefield D (January 2004). "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. doi:10.1167/iovs.03-0046. PMID   14691161.
16. Miyazono K (January 2012). "Ectodomain shedding of HB-EGF: a potential target for cancer therapy". J. Biochem. 151 (1): 1–3. doi: 10.1093/jb/mvr120 . PMID   21976708.
17. Iwamoto R, Mekada E (2006). "ErbB and HB-EGF signaling in heart development and function". Cell Struct. Funct. 31 (1): 1–14. doi: 10.1247/csf.31.1 . PMID   16508205.
18. Zhang H, Sunnarborg SW, McNaughton KK, Johns TG, Lee DC, Faber JE (May 2008). "Heparin-binding epidermal growth factor-like growth factor signaling in flow-induced arterial remodeling". Circ. Res. 102 (10): 1275–85. doi:10.1161/CIRCRESAHA.108.171728. PMC   2752633 . PMID   18436796.
19. Shirakata Y, Kimura R, Nanba D, Iwamoto R, Tokumaru S, Morimoto C, Yokota K, Nakamura M, Sayama K, Mekada E, Higashiyama S, Hashimoto K (June 2005). "Heparin-binding EGF-like growth factor accelerates keratinocyte migration and skin wound healing". J. Cell Sci. 118 (Pt 11): 2363–70. doi:10.1242/jcs.02346. PMID   15923649. S2CID   17496049.
20. Marikovsky M, Breuing K, Liu PY, Eriksson E, Higashiyama S, Farber P, Abraham J, Klagsbrun M (May 1993). "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. Bibcode:1993PNAS...90.3889M. doi: 10.1073/pnas.90.9.3889 . PMC   46411 . PMID   8483908.
21. Leach RE, Khalifa R, Armant DR, Brudney A, Das SK, Dey SK, Fazleabas AT (September 2001). "Heparin-binding EGF-like growth factor modulation by antiprogestin and CG in the baboon (Papio anubis)". J. Clin. Endocrinol. Metab. 86 (9): 4520–8. doi: 10.1210/jcem.86.9.7835 . PMID   11549702.
22. Chen CL, Yu X, James IO, Zhang HY, Yang J, Radulescu A, Zhou Y, Besner GE (March 2012). "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. doi:10.1038/labinvest.2011.167. PMC   3289750 . PMID   22157721.
23. 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 (June 2009). "Muscle-specific overexpression of heparin-binding epidermal growth factor-like growth factor increases peripheral glucose disposal and insulin sensitivity". Endocrinology. 150 (6): 2683–91. doi: 10.1210/en.2008-1647 . PMID   19264873.

Further reading

• Higashiyama S, Lau K, Besner GE, et al. (1992). "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. doi: 10.1016/S0021-9258(18)42682-8 . PMID   1556128.
• Yoshizumi M, Kourembanas S, Temizer DH, et al. (1992). "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. doi: 10.1016/S0021-9258(19)50112-0 . PMID   1577791.
• Higashiyama S, Abraham JA, Miller J, et al. (1991). "A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF". Science. 251 (4996): 936–9. Bibcode:1991Sci...251..936H. doi:10.1126/science.1840698. PMID   1840698. S2CID   23639487.
• Iwamoto R, Senoh H, Okada Y, et al. (1991). "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. doi: 10.1016/S0021-9258(18)54947-4 . PMID   1939101.
• Hayes H, Kaneda Y, Uchida T, Okada Y (1988). "Regional assignment of the gene for diphtheria toxin sensitivity using subchromosomal fragments in microcell hybrids". Chromosoma. 96 (1): 26–32. doi:10.1007/BF00285879. PMID   3436221. S2CID   35349033.
• Bennett KL, Jackson DG, Simon JC, et al. (1995). "CD44 isoforms containing exon V3 are responsible for the presentation of heparin-binding growth factor". J. Cell Biol. 128 (4): 687–98. doi:10.1083/jcb.128.4.687. PMC   2199889 . PMID   7532176.
• Pathak BG, Gilbert DJ, Harrison CA, et al. (1995). "Mouse chromosomal location of three EGF receptor ligands: amphiregulin (Areg), betacellulin (Btc), and heparin-binding EGF (Hegfl)". Genomics. 28 (1): 116–8. doi:10.1006/geno.1995.1116. PMID   7590736.
• Mitamura T, Higashiyama S, Taniguchi N, et al. (1995). "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. doi: 10.1074/jbc.270.3.1015 . PMID   7836353.
• Hashimoto K, Higashiyama S, Asada H, et al. (1994). "Heparin-binding epidermal growth factor-like growth factor is an autocrine growth factor for human keratinocytes". J. Biol. Chem. 269 (31): 20060–6. doi: 10.1016/S0021-9258(17)32127-0 . PMID   8051092.
• Kobrin MS, Funatomi H, Friess H, et al. (1994). "Induction and expression of heparin-binding EGF-like growth factor in human pancreatic cancer". Biochem. Biophys. Res. Commun. 202 (3): 1705–9. doi:10.1006/bbrc.1994.2131. PMID   8060360.
• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID   8125298.
• Thompson SA, Higashiyama S, Wood K, et al. (1994). "Characterization of sequences within heparin-binding EGF-like growth factor that mediate interaction with heparin". J. Biol. Chem. 269 (4): 2541–9. doi: 10.1016/S0021-9258(17)41979-X . PMID   8300582.
• Fen Z, Dhadly MS, Yoshizumi M, et al. (1993). "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. doi:10.1021/bi00082a014. PMID   8347598.
• Elenius K, Paul S, Allison G, et al. (1997). "Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation". EMBO J. 16 (6): 1268–78. doi:10.1093/emboj/16.6.1268. PMC   1169725 . PMID   9135143.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID   9373149.
• Louie GV, Yang W, Bowman ME, Choe S (1998). "Crystal structure of the complex of diphtheria toxin with an extracellular fragment of its receptor". Mol. Cell. 1 (1): 67–78. doi: 10.1016/S1097-2765(00)80008-8 . PMID   9659904.
• Borer JG, Park JM, Atala A, et al. (1999). "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. PMID   10576204.
• Nakamura K, Mitamura T, Takahashi T, et al. (2000). "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. doi: 10.1074/jbc.M907971199 . PMID   10749879.
• Duque JL, Adam RM, Mullen JS, et al. (2001). "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. doi:10.1097/00005392-200101000-00080. PMID   11125426.
• Lin J, Hutchinson L, Gaston SM, et al. (2001). "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. doi: 10.1074/jbc.M010237200 . PMID   11340068.

External links

• heparin-binding EGF-like growth factor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)