Heparin-binding EGF-like growth factor

Last updated
HBEGF
Protein HBEGF PDB 1xdt.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases HBEGF , DTR, DTS, DTSF, HEGFL, heparin binding EGF like growth factor
External IDs OMIM: 126150 MGI: 96070 HomoloGene: 1466 GeneCards: HBEGF
Orthologs
SpeciesHumanMouse
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
View/Edit Human View/Edit Mouse

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.

Contents

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]

Related Research Articles

<span class="mw-page-title-main">Epidermal growth factor</span> Protein that stimulates cell division and differentiation

Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-kDa and has 53 amino acid residues and three intramolecular disulfide bonds.

<span class="mw-page-title-main">Amphiregulin</span> Protein-coding gene in the species Homo sapiens

Amphiregulin, also known as AREG, is a protein synthesized as a transmembrane glycoprotein with 252 aminoacids and it is encoded by the AREG gene. in humans.

<span class="mw-page-title-main">Pleiotrophin</span> Protein in humans

Pleiotrophin (PTN) also known as heparin-binding brain mitogen (HBBM) or heparin-binding growth factor 8 (HBGF-8) or neurite growth-promoting factor 1 (NEGF1) or heparin affinity regulatory peptide (HARP) or heparin binding growth associated molecule (HB-GAM) is a protein that in humans is encoded by the PTN gene. Pleiotrophin is an 18-kDa growth factor that has a high affinity for heparin. It is structurally related to midkine and retinoic acid induced heparin-binding protein.

<span class="mw-page-title-main">Diphtheria toxin</span> Exotoxin

Diphtheria toxin is an exotoxin secreted mainly by Corynebacterium diphtheriae but also by Corynebacterium ulcerans and Corynebacterium pseudotuberculosis, the pathogenic bacterium that causes diphtheria. The toxin gene is encoded by a prophage called corynephage β. The toxin causes the disease in humans by gaining entry into the cell cytoplasm and inhibiting protein synthesis.

<span class="mw-page-title-main">Midkine</span> Protein-coding gene in the species Homo sapiens

Midkine, also known as neurite growth-promoting factor 2 (NEGF2), is a protein that in humans is encoded by the MDK gene.

<span class="mw-page-title-main">SNX1</span> Protein-coding gene in the species Homo sapiens

Sorting nexin-1 is a protein that in humans is encoded by the SNX1 gene. The protein encoded by this gene is a sorting nexin. SNX1 is a component of the retromer complex.

<span class="mw-page-title-main">GRB10</span> Protein-coding gene in the species Homo sapiens

Growth factor receptor-bound protein 10 also known as insulin receptor-binding protein Grb-IR is a protein that in humans is encoded by the GRB10 gene.

<span class="mw-page-title-main">Epiregulin</span> Protein found in humans

Epiregulin (EPR) is a protein that in humans is encoded by the EREG gene.

The EGF module-containing Mucin-like hormone Receptors (EMRs) are closely related subgroup of G protein-coupled receptors (GPCRs). These receptors have a unique hybrid structure in which an extracellular epidermal growth factor (EGF)-like domain is fused to a GPCR domain through a mucin-like stalk. There are four variants of EMR labeled 1–4, each encoded by a separate gene. These receptors are predominantly expressed in cells of the immune system and bind ligands such as CD55.

<span class="mw-page-title-main">ERBB3</span> Protein found in humans

Receptor tyrosine-protein kinase erbB-3, also known as HER3, is a membrane bound protein that in humans is encoded by the ERBB3 gene.

<span class="mw-page-title-main">ERBB4</span> Protein-coding gene in the species Homo sapiens

Receptor tyrosine-protein kinase erbB-4 is an enzyme that in humans is encoded by the ERBB4 gene. Alternatively spliced variants that encode different protein isoforms have been described; however, not all variants have been fully characterized.

<span class="mw-page-title-main">Fibroblast growth factor receptor 4</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor receptor 4 is a protein that in humans is encoded by the FGFR4 gene. FGFR4 has also been designated as CD334.

<span class="mw-page-title-main">BAG1</span> Protein-coding gene in the species Homo sapiens

BAG family molecular chaperone regulator 1 is a protein that in humans is encoded by the BAG1 gene.

<span class="mw-page-title-main">EGF-like domain</span> Protein domain named after the epidermal growth factor protein

The EGF-like domain is an evolutionary conserved protein domain, which derives its name from the epidermal growth factor where it was first described. It comprises about 30 to 40 amino-acid residues and has been found in a large number of mostly animal proteins. Most occurrences of the EGF-like domain are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted. An exception to this is the prostaglandin-endoperoxide synthase. The EGF-like domain includes 6 cysteine residues which in the epidermal growth factor have been shown to form 3 disulfide bonds. The structures of 4-disulfide EGF-domains have been solved from the laminin and integrin proteins. The main structure of EGF-like domains is a two-stranded β-sheet followed by a loop to a short C-terminal, two-stranded β-sheet. These two β-sheets are usually denoted as the major (N-terminal) and minor (C-terminal) sheets. EGF-like domains frequently occur in numerous tandem copies in proteins: these repeats typically fold together to form a single, linear solenoid domain block as a functional unit.

<span class="mw-page-title-main">Syndecan-3</span> Protein-coding gene in the species Homo sapiens

Syndecan-3 is a protein that in humans is encoded by the SDC3 gene.

<span class="mw-page-title-main">Teratocarcinoma-derived growth factor 1</span> Protein-coding gene in the species Homo sapiens

Teratocarcinoma-derived growth factor 1 is a protein that in humans is encoded by the TDGF1 gene. The protein is an extracellular, membrane-bound signaling protein that plays an essential role in embryonic development and tumor growth. Mutations in this gene are associated with forebrain defects. Pseudogenes of this gene are found on chromosomes 2, 3, 6, 8, 19 and X. Alternate splicing results in multiple transcript variants.

<span class="mw-page-title-main">FGFBP1</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor-binding protein 1 is a protein that in humans is encoded by the FGFBP1 gene.

<span class="mw-page-title-main">STAB1</span> Protein-coding gene in the species Homo sapiens

Stabilin-1 is a protein that in humans is encoded by the STAB1 gene.

<span class="mw-page-title-main">NRD1</span> Protein-coding gene in the species Homo sapiens

Nardilysin is a protein that in humans is encoded by the NRD1 gene.

CRM197 is a non-toxic mutant of diphtheria toxin, currently used as a carrier protein for polysaccharides and haptens to make them immunogenic. There is some dispute about the toxicity of CRM197, with evidence that it is toxic to yeast cells and some mammalian cell lines.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000113070 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 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. 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

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.