Gene Symbol: Hbegf
Description: heparin-binding EGF-like growth factor
Alias: AW047313, Dtr, Dts, Hegfl, proheparin-binding EGF-like growth factor, diphtheria toxin receptor, heparin binding epidermal growth factor-like growth factor
Species: mouse
Products:     Hbegf

Top Publications

  1. Krishnamoorthy M, Heimburg Molinaro J, Bargo A, Nash R, Nash R. Heparin binding epidermal growth factor-like growth factor and PD169316 prevent apoptosis in mouse embryonic stem cells. J Biochem. 2009;145:177-84 pubmed publisher
    ..These results suggest a role for CD9 as an endogenous suppressor of apoptosis, an effect that is mimicked by HB-EGF and PD169316. ..
  2. Umeda Y, Miyazaki Y, Shiinoki H, Higashiyama S, Nakanishi Y, Hieda Y. Involvement of heparin-binding EGF-like growth factor and its processing by metalloproteinases in early epithelial morphogenesis of the submandibular gland. Dev Biol. 2001;237:202-11 pubmed
    ..Our results provide the first evidence that HB-EGF is a crucial regulator of epithelial morphogenesis during organ development, highlighting the importance of its processing by metalloproteinases. ..
  3. Hnasko R, Ben Jonathan N. Prolactin regulation by heparin-binding growth factors expressed in mouse pituitary cell lines. Endocrine. 2003;20:35-44 pubmed
    ..The distinct heparin-binding factor that stimulates PRL gene transcription remains to be identified. ..
  4. Wang Z, Jin C, Li H, Li C, Hou Q, Liu M, et al. GPR48-Induced keratinocyte proliferation occurs through HB-EGF mediated EGFR transactivation. FEBS Lett. 2010;584:4057-62 pubmed publisher
    ..Confirmation that GPR48 mediates EGFR signaling pathway through HB-EGF was subsequently performed using an inhibitor of HB-EGF. ..
  5. Higashiyama S, Abraham J, Miller J, Fiddes J, Klagsbrun M. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science. 1991;251:936-9 pubmed
    ..HB-EGF is also expressed in cultured human macrophages and may be involved in macrophage-mediated cellular proliferation. ..
  6. Xie H, Wang H, Tranguch S, Iwamoto R, Mekada E, DeMayo F, et al. Maternal heparin-binding-EGF deficiency limits pregnancy success in mice. Proc Natl Acad Sci U S A. 2007;104:18315-20 pubmed
    ..However, the molecular basis of this interaction is not clearly understood. Exploiting genomic Hbegf mutant mice, we show here that maternal deficiency of heparin-binding EGF-like growth factor (HB-EGF) defers on-..
  7. Abraham J, Damm D, Bajardi A, Miller J, Klagsbrun M, Ezekowitz R. Heparin-binding EGF-like growth factor: characterization of rat and mouse cDNA clones, protein domain conservation across species, and transcript expression in tissues. Biochem Biophys Res Commun. 1993;190:125-33 pubmed
    ..Northern blotting experiments using the HB-EGF clones as probes revealed HB-EGF transcript expression in multiple tissues, particularly lung, skeletal muscle, brain, and heart. ..
  8. Jin K, Mao X, Del Rio Guerra G, Jin L, Greenberg D. Heparin-binding epidermal growth factor-like growth factor stimulates cell proliferation in cerebral cortical cultures through phosphatidylinositol 3'-kinase and mitogen-activated protein kinase. J Neurosci Res. 2005;81:497-505 pubmed
    ..These findings help to clarify the molecular mechanisms through which HB-EGF operates. ..
  9. Jackson L, Qiu T, Sunnarborg S, 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 pubmed
    ..These results suggest that cardiac valvulogenesis is dependent on EGFR activation by TACE-derived soluble HB-EGF, and that EGFR signaling is required to regulate bone morphogenetic protein signaling in this context. ..

More Information


  1. Means A, Ray K, Singh A, Washington M, Whitehead R, Harris R, et al. Overexpression of heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia. Gastroenterology. 2003;124:1020-36 pubmed
    ..Many of the observed phenotypes appeared to involve altered cell adhesion. These data support a role for islet factors in the development of both endocrine and exocrine disease. ..
  2. Bollée 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 pubmed publisher
    ..This suggests that targeting the HB-EGF-EGFR pathway could also be beneficial in treatment of human RPGN. ..
  3. Higashiyama S, Nanba D. ADAM-mediated ectodomain shedding of HB-EGF in receptor cross-talk. Biochim Biophys Acta. 2005;1751:110-7 pubmed
    ..Here we focus on the ectodomain shedding of HB-EGF by ADAMs, which is not only a key event of receptor cross-talk but also a novel intercellular signaling by the carboxy-terminal fragment (CTF signal). ..
  4. 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 pubmed
  5. Das S, Wang X, Paria B, Damm D, Abraham J, Klagsbrun M, et al. 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. 1994;120:1071-83 pubmed
    ..These results suggest possible interactions between the uterine HB-EGF and blastocyst EGF-R very early in the process of implantation, earlier than any other embryo-uterine interactions defined to date at the molecular level. ..
  6. Chen X, Raab G, Deutsch U, Zhang J, Ezzell R, Klagsbrun M. Induction of heparin-binding EGF-like growth factor expression during myogenesis. Activation of the gene by MyoD and localization of the transmembrane form of the protein on the myotube surface. J Biol Chem. 1995;270:18285-94 pubmed
  7. 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 U S A. 2003;100:3221-6 pubmed
    ..In addition, constitutive tyrosine phosphorylation of both ErbB2 and ErbB4 was significantly reduced in HB(del/del) hearts. It was concluded that HB-EGF activation of receptor tyrosine kinases is essential for normal heart function. ..
  8. Raab G, Klagsbrun M. Heparin-binding EGF-like growth factor. Biochim Biophys Acta. 1997;1333:F179-99 pubmed
    ..HB-EGF has been implicated as a participant in a variety of normal physiological processes such as blastocyst implantation and wound healing, and in pathological processes such as tumor growth, SMC hyperplasia and atherosclerosis. ..
  9. Nishi E, Klagsbrun M. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a mediator of multiple physiological and pathological pathways. Growth Factors. 2004;22:253-60 pubmed
  10. Izumi Y, Hirata M, Hasuwa H, Iwamoto R, Umata T, Miyado K, et al. A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J. 1998;17:7260-72 pubmed
    ..These results suggest that MDC9 and PKCdelta are involved in the stimulus-coupled shedding of the proHB-EGF ectodomain. ..
  11. Mine N, Iwamoto R, Mekada E. HB-EGF promotes epithelial cell migration in eyelid development. Development. 2005;132:4317-26 pubmed
  12. Lue H, Yang X, Wang R, Qian W, Xu R, LYLES R, et al. LIV-1 promotes prostate cancer epithelial-to-mesenchymal transition and metastasis through HB-EGF shedding and EGFR-mediated ERK signaling. PLoS ONE. 2011;6:e27720 pubmed publisher
    ..LIV-1 could be an attractive therapeutic target for the eradication of pre-existing human prostate cancer and bone and soft tissue metastases. ..
  13. Wei J, Zhou Y, Besner G. Heparin-binding EGF-like growth factor and enteric neural stem cell transplantation in the prevention of experimental necrotizing enterocolitis in mice. Pediatr Res. 2015;78:29-37 pubmed publisher
    ..HB-EGF and NSC reduce intestinal injury and improve gut barrier function and intestinal motility in experimental NEC. Combined HB-EGF and NSC transplantation may represent a potential future therapy to prevent NEC. ..
  14. Capone C, Dabertrand F, Baron Menguy C, Chalaris A, Ghezali L, Domenga Denier V, et al. Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics. elife. 2016;5: pubmed publisher
    ..These results support the concept that the balance of TIMP3 and ADAM17 activity modulates CBF through regulation of myocyte KV channel number. ..
  15. 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 pubmed
    ..These results indicate that expression of HB-EGF and generation of its soluble form, followed by activation of EGFR and ErbB2, are pivotal processes in tRA-induced epidermal hyperplasia. ..
  16. Guo Y, Ding Q, Chen L, Ji C, Hao H, Wang J, et al. Overexpression of Heparin-Binding Epidermal Growth Factor-Like Growth Factor Mediates Liver Fibrosis in Transgenic Mice. Am J Med Sci. 2017;354:199-210 pubmed publisher
    ..Our investigation confirmed the profibrotic effect of HB-EGF on the liver using a Tg mouse model. This result may contribute to the elucidation of HB-EGF as a therapeutic target in liver fibrosis. ..
  17. Mulder G, Nijboer W, Seelen M, Sandovici M, Bos E, Melenhorst W, et al. Heparin binding epidermal growth factor in renal ischaemia/reperfusion injury. J Pathol. 2010;221:183-92 pubmed publisher
    ..Absence of HB-EGF and inhibition of the EGF receptor in the early phase of IRI has protective effects, suggesting a modulating role for HB-EGF. ..
  18. Inoue Y, Tsuruma K, Nakanishi T, Oyagi A, Ohno Y, Otsuka T, et al. Role of heparin-binding epidermal growth factor-like growth factor in light-induced photoreceptor degeneration in mouse retina. Invest Ophthalmol Vis Sci. 2013;54:3815-29 pubmed publisher
    ..It therefore warrants investigation as a potential therapeutic target for such light-induced retinal diseases as age-related macular degeneration. ..
  19. Serrano J, Scavo L, Roth J, de la Rosa E, De Pablo F. A novel chicken homeobox-containing gene expressed in neurulating embryos. Biochem Biophys Res Commun. 1993;190:270-6 pubmed
    ..Using the highly sensitive polymerase chain reaction (PCR) to amplify cDNAs from embryonic RNAs from E0 (unincubated blastoderm) to E4, we confirmed the restricted expression of this homeobox sequence to the period of neurulation (E1). ..
  20. Maier H, Meixner M, Hartmann D, Sandhoff R, Wang Eckhardt L, Zöller I, et al. Normal fur development and sebum production depends on fatty acid 2-hydroxylase expression in sebaceous glands. J Biol Chem. 2011;286:25922-34 pubmed publisher
    ..These results underline the importance of the sebaceous glands and suggest a role of specific sebaceous gland or sebum lipids, synthesized by FA2H, in the hair follicle homeostasis. ..
  21. Reese J, Binart N, Brown N, Ma W, Paria B, Das S, et al. Implantation and decidualization defects in prolactin receptor (PRLR)-deficient mice are mediated by ovarian but not uterine PRLR. Endocrinology. 2000;141:1872-81 pubmed
    ..The function of uterine PRLR remains unclear. However, the eventual loss of pregnancy in P4-treated PRLR-/- mice suggests that uterine PRLR may be essential for the support of late gestation. ..
  22. Takazaki R, Shishido Y, Iwamoto R, Mekada E. Suppression of the biological activities of the epidermal growth factor (EGF)-like domain by the heparin-binding domain of heparin-binding EGF-like Growth Factor. J Biol Chem. 2004;279:47335-43 pubmed
    ..Thus, we conclude that the heparin-binding domain serves as a negative regulator of this growth factor. ..
  23. MacGrogan D, D Amato G, Travisano S, Martínez Poveda B, Luxan G, del Monte Nieto G, et al. Sequential Ligand-Dependent Notch Signaling Activation Regulates Valve Primordium Formation and Morphogenesis. Circ Res. 2016;118:1480-97 pubmed publisher
    ..Significantly, the negative regulator of mesenchyme proliferation, Hbegf, was markedly reduced in Jag1-mutant valves...
  24. Lim J, Lee D, Song H, Kim K, Yoon T, Gye M, et al. Heparin-binding epidermal growth factor (HB-EGF) may improve embryonic development and implantation by increasing vitronectin receptor (integrin alphanubeta3) expression in peri-implantation mouse embryos. J Assist Reprod Genet. 2006;23:111-9 pubmed
    ..HB-EGF may improve implantation by accelerating expression of integrin alphanubeta3 in peri-implantation mouse embryos. ..
  25. van Blijswijk J, Schraml B, Rogers N, Whitney P, Zelenay S, Acton S, et al. Altered lymph node composition in diphtheria toxin receptor-based mouse models to ablate dendritic cells. J Immunol. 2015;194:307-15 pubmed publisher
    ..Many such models rely on transgenic diphtheria toxin receptor (DTR) expression driven by DC-restricted promoters...
  26. Ashok A, Rai N, Raza W, Pandey R, Bandyopadhyay S. Chronic cerebral hypoperfusion-induced impairment of Aβ clearance requires HB-EGF-dependent sequential activation of HIF1α and MMP9. Neurobiol Dis. 2016;95:179-93 pubmed publisher
    ..Consequently, CCH-mediated hippocampal RAGE and LRP-1 deregulation together with BBB damage impair Aβ transport and clearance where HB-EGF plays a pivotal role. ..
  27. 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 pubmed
    ..These results indicate that ectodomain shedding of proHB-EGF is essential for HB-EGF function in vivo, and that this process requires strict control. ..
  28. Liu J, Gao F, Liu Y, Dou H, Yan J, Fan Z, et al. HB-EGF regulates Prss56 expression during mouse decidualization via EGFR/ERK/EGR2 signaling pathway. J Endocrinol. 2017;234:247-254 pubmed publisher
    ..Collectively, Prss56 expression at implantation site is modulated by HB-EGF/EGFR/ERK signaling pathway and involved in mouse decidualization. ..
  29. Huotari M, Miettinen P, Palgi J, Koivisto T, Ustinov J, Harari D, et al. ErbB signaling regulates lineage determination of developing pancreatic islet cells in embryonic organ culture. Endocrinology. 2002;143:4437-46 pubmed
    ..BTC, acting through EGF-R/erbB-1, is important for the differentiation of beta-cells. This could be applied in the targeted differentiation of stem cells into insulin-producing cells. ..
  30. Hooper K, Eidels L. Glutamic acid 141 of the diphtheria toxin receptor (HB-EGF precursor) is critical for toxin binding and toxin sensitivity. Biochem Biophys Res Commun. 1996;220:675-80 pubmed
    The transmembrane precursor of the monkey heparin-binding EGF-like growth factor also functions as a diphtheria toxin receptor. The mouse precursor does not bind the toxin...
  31. Sasaki K, Omotuyi O, Ueda M, Shinohara K, Ueda H. NMDA receptor agonists reverse impaired psychomotor and cognitive functions associated with hippocampal Hbegf-deficiency in mice. Mol Brain. 2015;8:83 pubmed publisher
    ..However, little is known of such dysfunctions in hippocampus-specific Hbegf cKO mice...
  32. Yahata Y, Shirakata Y, Tokumaru S, Yang L, Dai X, Tohyama M, et al. A novel function of angiotensin II in skin wound healing. Induction of fibroblast and keratinocyte migration by angiotensin II via heparin-binding epidermal growth factor (EGF)-like growth factor-mediated EGF receptor transactivation. J Biol Chem. 2006;281:13209-16 pubmed
  33. Song H, Lim H, Paria B, Matsumoto H, Swift L, Morrow J, et al. Cytosolic phospholipase A2alpha is crucial [correction of A2alpha deficiency is crucial] for 'on-time' embryo implantation that directs subsequent development. Development. 2002;129:2879-89 pubmed
  34. He L, Marneros A. Macrophages are essential for the early wound healing response and the formation of a fibrovascular scar. Am J Pathol. 2013;182:2407-17 pubmed publisher
    ..Thus, macrophages are essential for the early wound healing response and the formation of a fibrovascular scar. ..
  35. Paria B, Ma W, Tan J, Raja S, Das S, Dey S, et al. Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors. Proc Natl Acad Sci U S A. 2001;98:1047-52 pubmed
    ..Significantly, beads containing BMP-2 do not themselves elicit an implantation response but affect the spacing of implantation sites induced by blastocysts cotransferred with the beads. ..
  36. Kera H, Yuki S, Nogawa H. FGF7 signals are relayed to autocrine EGF family growth factors to induce branching morphogenesis of mouse salivary epithelium. Dev Dyn. 2014;243:552-9 pubmed publisher
    ..Reverse transcriptase polymerase chain reaction studies showed that three members, Tgfa, Hbegf,and Nrg1 of the EGF family were expressed in the epithelium cultured with FGF7?+?LPA as well as in the epithelium ..
  37. Hayashi Y, Liu C, Jester J, Hayashi M, Wang I, Funderburgh J, et al. Excess biglycan causes eyelid malformation by perturbing muscle development and TGF-alpha signaling. Dev Biol. 2005;277:222-34 pubmed
  38. Wu L, Liu C, Jiang M, Jiang Y, Wang Q, Lu Z, et al. Defective eyelid leading edge cell migration in C57BL/6-corneal opacity mice with an "eye open at birth" phenotype. Genet Mol Res. 2016;15: pubmed publisher
    ..Quantitative real-time polymerase chain reaction analysis showed that expression of the Hbegf gene was significantly down-regulated in the eyelids of B6- Co mice at E16.5, compared to B6 mice...
  39. Richardson G, Bazzi H, Fantauzzo K, Waters J, Crawford H, Hynd P, et al. KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin. Development. 2009;136:2153-64 pubmed publisher
    ..of primary pelage and whisker follicle development is exposed to increased levels of two ectopic EGFR ligands (HBEGF and amphiregulin) and the FGFR2(IIIb) receptor ligand KGF, follicle formation is inhibited in a time- and dose-..
  40. Oyagi A, Oida Y, Kakefuda K, Shimazawa M, Shioda N, Moriguchi S, et al. Generation and characterization of conditional heparin-binding EGF-like growth factor knockout mice. PLoS ONE. 2009;4:e7461 pubmed publisher
    ..These results suggest the alterations affecting HB-EGF signaling could comprise a contributing factor in psychiatric disorder. ..
  41. Kawasaki H, Saotome T, Usui T, Ohama T, Sato K. Regulation of intestinal myofibroblasts by KRas-mutated colorectal cancer cells through heparin-binding epidermal growth factor-like growth factor. Oncol Rep. 2017;37:3128-3136 pubmed publisher
    ..These results suggest that HB-EGF secreted from KRas-mutated colorectal cancer cells promotes IMF migration through ERK and JNK activation, which, in turn, could support cancer progression. ..
  42. Monslow J, Sato N, Mack J, Maytin E. Wounding-induced synthesis of hyaluronic acid in organotypic epidermal cultures requires the release of heparin-binding egf and activation of the EGFR. J Invest Dermatol. 2009;129:2046-58 pubmed publisher
    ..In summary, rapid HA accumulation after epidermal wounding occurs through a mechanism requiring cleavage of HB-EGF and activation of EGFR signaling. ..
  43. Hosur V, Johnson K, Burzenski L, Stearns T, Maser R, Shultz L. Rhbdf2 mutations increase its protein stability and drive EGFR hyperactivation through enhanced secretion of amphiregulin. Proc Natl Acad Sci U S A. 2014;111:E2200-9 pubmed publisher
    ..This work underscores the physiological prominence of iRhom2 in controlling EGFR signaling events involved in wound healing and neoplastic growth, and yields insight into the function of key iRhom2 domains. ..
  44. Robey R, Ma J, Santos A, Noboa O, Coy P, Bryson J. Regulation of mesangial cell hexokinase activity and expression by heparin-binding epidermal growth factor-like growth factor: epidermal growth factors and phorbol esters increase glucose metabolism via a common mechanism involving classic mitogen-ac. J Biol Chem. 2002;277:14370-8 pubmed
    ..These findings suggest a novel mechanism whereby growth factors may couple metabolism to glomerular injury. ..
  45. Liu Z, Armant D. Lysophosphatidic acid regulates murine blastocyst development by transactivation of receptors for heparin-binding EGF-like growth factor. Exp Cell Res. 2004;296:317-26 pubmed
    ..Transactivation of ErbB1 or ErbB4 by HB-EGF could represent a convergent signaling pathway accessed in the trophoblast by stimuli that mobilize Ca2+(i). ..
  46. Pascall J, Ellis P, Brown K. Characterisation of the rat heparin-binding epidermal growth factor-like growth factor gene promoter. Biochim Biophys Acta. 2000;1492:434-40 pubmed
    ..Additional studies are therefore required to identify Raf/MAP kinase responsive elements in the HB-EGF gene. ..
  47. Zhang X, Liang X, Wang T, Liang X, Zuo R, Deng W, et al. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) induction on Snail expression during mouse decidualization. Mol Cell Endocrinol. 2013;381:272-9 pubmed publisher
    ..Cox-2 was regulated by Snail. The current findings demonstrate that Snail can relate with HB-EGF, Stat3 and Cox-2 and may play a role during mouse embryo implantation and decidualization. ..
  48. Smith J, Pozzi A, Dhawan P, Singh A, Harris R. Soluble HB-EGF induces epithelial-to-mesenchymal transition in inner medullary collecting duct cells by upregulating Snail-2. Am J Physiol Renal Physiol. 2009;296:F957-65 pubmed publisher
    ..In summary, sustained exposure to sHB-EGF induces epithelial-to-mesenchymal transition of IMCD cells, in part by upregulating the E-cadherin transcriptional repressor Snail-2. ..
  49. Radulescu A, Zhang H, Chen C, Chen Y, Zhou Y, Yu X, et al. Heparin-binding EGF-like growth factor promotes intestinal anastomotic healing. J Surg Res. 2011;171:540-50 pubmed publisher
    ..WT mice that received HB-EGF had increased bursting pressures compared with non-HB-EGF treated mice. Our results demonstrate that HB-EGF is an important factor involved in the healing of intestinal anastomoses. ..
  50. Yu S, Geng Q, Ma J, Sun F, Yu Y, Pan Q, et al. Heparin-binding EGF-like growth factor and miR-1192 exert opposite effect on Runx2-induced osteogenic differentiation. Cell Death Dis. 2013;4:e868 pubmed publisher
    ..Runx2 specifically binds to the Hbegf promoter, suggesting that Hbegf transcription is directly inhibited by Runx2...
  51. Jin N, Cho S, Raso M, Wistuba I, Smith Y, Yang Y, et al. Mig-6 is required for appropriate lung development and to ensure normal adult lung homeostasis. Development. 2009;136:3347-56 pubmed publisher
    ..These results demonstrate that Mig-6 is required for prenatal and perinatal lung development, in part through the regulation of EGF signaling, as well as for maintaining proper pulmonary vascularization. ..
  52. Chalothorn D, Moore S, Zhang H, Sunnarborg S, Lee D, Faber J. Heparin-binding epidermal growth factor-like growth factor, collateral vessel development, and angiogenesis in skeletal muscle ischemia. Arterioscler Thromb Vasc Biol. 2005;25:1884-90 pubmed
    ..This argues against compensation by other EGF receptor ligands. Our results suggest that HB-EGF is not required for arteriogenesis or angiogenesis in hindlimb ischemia. ..
  53. Ling S, Chang X, Schultz L, Lee T, Chaux A, Marchionni L, et al. An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer. Cancer Res. 2011;71:3812-21 pubmed publisher
    ..These results identify a novel, potentially oncogenic signaling axis linking urothelial injury to UroCa. Inhibiting this axis is feasible through a variety of pharmacologic approaches and may have clinical utility...
  54. Prince R, Schreiter E, Zou P, Wiley H, Ting A, Lee R, 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 pubmed publisher
  55. Zhang H, Chalothorn D, Jackson L, Lee D, Faber J. Transactivation of epidermal growth factor receptor mediates catecholamine-induced growth of vascular smooth muscle. Circ Res. 2004;95:989-97 pubmed
    ..This trophic pathway may link sympathetic activity to arterial wall growth in adaptive remodeling and hypertrophic disease. ..
  56. Sierro F, Biben C, Martínez Muñoz L, Mellado M, Ransohoff R, Li M, et al. Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proc Natl Acad Sci U S A. 2007;104:14759-64 pubmed
    ..Our results reveal a specialized role for CXCR7 in endothelial biology and valve development and highlight the distinct developmental role of evolutionary conserved chemokine receptors such as CXCR7 and CXCR4. ..
  57. Benson G, Lim H, Paria B, Satokata I, Dey S, Maas R. Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression. Development. 1996;122:2687-96 pubmed
    ..These results show that Hoxa-10 is required during morphogenesis for proper patterning of the reproductive tract and in the adult uterus for peri-implantation events. ..
  58. Yang J, Radulescu A, Chen C, Zhang H, James I, Besner G. Heparin-binding epidermal growth factor-like growth factor improves intestinal barrier function and reduces mortality in a murine model of peritonitis. Surgery. 2013;153:52-62 pubmed publisher
    ..05). HB-EGF gene KO increases susceptibility to peritonitis-induced intestinal injury, which can be reversed by administration of HB-EGF. These results support a protective role of HB-EGF in peritonitis-induced sepsis. ..
  59. Iwamoto R, Mine N, Mizushima H, Mekada E. ErbB1 and ErbB4 generate opposing signals regulating mesenchymal cell proliferation during valvulogenesis. J Cell Sci. 2017;130:1321-1332 pubmed publisher
    ..Our study demonstrates that opposing signals generated by different ErbB dimer combinations function in the same cardiac cushion mesenchymal cells for proper cardiac valve formation. ..
  60. Sakamoto K, Khai N, Wang Y, Irie R, Takamatsu H, Matsufuji H, et al. Heparin-binding epidermal growth factor-like growth factor and hepatocyte growth factor inhibit cholestatic liver injury in mice through different mechanisms. Int J Mol Med. 2016;38:1673-1682 pubmed publisher
    ..Our results contribute to a better understanding of the pathophysiologic roles of HB-EGF and HGF, as well as to the development of novel effective therapies for cholestatic liver injuries. ..
  61. Caric D, Raphael H, Viti J, Feathers A, Wancio D, Lillien L. EGFRs mediate chemotactic migration in the developing telencephalon. Development. 2001;128:4203-16 pubmed
    ..Our findings suggest that developmental changes in EGFR expression, together with changes in ligand expression regulate the migration of specific populations of cells in the telencephalon by a chemoattractive mechanism. ..
  62. Assimacopoulos S, Grove E, Ragsdale C. Identification of a Pax6-dependent epidermal growth factor family signaling source at the lateral edge of the embryonic cerebral cortex. J Neurosci. 2003;23:6399-403 pubmed
    ..We find that the antihem is lost in mice homozygous for the Small eye (Pax6) mutation and suggest the loss of EGF signaling at least partially explains defects in cortical patterning and cell migration in Small eye mice. ..
  63. Edwards J, Zhang X, Mosser D. The expression of heparin-binding epidermal growth factor-like growth factor by regulatory macrophages. J Immunol. 2009;182:1929-39 pubmed publisher
    ..These observations indicate that in addition to the secretion of the anti-inflammatory cytokine IL-10, another novel characteristic of regulatory macrophages is the production of angiogenic HB-EGF. ..
  64. Zeng F, Kloepfer L, Finney C, Diedrich A, Harris R. Specific endothelial heparin-binding EGF-like growth factor deletion ameliorates renal injury induced by chronic angiotensin II infusion. Am J Physiol Renal Physiol. 2016;311:F695-F707 pubmed publisher
    ..Inhibition of HB-EGF shedding could be a potential therapeutic strategy for chronic kidney disease. ..
  65. Oyagi A, Moriguchi S, Nitta A, Murata K, Oida Y, Tsuruma K, et al. Heparin-binding EGF-like growth factor is required for synaptic plasticity and memory formation. Brain Res. 2011;1419:97-104 pubmed publisher
    ..These results confirm the importance of the HB-EGF in synaptic plasticity and memory formation. ..
  66. Yan F, Liu L, Dempsey P, Tsai Y, Raines E, Wilson C, et al. A Lactobacillus rhamnosus GG-derived soluble protein, p40, stimulates ligand release from intestinal epithelial cells to transactivate epidermal growth factor receptor. J Biol Chem. 2013;288:30742-51 pubmed publisher
    ..Thus, these data define a mechanism of a probiotic-derived soluble protein in modulating intestinal epithelial cell homeostasis through ADAM17-mediated HB-EGF release, leading to transactivation of EGFR. ..
  67. Mitchell C, Nivison M, Jackson L, Fox R, Lee D, Campbell J, et al. Heparin-binding epidermal growth factor-like growth factor links hepatocyte priming with cell cycle progression during liver regeneration. J Biol Chem. 2005;280:2562-8 pubmed
    ..Moreover, we show that hepatocyte DNA replication was delayed in HB-EGF knock-out mice. In summary, we show that HB-EGF is a key factor for hepatocyte progression through G(1)/S transition during liver regeneration. ..
  68. Puschmann T, Zandén C, Lebkuechner I, Philippot C, de Pablo Y, Liu J, et al. HB-EGF affects astrocyte morphology, proliferation, differentiation, and the expression of intermediate filament proteins. J Neurochem. 2014;128:878-89 pubmed publisher
  69. Zhou Z, Harding P. Amino-terminal deletion of heparin-binding epidermal growth factor-like growth factor4-127 stimulates cell proliferation but lacks insulin-like activity. Cell Prolif. 2007;40:213-30 pubmed
  70. Zhang H, Sunnarborg S, McNaughton K, Johns T, Lee D, Faber J. Heparin-binding epidermal growth factor-like growth factor signaling in flow-induced arterial remodeling. Circ Res. 2008;102:1275-85 pubmed publisher
    ..These findings suggest that HB-EGF signaling is required for low flow-induced hypertrophic remodeling and may participate in vascular wall disease and remodeling. ..
  71. Van Leuven F, Hilliker C, Serneels L, Umans L, Overbergh L, De Strooper B, et al. Cloning, characterization, and chromosomal localization to 4p16 of the human gene (LRPAP1) coding for the alpha 2-macroglobulin receptor-associated protein and structural comparison with the murine gene coding for the 44-kDa heparin-binding protein. Genomics. 1995;25:492-500 pubmed
    ..The first patient, with karyotype 46,XY,del4(p14-p16.1), had retained both copies of the LRPAP1 gene. In contrast, the other patient, with karyotype 46,XY,del4(p15.3-pter), displayed no signal for LRPAP1 on the deleted chromosome. ..
  72. Nanba D, Kinugasa Y, Morimoto C, Koizumi M, Yamamura H, Takahashi K, et al. Loss of HB-EGF in smooth muscle or endothelial cell lineages causes heart malformation. Biochem Biophys Res Commun. 2006;350:315-21 pubmed
    ..These results suggest that expression of HB-EGF in smooth muscle and/or endothelial cell lineages is essential for proper heart development and function in mice. ..
  73. 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. 2013;437:185-91 pubmed publisher
    ..In conclusion, our data suggest a possible protective role of HB-EGF in cholestatic liver fibrosis. ..
  74. Nakagawa T, Guichard A, Castro C, Xiao Y, Rizen M, Zhang H, et al. Characterization of a human rhomboid homolog, p100hRho/RHBDF1, which interacts with TGF-alpha family ligands. Dev Dyn. 2005;233:1315-31 pubmed
    ..The characterization of this protein extends our understanding of the rhomboid family of regulatory proteins. ..
  75. Sisson T, Mendez M, Choi K, Subbotina N, Courey A, Cunningham A, et al. Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. Am J Respir Crit Care Med. 2010;181:254-63 pubmed publisher
    ..A transgenic mouse was generated to express the human diphtheria toxin receptor on type II alveolar epithelial cells...
  76. Lian H, Ma Y, Feng J, Dong W, Yang Q, Lu D, et al. Heparin-binding EGF-like growth factor induces heart interstitial fibrosis via an Akt/mTor/p70s6k pathway. PLoS ONE. 2012;7:e44946 pubmed publisher
    ..HB-EGF-induced proliferation was completely diminished in the presence of Rapa. These results suggest that HB-EGF induced heart fibrosis and proliferation of cardiac fibroblasts occurs through activation of the Akt/mTor/p70s6k pathway. ..
  77. Jiang S, Chiou Y, Wang E, Lin H, Lin Y, Chi Y, et al. Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of Pkd1. Am J Pathol. 2006;168:205-20 pubmed
    ..Abnormalities in Na(+)/K(+)-ATPase, aquaporin-2, and vasopressin V2 receptor expression were also identified. This mouse model may be suitable for further studies of progression and therapeutic interventions of ADPKD. ..
  78. Ozbilgin M, Aktas C, Uluer E, Buyukuysal M, Gareveran M, Kurtman C. Influence of Radiation Exposure During Radiotherapy. Evidence for the Increase of Versican and Heparin-Binding EGF-like Growth Factor Concentrations. Anal Quant Cytopathol Histpathol. 2016;38:126-32 pubmed
    ..The observed increase of versican and HB-EGF concentrations in the normal tissue matrix after radiation exposure may play a role in the side effects of radiotherapy. ..
  79. 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 pubmed publisher
  80. Santa Maria P, Gottlieb P, Santa Maria C, Kim S, Puria S, Yang Y. Functional Outcomes of Heparin-Binding Epidermal Growth Factor-Like Growth Factor for Regeneration of Chronic Tympanic Membrane Perforations in Mice. Tissue Eng Part A. 2017;23:436-444 pubmed publisher
  81. Sinclair N, Ai W, Raychowdhury R, Bi M, Wang T, Koh T, et al. Gastrin regulates the heparin-binding epidermal-like growth factor promoter via a PKC/EGFR-dependent mechanism. Am J Physiol Gastrointest Liver Physiol. 2004;286:G992-9 pubmed
    ..The cis-acting element mediating gastrin responsiveness was mapped to the -69 to -58 region of the HB-EGF promoter. Gastrin stimulation was PKC dependent and at least partially mediated by activation of the EGF receptor. ..
  82. Pathak B, Gilbert D, Harrison C, Luetteke N, Chen X, Klagsbrun M, et al. Mouse chromosomal location of three EGF receptor ligands: amphiregulin (Areg), betacellulin (Btc), and heparin-binding EGF (Hegfl). Genomics. 1995;28:116-8 pubmed
    The products of five distinct loci, Egf, Tgfa, Areg, Btc, and Hegfl act as ligands for the epidermal growth factor receptor...
  83. Ongusaha P, Kwak J, Zwible A, Macip S, Higashiyama S, Taniguchi N, et al. HB-EGF is a potent inducer of tumor growth and angiogenesis. Cancer Res. 2004;64:5283-90 pubmed
    ..These findings establish s-HB-EGF as a potent inducer of tumor growth and angiogenesis and suggest that therapeutic intervention aimed at the inhibition of s-HB-EGF functions may be useful in cancer treatment. ..