Characterization of sequences within heparin-binding EGF-like growth factor that mediate interaction with heparin.

Heparin-binding (HB) epidermal growth factor (EGF)-like growth factor (HB-EGF), a member of the EGF protein family, is a potent mitogen for fibroblasts, smooth muscle cells, and keratinocytes that was initially identified as a secreted product of macrophage-like cells. HB-EGF and EGF appear to act on target cells utilizing the same receptor, but HB-EGF is distinguishable from EGF by its strong affinity for heparin. To facilitate studies of structure-function relationships in HB-EGF, a bacterial recombinant expression system was established that produced biologically active HB-EGF with the expected disulfide bonding pattern. Mutagenesis and protease digestion studies of the recombinant HB-EGF, coupled with heparin-binding analyses of synthetic peptides, indicated that the sequences within HB-EGF mediating its interaction with heparin are located primarily in a stretch of 21 amino acids characterized by a high content of lysine and arginine residues. Most of this heparin-binding domain lies in an amino-terminal region of HB-EGF that has no counterpart in EGF, but a portion of the 21-residue sequence extends into the EGF-like region of HB-EGF. In addition, the mutagenesis and synthetic peptide studies indicated that sequences in HB-EGF lying outside of the 21-residue stretch can also influence the interaction with heparin. Finally, a synthetic peptide derived from the 21-residue stretch was found to compete with HB-EGF for binding to Chinese hamster ovary cells, suggesting that the heparin-binding sequences in HB-EGF may also mediate the interaction of this factor with cell surface heparan sulfate proteoglycan.

• Publication year

  1994

• Venue

  Journal of Biological Chemistry

• Publication date

  1994-01-28

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1016/S0021-9258(17)41979-XPMID 8300582
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Heparin-binding transforming growth factor alpha-Pseudomonas exotoxin A. A heparan sulfate-modulated recombinant toxin cytotoxic to cancer cells and proliferating smooth muscle cells.

  1993cited by this paper
• Heparin-binding EGF-like growth factor stimulation of smooth muscle cell migration: dependence on interactions with cell surface heparan sulfate

  1993cited by this paper
• An essential heparin-binding domain in the fibroblast growth factor receptor kinase.

  1993cited by this paper
• Betacellulin: a mitogen from pancreatic beta cell tumors.

  1993cited by this paper
• Developmental regulation of neural response to FGF-1 and FGF-2 by heparan sulfate proteoglycan.

  1993cited by this paper
• Heparin-binding EGF-like growth factor: characterization of rat and mouse cDNA clones, protein domain conservation across species, and transcript expression in tissues.

  1993cited by this paper
• Interaction of heparin-binding EGF-like growth factor (HB-EGF) with the epidermal growth factor receptor: modulation by heparin, heparinase, or synthetic heparin-binding HB-EGF fragments.

  1992cited by this paper
• Basic fibroblast growth factor is internalized through both receptor-mediated and heparan sulfate-mediated mechanisms.

  1992cited by this paper
• Identification of Heregulin, a Specific Activator of p185erbB2

  1992cited by this paper
• The binding of vascular endothelial growth factor to its receptors is dependent on cell surface-associated heparin-like molecules.

  1992cited by this paper
• Repression of myogenic differentiation by aFGF, bFGF, and K-FGF is dependent on cellular heparan sulfate

  1992cited by this paper
• Heparin is required for cell-free binding of basic fibroblast growth factor to a soluble receptor and for mitogenesis in whole cells

  1992cited by this paper
• Neu differentiation factor: a transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit.

  1992cited by this paper
• Inhibition of autonomous human keratinocyte proliferation and amphiregulin mitogenic activity by sulfated polysaccharides

  1992cited by this paper
• Structure of heparin-binding EGF-like growth factor. Multiple forms, primary structure, and glycosylation of the mature protein.

  1992cited by this paper
• Compartmentalization of PDGF on extracellular binding sites dependent on exon-6-encoded sequences

  1992cited by this paper
• Induction of heparin-binding epidermal growth factor-like growth factor mRNA by phorbol ester and angiotensin II in rat aortic smooth muscle cells.

  1992cited by this paper
• Ligand specificity and heparin dependence of fibroblast growth factor receptors 1 and 3.

  1992cited by this paper
• A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF

  1991cited by this paper
• Proteoglycans as modulators of growth factor activities.

  1991cited by this paper
• Expression of two different forms of fibroblast growth factor receptor 1 in different mouse tissues and cell lines.

  1991cited by this paper
• Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor.

  1991cited by this paper
• A dual receptor system is required for basic fibroblast growth factor activity.

  1991cited by this paper
• Identification of a cell retention signal in the B-chain of platelet-derived growth factor and in the long splice version of the A-chain.

  1991cited by this paper
• A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin

  1991cited by this paper
• The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA.

  1991cited by this paper
• Identification of heparan sulfate proteoglycan as a high affinity receptor for acidic fibroblast growth factor (aFGF) in a parathyroid cell line.

  1991cited by this paper
• Glycosaminoglycans: molecular properties, protein interactions, and role in physiological processes.

  1991cited by this paper
• Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation

  1991cited by this paper
• Isolation and characterization of a macrophage-derived heparin-binding growth factor.

  1990cited by this paper
• Structure, expression and function of a schwannoma-derived growth factor

  1990cited by this paper
• Structure and function of human amphiregulin: a member of the epidermal growth factor family.

  1989cited by this paper
• Construction of mutant and chimeric genes using the polymerase chain reaction.

  1989cited by this paper
• Molecular Modeling of Protein‐Glycosaminoglycan Interactions

  1989cited by this paper
• Endothelial cell-derived heparan sulfate binds basic fibroblast growth factor and protects it from proteolytic degradation

  1988cited by this paper
• The purification of fully active recombinant transforming growth factor alpha produced in Escherichia coli.

  1986cited by this paper
• "ATG vectors' for regulated high-level expression of cloned genes in Escherichia coli.

  1985cited by this paper
• Differential effects of epidermal growth factor, transforming growth factor, and insulin on DNA and protein synthesis and morphology in serum-free cultures of AKR-2B cells.

  1984cited by this paper
• Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor.

  1984cited by this paper
• Oligonucleotide-directed mutagenesis of DNA fragments cloned into M13 vectors.

  1983cited by this paper
• Construction and characterization of the chloramphenicol-resistance gene cartridge: a new approach to the transcriptional mapping of extrachromosomal elements.

  1982cited by this paper
• The synthesis of cystine peptides by iodine oxidation of s trityl cysteine and s acetamidomethyl cysteine peptides

  1980cited by this paper
• Nucleotide sequence of the promoter--operator region of the tryptophan operon of Escherichia coli.

  1978cited by this paper
• Construction and characterization of new cloning vehicles. II. A multipurpose cloning system.

  1977cited by this paper
• Epidermal growth factor. Location of disulfide bonds.

  1973cited by this paper
• Experiments in molecular genetics

  1972cited by this paper

• Development of the FP121 series: Hybrid proteins mimicking marine adhesive proteins with cell adhesion and proliferation activity

  2025cites this paper
• Heparin, an active excipient to carry biosignal molecules: Applications in tissue engineering - A review.

  2025cites this paper
• The Multiple Functions of HB-EGF in Female Reproduction and Related Cancer: Molecular Mechanisms and Targeting Strategies

  2024cites this paper
• Fibulin7 Mediated Pathological Cardiac Remodeling through EGFR Binding and EGFR‐Dependent FAK/AKT Signaling Activation

  2023cites this paper
• Modeling methamphetamine use disorder and relapse in animals: short- and long-term epigenetic, transcriptional., and biochemical consequences in the rat brain.

  2023cites this paper
• Switching mechanism from AR to EGFR signaling via 3-O-sulfated heparan sulfate in castration-resistant prostate cancer

  2023cites this paper
• Fibroblast growth factor 2.

  2023cites this paper
• Heparanase Inhibition by Pixatimod (PG545): Basic Aspects and Future Perspectives.

  2020cites this paper
• Role of Heparin-Binding Epidermal Growth Factor-Like Growth Factor in Oxidative Stress-Associated Metabolic Diseases

  2020cites this paper
• Quantitative Study of Membrane Nano-organization by Single Nanoparticle Imaging

  2019cites this paper
• Specific Activity of Recombinant Modified Human Glucagon-Like Peptide 1

  2019cites this paper
• Hyaluronan/collagen hydrogels containing sulfated hyaluronan improve wound healing by sustained release of heparin-binding EGF-like growth factor.

  2019cites this paper
• Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα.

  2019cites this paper
• Stat5 phosphorylation is responsible for the excessive potency of HB‐EGF

  2018cites this paper
• Xenobiotic Binding Domain of Glutathione S-Transferase Has Cryptic Antimicrobial Peptides

  2018cites this paper
• Heparan sulfate as a regulator of inflammation and immunity

  2018cites this paper
• Heparin-Binding Epidermal Growth Factor-Like Growth Factor as a Critical Mediator of Tissue Repair and Regeneration.

  2018cites this paper
• Correction for “ Highly efficient delivery of functional cargoes by the synergistic effect of GAG binding motifs and cell-penetrating peptides

  2017cites this paper
• Dual-function synthetic peptide derived from BMP4 for highly efficient tumor targeting and antiangiogenesis

  2016cites this paper
• Role of Wnt and Notch signalling pathways on the neural differentiation of human Müller stem cells and their modulation by growth factors

  2016cites this paper
• The Modified Heparin-Binding l-Asparaginase of Wolinella succinogenes

  2016influential citation
• Classification: Biological Sciences: Cell biology Title: Highly Efficient Delivery of Functional Cargoes by the Synergistic Effect of GAG Binding Motifs and Cell-Penetrating Peptides

  2016cites this paper
• Highly efficient delivery of functional cargoes by the synergistic effect of GAG binding motifs and cell-penetrating peptides

  2016cites this paper
• Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries

  2015cites this paper
• Heparin Binding–Epidermal Growth Factor-Like Growth Factor for the Regeneration of Chronic Tympanic Membrane Perforations in Mice

  2015influential citation
• High‐level expression and purification of soluble bioactive recombinant human heparin‐binding epidermal growth factor in Escherichia coli

  2015cites this paper
• Heparin/Heparan Sulfate Proteoglycans Glycomic Interactome in Angiogenesis: Biological Implications and Therapeutical Use

  2015cites this paper
• Corneal wound healing, a newly identified function of CAP37, is mediated by protein kinase C delta (PKCδ).

  2014cites this paper
• Heparin-binding epidermal growth factor-like growth factor (HB-EGF) and proteolytic processing by a disintegrin and metalloproteinases (ADAM): a regulator of several pathways.

  2014cites this paper
• Studies on nStudies on neutralizing anti-heparin-binding epidermal growth factor-like growth factor (HB-EGF) antibodies for drug development of cancer treatment

  2013cites this paper
• Recent Advances In Physiology Of Implantation: Potential Role Of Heparin In Assisted Conception

  2013cites this paper
• Recent Advances In Physiology Of Implantation : Potential Role Of Heparin In Assisted Conception

  2013cites this paper
• Heparin inhibits protective effect of ischemic preconditioning in ischemia/reperfusion-induced acute pancreatitis.

  2012cites this paper
• Heparin-modified dendrimer crosslinked collagen matrices for the delivery of heparin-binding epidermal growth factor.

  2012cites this paper
• Low-molecular-weight heparins induce decidual heparin-binding epidermal growth factor-like growth factor expression and promote survival of decidual cells undergoing apoptosis.

  2012cites this paper
• Dendrimer Crosslinked Collagen Gels Modified with Extracellular Matrix Components

  2012cites this paper
• In Vitro Evidences of Heparin's Effects on Embryo Implantation and Trophoblast Development

  2012cites this paper
• The cell-penetrating peptide domain from human heparin-binding epidermal growth factor-like growth factor (HB-EGF) has anti-inflammatory activity in vitro and in vivo.

  2012cites this paper
• Brief treatment with heparin-binding EGF-like growth factor, but not with EGF, is sufficient to accelerate epithelial wound healing.

  2011cites this paper
• Intestinal phenotype in mice overexpressing a heparin-binding EGF-like growth factor transgene in enterocytes

  2010cites this paper
• Decreased expression of heparin-binding epidermal growth factor-like growth factor as a newly identified pathogenic mechanism of antiphospholipid-mediated defective placentation.

  2010cites this paper
• Intra-articular Injection of HB-IGF-1 Sustains Delivery of IGF-1 to Cartilage through Binding to Chondroitin Sulfate

  2010cites this paper
• Intraarticular injection of heparin-binding insulin-like growth factor 1 sustains delivery of insulin-like growth factor 1 to cartilage through binding to chondroitin sulfate.

  2010cites this paper
• The heparin-binding domain of HB-EGF mediates localization to sites of cell-cell contact and prevents HB-EGF proteolytic release

  2010cites this paper
• This information is current as Experimental Asthma Model Th 17-Induced Airway Remodeling in an Epidermal Growth Factor Is Responsible for The Overexpression of Heparin-Binding

  2010cites this paper
• In vitro and in vivo growth factor delivery to chondrocytes and bone-marrow-derived stromal cells in cartilage and in self-assembling peptide scaffolds

  2010cites this paper
• The Overexpression of Heparin-Binding Epidermal Growth Factor Is Responsible for Th17-Induced Airway Remodeling in an Experimental Asthma Model

  2010cites this paper
• Gene expression profiling of TGFbeta2- and/or BMP7-treated trabecular meshwork cells: Identification of Smad7 as a critical inhibitor of TGF-beta2 signaling.

  2009cites this paper
• Role of the interaction of proHB-EGF with heparan sulfate proteoglycans

  2009cites this paper
• The heparanome and regulation of cell function: structures, functions and challenges.

  2008cites this paper
• The expression of the epidermal growth factor receptor on human monocytes and macrophages and its potential role in atherosclerosis

  2008cites this paper
• Controlled release of heparin-binding growth factors using heparin-containing particulate systems for tissue regeneration

  2008cites this paper
• Protective and therapeutic effect of heparin in acute pancreatitis.

  2008cites this paper
• Controlled release of heparin-binding growth factors using heparin-containing particulate systems for tissue regeneration.

  2008cites this paper
• Engineering insulin‐like growth factor‐1 for local delivery

  2008cites this paper
• The significance of disulfide bonding in biological activity of HB-EGF, a mutagenesis approach.

  2008cites this paper
• Antimicrobial peptides derived from growth factors

  2007cites this paper
• The binding of human betacellulin to heparin, heparan sulfate and related polysaccharides.

  2007influential citation
• Amino‐terminal deletion of heparin‐binding epidermal growth factor‐like growth factor4−127 stimulates cell proliferation but lacks insulin‐like activity

  2007cites this paper
• 5-HT2A Receptor Induces ERK Phosphorylation and Proliferation through ADAM-17 Tumor Necrosis Factor-α-converting Enzyme (TACE) Activation and Heparin-bound Epidermal Growth Factor-like Growth Factor (HB-EGF) Shedding in Mesangial Cells*

  2006cites this paper
• The epidermal growth factor receptors and their family of ligands: their putative role in atherogenesis.

  2006cites this paper
• HaCaT keratinocyte migration is dependent on epidermal growth factor receptor signaling and glycogen synthase kinase-3alpha.

  2006cites this paper
• Comparative effects of heparin-binding epidermal growth factor-like growth factor on the growth of cultured human uterine leiomyoma cells and myometrial cells.

  2005cites this paper
• Heparin‐binding epidermal growth factor‐like growth factor stimulates cell proliferation in cerebral cortical cultures through phosphatidylinositol 3′‐kinase and mitogen‐activated protein kinase

  2005influential citation
• Gene expression and immunolocalization of heparin-binding epidermal growth factor-like growth factor and human epidermal growth factor receptors in human corpus luteum.

  2005cites this paper
• Raf and VEGF: emerging therapeutic targets in Kaposi's sarcoma-associated herpesvirus infection and angiogenesis in hematopoietic and nonhematopoietic tumors

  2005cites this paper
• Capillary zone electrophoresis characterization of low molecular weight heparin binding to interleukin 2.

  2005cites this paper
• ADAM-mediated ectodomain shedding of HB-EGF in receptor cross-talk.

  2005cites this paper
• A Short Form of the Heparin-binding EGF-like Growth Factor with a Changed EGF Domain

  2004cites this paper
• Nardilysin, a basic residues specific metallopeptidase that mediates cell migration and proliferation.

  2004cites this paper
• Heparin-binding Epidermal Growth Factor-like Growth Factor (HB-EGF) is a Mediator of Multiple Physiological and Pathological Pathways

  2004influential citation
• Metalloproteinase-mediated shedding of heparin-binding EGF-like growth factor and its pathophysiological roles.

  2004cites this paper
• 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*

  2004cites this paper
• N-Unsubstituted Glucosamine Residues in Heparan Sulfate and Their Potential Relation to Alzheimer's Disease

  2003cites this paper
• Liver regeneration in heparin-binding EGF-like growth factor transgenic mice after partial hepatectomy.

  2003cites this paper
• The chemical synthesis and binding affinity to the EGF receptor of the EGF‐like domain of heparin‐binding EGF‐like growth factor (HB‐EGF)

  2003cites this paper
• Heparin-binding EGF-like growth factor regulates elastin and FGF-2 expression in pulmonary fibroblasts.

  2003cites this paper
• Glypican‐3, overexpressed in hepatocellular carcinoma, modulates FGF2 and BMP‐7 signaling

  2003cites this paper
• Latent transforming growth factor β-binding protein-3 and fibulin-1C interact with the extracellular domain of the heparin-binding EGF-like growth factor precursor

  2002cites this paper
• Roles of cell adhesion molecules in tumor angiogenesis induced by cotransplantation of cancer and endothelial cells to nude rats.

  2002cites this paper
• The Membrane Protein CD 9 / DRAP 27 Potentiates the Juxtacrine Growth Factor Activity of the Membrane-anchored Heparin-binding EGF-like Growth Factor

  2002cites this paper
• The metalloendopeptidase nardilysin (NRDc) is potently inhibited by heparin-binding epidermal growth factor-like growth factor (HB-EGF).

  2002cites this paper
• Receptor-Based Antidote for Diphtheria

  2002cites this paper
• Heparin-protein interactions.

  2002cites this paper
• Heparin‐Binding Epidermal Growth Factor (HB‐EGF)

  2002cites this paper
• A role of heparin-binding epidermal growth factor-like growth factor in cardiac remodeling after myocardial infarction.

  2002cites this paper
• Heparin‐Protein‐Wechselwirkungen

  2002cites this paper
• Heparin-binding EGF-like growth factor decreases apoptosis in intestinal epithelial cells in vitro.

  2001cites this paper
• Heparin-Binding EGF-Like Growth Factor: Hepatotrophic Factor in Liver Regeneration

  2001cites this paper
• Site-directed Mutagenesis of Heparin-binding EGF-like Growth Factor (HB-EGF): Analysis of O-glycosylation Sites and Properties

  2001cites this paper
• Involvement of heparin-binding EGF-like growth factor and its processing by metalloproteinases in early epithelial morphogenesis of the submandibular gland.

  2001cites this paper
• Chronic Shear Stress Effects on Endothelial Cell Response

  2001cites this paper
• Quantitative analysis of the EGF receptor autocrine system reveals cryptic regulation of cell response by ligand capture.

  2001cites this paper
• Effects of EGF receptor ligands on fetal ovine myoblasts.

  2001cites this paper
• N‐arginine dibasic convertase is a specific receptor for heparin‐binding EGF‐like growth factor that mediates cell migration

  2001cites this paper
• Heparin-binding EGF-like growth factor: a juxtacrine growth factor.

  2000cites this paper
• Heparin-binding EGF-like growth factor is up-regulated in the obstructed kidney in a cell- and region-specific manner and acts to inhibit apoptosis.

  2000cites this paper
• Heparin-binding epidermal growth factor-like growth factor is expressed in the adhesive lesions of experimental focal glomerular sclerosis.

  1999cites this paper
• Heparin-binding EGF-like growth factor interacts with mouse blastocysts independently of ErbB1: a possible role for heparan sulfate proteoglycans and ErbB4 in blastocyst implantation.

  1999cites this paper
• Structural requirements for the tissue-specific and tissue-general functions of the Caenorhabditis elegans epidermal growth factor LIN-3.

  1999cites this paper