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Q99075 (HBEGF_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 140. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Proheparin-binding EGF-like growth factor

Cleaved into the following chain:

  1. Heparin-binding EGF-like growth factor
    Short name=HB-EGF
    Short name=HBEGF
    Alternative name(s):
    Diphtheria toxin receptor
    Short name=DT-R
Gene names
Name:HBEGF
Synonyms:DTR, DTS, HEGFL
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length208 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Growth factor that mediates its effects via EGFR, ERBB2 and ERBB4. Required for normal cardiac valve formation and normal heart function. Promotes smooth muscle cell proliferation. May be involved in macrophage-mediated cellular proliferation. It is mitogenic for fibroblasts, but not endothelial cells. It is able to bind EGF receptor/EGFR with higher affinity than EGF itself and is a far more potent mitogen for smooth muscle cells than EGF. Also acts as a diphtheria toxin receptor.

Subunit structure

Interacts with FBLN1 By similarity. Interacts with EGFR and ERBB4. Ref.9

Subcellular location

Heparin-binding EGF-like growth factor: Secretedextracellular space. Note: Mature HB-EGF is released into the extracellular space and probably binds to a receptor.

Proheparin-binding EGF-like growth factor: Cell membrane; Single-pass type I membrane protein.

Post-translational modification

Several N-termini have been identified by direct sequencing. The forms with N-termini 63, 73 and 74 have been tested and found to be biologically active.

O-glycosylated with core 1 or possibly core 8 glycans. Thr-47 is a minor glycosylation site compared to Thr-44. Ref.7 Ref.11 Ref.12

Sequence similarities

Contains 1 EGF-like domain.

Ontologies

Keywords
   Cellular componentCell membrane
Membrane
Secreted
   DomainEGF-like domain
Signal
Transmembrane
Transmembrane helix
   LigandHeparin-binding
   Molecular functionGrowth factor
Receptor
   PTMDisulfide bond
Glycoprotein
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processFc-epsilon receptor signaling pathway

Traceable author statement. Source: Reactome

epidermal growth factor receptor signaling pathway

Inferred from mutant phenotype PubMed 17655843. Source: BHF-UCL

fibroblast growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

innate immune response

Traceable author statement. Source: Reactome

muscle organ development

Traceable author statement PubMed 8347598. Source: ProtInc

negative regulation of elastin biosynthetic process

Inferred from electronic annotation. Source: Ensembl

neurotrophin TRK receptor signaling pathway

Traceable author statement. Source: Reactome

phosphatidylinositol-mediated signaling

Traceable author statement. Source: Reactome

positive regulation of cell growth

Inferred from electronic annotation. Source: Ensembl

positive regulation of cell migration

Inferred from mutant phenotype PubMed 17655843. Source: BHF-UCL

positive regulation of keratinocyte migration

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein kinase B signaling

Inferred from mutant phenotype PubMed 17655843. Source: BHF-UCL

positive regulation of smooth muscle cell proliferation

Inferred from electronic annotation. Source: Ensembl

positive regulation of wound healing

Inferred from mutant phenotype PubMed 17655843. Source: BHF-UCL

regulation of heart contraction

Inferred from electronic annotation. Source: Ensembl

signal transduction

Traceable author statement Ref.1. Source: ProtInc

wound healing, spreading of epidermal cells

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentcell surface

Non-traceable author statement PubMed 15289334. Source: UniProtKB

extracellular region

Traceable author statement. Source: Reactome

extracellular space

Traceable author statement PubMed 15389565. Source: UniProtKB

integral component of plasma membrane

Traceable author statement PubMed 15389565. Source: UniProtKB

   Molecular_functionepidermal growth factor receptor binding

Traceable author statement PubMed 10749879. Source: ProtInc

growth factor activity

Inferred from direct assay PubMed 12070119. Source: UniProtKB

heparin binding

Inferred from mutant phenotype PubMed 8300582. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 1919 Potential
Chain20 – 208189Proheparin-binding EGF-like growth factor
PRO_0000302803
Propeptide20 – 6243Or 72, or 73, or 76, or 81
PRO_0000007611
Chain63 – 14886Heparin-binding EGF-like growth factor
PRO_0000007612
Propeptide149 – 20860C-terminal Potential
PRO_0000007613

Regions

Topological domain20 – 160141Extracellular Potential
Transmembrane161 – 18424Helical; Potential
Topological domain185 – 20824Cytoplasmic Potential
Domain104 – 14441EGF-like

Sites

Site1411Plays a critical role in diphtheria toxin binding and toxin sensitivity By similarity

Amino acid modifications

Glycosylation371O-linked (GalNAc...) Probable
Glycosylation381O-linked (GalNAc...) Probable
Glycosylation441O-linked (GalNAc...) Ref.11 Ref.12
Glycosylation471O-linked (GalNAc...) Ref.11
Glycosylation751O-linked (GalNAc...) Ref.7
Glycosylation851O-linked (GalNAc...) Ref.7
Disulfide bond108 ↔ 121 By similarity
Disulfide bond116 ↔ 132 By similarity
Disulfide bond134 ↔ 143 By similarity

Secondary structure

............. 208
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q99075 [UniParc].

Last modified June 1, 1994. Version 1.
Checksum: 2C43C9D1D8291B51

FASTA20823,067
        10         20         30         40         50         60 
MKLLPSVVLK LFLAAVLSAL VTGESLERLR RGLAAGTSNP DPPTVSTDQL LPLGGGRDRK 

        70         80         90        100        110        120 
VRDLQEADLD LLRVTLSSKP QALATPNKEE HGKRKKKGKG LGKKRDPCLR KYKDFCIHGE 

       130        140        150        160        170        180 
CKYVKELRAP SCICHPGYHG ERCHGLSLPV ENRLYTYDHT TILAVVAVVL SSVCLLVIVG 

       190        200 
LLMFRYHRRG GYDVENEEKV KLGMTNSH 

« Hide

References

« Hide 'large scale' references
[1]"A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF."
Higashiyama S., Abraham J.A., Miller J., Fiddes J.C., Klagsbrun M.
Science 251:936-939(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 73-93.
Tissue: Macrophage.
[2]NIEHS SNPs program
Submitted (OCT-2002) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]"The DNA sequence and comparative analysis of human chromosome 5."
Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S. expand/collapse author list , Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.
Nature 431:268-274(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Eye.
[7]"Structure of heparin-binding EGF-like growth factor. Multiple forms, primary structure, and glycosylation of the mature protein."
Higashiyama S., Lau K., Besner G.E., Abraham J.A., Klagsbrun M.
J. Biol. Chem. 267:6205-6212(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 63-141 AND 143-148, GLYCOSYLATION AT THR-75 AND THR-85.
Tissue: Histiocytic lymphoma.
[8]"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."
Mitamura T., Higashiyama S., Taniguchi N., Klagsbrun M., Mekada E.
J. Biol. Chem. 270:1015-1019(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: DOMAIN TOXIN BINDING.
[9]"Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation."
Elenius K., Paul S., Allison G., Sun J., Klagsbrun M.
EMBO J. 16:1268-1278(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ERBB4.
[10]"ErbB and HB-EGF signaling in heart development and function."
Iwamoto R., Mekada E.
Cell Struct. Funct. 31:1-14(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[11]"Human urinary glycoproteomics; attachment site specific analysis of N-and O-linked glycosylations by CID and ECD."
Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.
Mol. Cell. Proteomics 0:0-0(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION AT THR-44 AND THR-47, STRUCTURE OF CARBOHYDRATES, IDENTIFICATION BY MASS SPECTROMETRY.
[12]"LC-MS/MS characterization of O-glycosylation sites and glycan structures of human cerebrospinal fluid glycoproteins."
Halim A., Ruetschi U., Larson G., Nilsson J.
J. Proteome Res. 12:573-584(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION AT THR-37; SER-38 AND THR-44, IDENTIFICATION BY MASS SPECTROMETRY.
[13]"Crystal structure of the complex of diphtheria toxin with an extracellular fragment of its receptor."
Louie G.V., Yang W., Bowman M.E., Choe S.
Mol. Cell 1:67-78(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF 73-147 IN COMPLEX WITH TOX.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M60278 mRNA. Translation: AAA35956.1.
AY164533 Genomic DNA. Translation: AAN46738.1.
AK313202 mRNA. Translation: BAG36018.1.
AC004634 Genomic DNA. Translation: AAC15470.1.
CH471062 Genomic DNA. Translation: EAW62069.1.
BC033097 mRNA. Translation: AAH33097.1.
CCDSCCDS4223.1.
PIRA38432.
RefSeqNP_001936.1. NM_001945.2.
UniGeneHs.592942.
Hs.799.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1XDTX-ray2.65R73-147[»]
2M8SNMR-B185-208[»]
ProteinModelPortalQ99075.
SMRQ99075. Positions 107-147.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108172. 9 interactions.
DIPDIP-114N.
IntActQ99075. 1 interaction.
MINTMINT-1511911.
STRING9606.ENSP00000230990.

PTM databases

PhosphoSiteQ99075.

Polymorphism databases

DMDM544477.

Proteomic databases

PaxDbQ99075.
PRIDEQ99075.

Protocols and materials databases

DNASU1839.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000230990; ENSP00000230990; ENSG00000113070.
ENST00000507104; ENSP00000425696; ENSG00000113070.
GeneID1839.
KEGGhsa:1839.
UCSCuc003lfi.3. human.

Organism-specific databases

CTD1839.
GeneCardsGC05M139694.
HGNCHGNC:3059. HBEGF.
HPAHPA053243.
MIM126150. gene.
neXtProtNX_Q99075.
PharmGKBPA27513.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG45526.
HOGENOMHOG000026782.
HOVERGENHBG053952.
InParanoidQ99075.
KOK08523.
OMAYSYDHTT.
OrthoDBEOG7VQJGP.
PhylomeDBQ99075.
TreeFamTF332773.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.
SignaLinkQ99075.

Gene expression databases

ArrayExpressQ99075.
BgeeQ99075.
CleanExHS_HBEGF.
GenevestigatorQ99075.

Family and domain databases

InterProIPR000742. EG-like_dom.
IPR013032. EGF-like_CS.
IPR015497. EGF_rcpt_ligand.
[Graphical view]
PANTHERPTHR10740. PTHR10740. 1 hit.
PfamPF00008. EGF. 1 hit.
[Graphical view]
SMARTSM00181. EGF. 1 hit.
[Graphical view]
PROSITEPS00022. EGF_1. 1 hit.
PS01186. EGF_2. 1 hit.
PS50026. EGF_3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ99075.
GeneWikiHeparin-binding_EGF-like_growth_factor.
GenomeRNAi1839.
NextBio7529.
PMAP-CutDBQ99075.
PROQ99075.
SOURCESearch...

Entry information

Entry nameHBEGF_HUMAN
AccessionPrimary (citable) accession number: Q99075
Secondary accession number(s): B2R821
Entry history
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: June 1, 1994
Last modified: July 9, 2014
This is version 140 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 5

Human chromosome 5: entries, gene names and cross-references to MIM