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Q99075

- HBEGF_HUMAN

UniProt

Q99075 - HBEGF_HUMAN

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Protein
Proheparin-binding EGF-like growth factor
Gene
HBEGF, DTR, DTS, HEGFL
Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

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.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei141 – 1411Plays a critical role in diphtheria toxin binding and toxin sensitivity By similarity

GO - Molecular functioni

  1. epidermal growth factor receptor binding Source: ProtInc
  2. growth factor activity Source: UniProtKB
  3. heparin binding Source: UniProtKB
Complete GO annotation...

GO - Biological processi

  1. Fc-epsilon receptor signaling pathway Source: Reactome
  2. epidermal growth factor receptor signaling pathway Source: BHF-UCL
  3. fibroblast growth factor receptor signaling pathway Source: Reactome
  4. innate immune response Source: Reactome
  5. muscle organ development Source: ProtInc
  6. negative regulation of elastin biosynthetic process Source: Ensembl
  7. neurotrophin TRK receptor signaling pathway Source: Reactome
  8. phosphatidylinositol-mediated signaling Source: Reactome
  9. positive regulation of cell growth Source: Ensembl
  10. positive regulation of cell migration Source: BHF-UCL
  11. positive regulation of keratinocyte migration Source: Ensembl
  12. positive regulation of protein kinase B signaling Source: BHF-UCL
  13. positive regulation of smooth muscle cell proliferation Source: Ensembl
  14. positive regulation of wound healing Source: BHF-UCL
  15. regulation of heart contraction Source: Ensembl
  16. signal transduction Source: ProtInc
  17. wound healing, spreading of epidermal cells Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Growth factor, Receptor

Keywords - Ligandi

Heparin-binding

Enzyme and pathway databases

ReactomeiREACT_115596. Signaling by ERBB4.
REACT_115755. Signaling by ERBB2.
REACT_115854. GRB2 events in ERBB2 signaling.
REACT_115961. PI3K events in ERBB4 signaling.
REACT_115993. SHC1 events in ERBB2 signaling.
REACT_116005. SHC1 events in ERBB4 signaling.
REACT_116008. PI3K events in ERBB2 signaling.
REACT_116022. Nuclear signaling by ERBB4.
REACT_121096. EGFR Transactivation by Gastrin.
REACT_147727. Constitutive PI3K/AKT Signaling in Cancer.
REACT_75829. PIP3 activates AKT signaling.
SignaLinkiQ99075.

Names & Taxonomyi

Protein namesi
Recommended name:
Proheparin-binding EGF-like growth factor
Cleaved into the following chain:
Heparin-binding EGF-like growth factor
Short name:
HB-EGF
Short name:
HBEGF
Alternative name(s):
Diphtheria toxin receptor
Short name:
DT-R
Gene namesi
Name:HBEGF
Synonyms:DTR, DTS, HEGFL
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 5

Organism-specific databases

HGNCiHGNC:3059. HBEGF.

Subcellular locationi

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

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini20 – 160141Extracellular Reviewed prediction
Add
BLAST
Transmembranei161 – 18424Helical; Reviewed prediction
Add
BLAST
Topological domaini185 – 20824Cytoplasmic Reviewed prediction
Add
BLAST

GO - Cellular componenti

  1. cell surface Source: UniProtKB
  2. extracellular region Source: Reactome
  3. extracellular space Source: UniProtKB
  4. integral component of plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane, Secreted

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA27513.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 1919 Reviewed prediction
Add
BLAST
Chaini20 – 208189Proheparin-binding EGF-like growth factor
PRO_0000302803Add
BLAST
Propeptidei20 – 6243Or 72, or 73, or 76, or 81
PRO_0000007611Add
BLAST
Chaini63 – 14886Heparin-binding EGF-like growth factor
PRO_0000007612Add
BLAST
Propeptidei149 – 20860C-terminal Reviewed prediction
PRO_0000007613Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi37 – 371O-linked (GalNAc...) Inferred
Glycosylationi38 – 381O-linked (GalNAc...) Inferred
Glycosylationi44 – 441O-linked (GalNAc...)2 Publications
Glycosylationi47 – 471O-linked (GalNAc...)1 Publication
Glycosylationi75 – 751O-linked (GalNAc...)1 Publication
Glycosylationi85 – 851O-linked (GalNAc...)1 Publication
Disulfide bondi108 ↔ 121 By similarity
Disulfide bondi116 ↔ 132 By similarity
Disulfide bondi134 ↔ 143 By similarity

Post-translational modificationi

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-44.3 Publications

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

PaxDbiQ99075.
PRIDEiQ99075.

PTM databases

PhosphoSiteiQ99075.

Miscellaneous databases

PMAP-CutDBQ99075.

Expressioni

Gene expression databases

ArrayExpressiQ99075.
BgeeiQ99075.
CleanExiHS_HBEGF.
GenevestigatoriQ99075.

Organism-specific databases

HPAiHPA053243.

Interactioni

Subunit structurei

Interacts with FBLN1 By similarity. Interacts with EGFR and ERBB4.1 Publication

Protein-protein interaction databases

BioGridi108172. 9 interactions.
DIPiDIP-114N.
IntActiQ99075. 1 interaction.
MINTiMINT-1511911.
STRINGi9606.ENSP00000230990.

Structurei

Secondary structure

Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Turni108 – 1147
Beta strandi117 – 1215
Turni125 – 1284
Beta strandi132 – 1343
Beta strandi138 – 1403
Beta strandi188 – 1958

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1XDTX-ray2.65R73-147[»]
2M8SNMR-B185-208[»]
ProteinModelPortaliQ99075.
SMRiQ99075. Positions 107-147.

Miscellaneous databases

EvolutionaryTraceiQ99075.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini104 – 14441EGF-like
Add
BLAST

Sequence similaritiesi

Contains 1 EGF-like domain.

Keywords - Domaini

EGF-like domain, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG45526.
HOGENOMiHOG000026782.
HOVERGENiHBG053952.
InParanoidiQ99075.
KOiK08523.
OMAiYSYDHTT.
OrthoDBiEOG7VQJGP.
PhylomeDBiQ99075.
TreeFamiTF332773.

Family and domain databases

InterProiIPR000742. EG-like_dom.
IPR013032. EGF-like_CS.
IPR015497. EGF_rcpt_ligand.
[Graphical view]
PANTHERiPTHR10740. PTHR10740. 1 hit.
PfamiPF00008. EGF. 1 hit.
[Graphical view]
SMARTiSM00181. EGF. 1 hit.
[Graphical view]
PROSITEiPS00022. EGF_1. 1 hit.
PS01186. EGF_2. 1 hit.
PS50026. EGF_3. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q99075-1 [UniParc]FASTAAdd to Basket

« Hide

MKLLPSVVLK LFLAAVLSAL VTGESLERLR RGLAAGTSNP DPPTVSTDQL    50
LPLGGGRDRK VRDLQEADLD LLRVTLSSKP QALATPNKEE HGKRKKKGKG 100
LGKKRDPCLR KYKDFCIHGE CKYVKELRAP SCICHPGYHG ERCHGLSLPV 150
ENRLYTYDHT TILAVVAVVL SSVCLLVIVG LLMFRYHRRG GYDVENEEKV 200
KLGMTNSH 208
Length:208
Mass (Da):23,067
Last modified:June 1, 1994 - v1
Checksum:i2C43C9D1D8291B51
GO

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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.
CCDSiCCDS4223.1.
PIRiA38432.
RefSeqiNP_001936.1. NM_001945.2.
UniGeneiHs.592942.
Hs.799.

Genome annotation databases

EnsembliENST00000230990; ENSP00000230990; ENSG00000113070.
ENST00000507104; ENSP00000425696; ENSG00000113070.
GeneIDi1839.
KEGGihsa:1839.
UCSCiuc003lfi.3. human.

Polymorphism databases

DMDMi544477.

Cross-referencesi

Web resourcesi

NIEHS-SNPs

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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 .
CCDSi CCDS4223.1.
PIRi A38432.
RefSeqi NP_001936.1. NM_001945.2.
UniGenei Hs.592942.
Hs.799.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
1XDT X-ray 2.65 R 73-147 [» ]
2M8S NMR - B 185-208 [» ]
ProteinModelPortali Q99075.
SMRi Q99075. Positions 107-147.
ModBasei Search...

Protein-protein interaction databases

BioGridi 108172. 9 interactions.
DIPi DIP-114N.
IntActi Q99075. 1 interaction.
MINTi MINT-1511911.
STRINGi 9606.ENSP00000230990.

PTM databases

PhosphoSitei Q99075.

Polymorphism databases

DMDMi 544477.

Proteomic databases

PaxDbi Q99075.
PRIDEi Q99075.

Protocols and materials databases

DNASUi 1839.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000230990 ; ENSP00000230990 ; ENSG00000113070 .
ENST00000507104 ; ENSP00000425696 ; ENSG00000113070 .
GeneIDi 1839.
KEGGi hsa:1839.
UCSCi uc003lfi.3. human.

Organism-specific databases

CTDi 1839.
GeneCardsi GC05M139694.
HGNCi HGNC:3059. HBEGF.
HPAi HPA053243.
MIMi 126150. gene.
neXtProti NX_Q99075.
PharmGKBi PA27513.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG45526.
HOGENOMi HOG000026782.
HOVERGENi HBG053952.
InParanoidi Q99075.
KOi K08523.
OMAi YSYDHTT.
OrthoDBi EOG7VQJGP.
PhylomeDBi Q99075.
TreeFami TF332773.

Enzyme and pathway databases

Reactomei REACT_115596. Signaling by ERBB4.
REACT_115755. Signaling by ERBB2.
REACT_115854. GRB2 events in ERBB2 signaling.
REACT_115961. PI3K events in ERBB4 signaling.
REACT_115993. SHC1 events in ERBB2 signaling.
REACT_116005. SHC1 events in ERBB4 signaling.
REACT_116008. PI3K events in ERBB2 signaling.
REACT_116022. Nuclear signaling by ERBB4.
REACT_121096. EGFR Transactivation by Gastrin.
REACT_147727. Constitutive PI3K/AKT Signaling in Cancer.
REACT_75829. PIP3 activates AKT signaling.
SignaLinki Q99075.

Miscellaneous databases

EvolutionaryTracei Q99075.
GeneWikii Heparin-binding_EGF-like_growth_factor.
GenomeRNAii 1839.
NextBioi 7529.
PMAP-CutDB Q99075.
PROi Q99075.
SOURCEi Search...

Gene expression databases

ArrayExpressi Q99075.
Bgeei Q99075.
CleanExi HS_HBEGF.
Genevestigatori Q99075.

Family and domain databases

InterProi IPR000742. EG-like_dom.
IPR013032. EGF-like_CS.
IPR015497. EGF_rcpt_ligand.
[Graphical view ]
PANTHERi PTHR10740. PTHR10740. 1 hit.
Pfami PF00008. EGF. 1 hit.
[Graphical view ]
SMARTi SM00181. EGF. 1 hit.
[Graphical view ]
PROSITEi PS00022. EGF_1. 1 hit.
PS01186. EGF_2. 1 hit.
PS50026. EGF_3. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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.
    , 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.
    , 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. 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.

Entry informationi

Entry nameiHBEGF_HUMAN
AccessioniPrimary (citable) accession number: Q99075
Secondary accession number(s): B2R821
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: June 1, 1994
Last modified: September 3, 2014
This is version 141 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 5
    Human chromosome 5: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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