Q99075 (HBEGF_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	208 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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: Secreted › extracellular 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-linked glycan attachment sites were determined by Edman degradation, O-glycanase digest suggests mucin-type glycosylation (done in HB-EGF purified from histiocytic lymphoma cell line U-937).
Sequence similarities	Contains 1 EGF-like domain.

Ontologies

Keywords
Cellular component	Cell membrane Membrane Secreted
Domain	EGF-like domain Signal Transmembrane Transmembrane helix
Ligand	Heparin-binding
Molecular function	Growth factor Receptor
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	epidermal growth factor receptor signaling pathway Inferred from mutant phenotype. Source: BHF-UCL muscle organ development Traceable author statement. Source: ProtInc positive regulation of protein kinase B signaling cascade Inferred from mutant phenotype. Source: BHF-UCL positive regulation of wound healing Inferred from mutant phenotype. Source: BHF-UCL
Cellular component	cell surface Non-traceable author statement. Source: UniProtKB extracellular space Traceable author statement. Source: UniProtKB integral to plasma membrane Traceable author statement. Source: UniProtKB
Molecular function	epidermal growth factor receptor binding Traceable author statement. Source: ProtInc eukaryotic cell surface binding Inferred from direct assay. Source: UniProtKB growth factor activity Inferred from electronic annotation. Source: UniProtKB-KW heparin binding Inferred from mutant phenotype. Source: UniProtKB receptor activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 19

19

Potential

Chain

20 – 208

189

Proheparin-binding EGF-like growth factor

PRO_0000302803

Propeptide

20 – 62

43

Or 72, or 73, or 76, or 81

PRO_0000007611

Chain

63 – 148

86

Heparin-binding EGF-like growth factor

PRO_0000007612

Propeptide

149 – 208

60

C-terminal Potential

PRO_0000007613

Regions

Topological domain

20 – 160

141

Extracellular Potential

Transmembrane

161 – 184

24

Helical; Potential

Topological domain

185 – 208

24

Cytoplasmic Potential

Domain

104 – 144

41

EGF-like

Sites

Site

141

1

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

Amino acid modifications

Glycosylation

75

1

O-linked (GalNAc...) Ref.7

Glycosylation

85

1

O-linked (GalNAc...) Ref.7

Disulfide bond

108 ↔ 121

By similarity

Disulfide bond

116 ↔ 132

By similarity

Disulfide bond

134 ↔ 143

By similarity

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

208

Helix Strand Turn

Details...

Turn

108 – 114

7

Beta strand

117 – 121

5

Turn

125 – 128

4

Beta strand

132 – 134

3

Beta strand

138 – 140

3

Sequences

	Sequence		Length	Mass (Da)
	Q99075 [UniParc]. Last modified June 1, 1994. Version 1. Checksum: 2C43C9D1D8291B51	FASTA	208	23,067
	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

References

	« Hide 'large scale' referencesShow '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: 1840698] [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: 14702039] [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: 15372022] [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. , 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: 15489334] [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: 1556128] [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: 7836353] [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: 9135143] [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: 16508205] [Abstract] Cited for: REVIEW.
[11]	"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: 9659904] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF 73-147 IN COMPLEX WITH TOX.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

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.

IPI

IPI00012948.

PIR

A38432.

RefSeq

NP_001936.1. NM_001945.2.

UniGene

Hs.799.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1XDT	X-ray	2.65	R	73-147	[»]

ProteinModelPortal

Q99075.

SMR

Q99075. Positions 107-147.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-114N.

MINT

MINT-1511911.

STRING

Q99075.

PTM databases

PhosphoSite

Q99075.

Polymorphism databases

DMDM

544477.

Proteomic databases

PRIDE

Q99075.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000230990; ENSP00000230990; ENSG00000113070.

GeneID

1839.

KEGG

hsa:1839.

UCSC

uc003lfi.1. human.

Organism-specific databases

CTD

1839.

GeneCards

GC05M139694.

H-InvDB

HIX0200772.

HGNC

HGNC:3059. HBEGF.

MIM

126150. gene.

neXtProt

NX_Q99075.

PharmGKB

PA27513.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

HBG125704.

HOVERGEN

HBG053952.

InParanoid

Q99075.

OMA

PTESTDQ.

OrthoDB

EOG476K1S.

PhylomeDB

Q99075.

Enzyme and pathway databases

Pathway_Interaction_DB

lysophospholipid_pathway. LPA receptor mediated events.
er_nongenomic_pathway. Plasma membrane estrogen receptor signaling.

Gene expression databases

ArrayExpress

Q99075.

Bgee

Q99075.

CleanEx

HS_HBEGF.

Genevestigator

Q99075.

GermOnline

ENSG00000113070. Homo sapiens.

Family and domain databases

InterPro

IPR006209. EGF.
IPR006210. EGF-like.
IPR013032. EGF-like_reg_CS.
IPR000742. EGF_3.
IPR015497. EGF_rcpt_ligand.
[Graphical view]

KO

K08523.

PANTHER

PTHR10740. EGF_rcpt_ligand. 1 hit.

Pfam

PF00008. EGF. 1 hit.
[Graphical view]

SMART

SM00181. EGF. 1 hit.
[Graphical view]

PROSITE

PS00022. EGF_1. 1 hit.
PS01186. EGF_2. 1 hit.
PS50026. EGF_3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

7529.

PMAP-CutDB

Q99075.

SOURCE

Search...

Entry information

Entry name

HBEGF_HUMAN

Accession

Primary (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:	January 25, 2012
This is version 116 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.