HBEGF

Summary

HBEGF (heparin binding EGF like growth factor, HGNC:3059) is a protein-coding gene on chromosome 5q31.3, encoding Proheparin-binding EGF-like growth factor (Q99075). Growth factor that mediates its effects via EGFR, ERBB2 and ERBB4.

Enables growth factor activity; heparin binding activity; and transmembrane receptor protein tyrosine kinase activator activity. Involved in several processes, including epidermal growth factor receptor signaling pathway; positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; and positive regulation of wound healing. Located in cell surface. Is active in extracellular space. Implicated in glomerulosclerosis and perinatal necrotizing enterocolitis.

Source: NCBI Gene 1839 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 19 total
• Druggable target: yes
• MANE Select transcript: NM_001945

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3059
Approved symbol	HBEGF
Name	heparin binding EGF like growth factor
Location	5q31.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000113070
Ensembl biotype	protein_coding
OMIM	126150
Entrez	1839

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 2 retained_intron

ENST00000230990, ENST00000482211, ENST00000498452, ENST00000950442, ENST00000950443, ENST00000950444

RefSeq mRNA: 1 — MANE Select: NM_001945 NM_001945

CCDS: CCDS4223

Canonical transcript exons

ENST00000230990 — 6 exons

Exon	Start	End
ENSE00000764833	140335872	140336027
ENSE00000764835	140342635	140342812
ENSE00003993834	140345911	140346084
ENSE00003993841	140332843	140334280
ENSE00003993843	140346283	140346603
ENSE00003993845	140334658	140334748

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 98.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.6788 / max 548.0916, expressed in 1583 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63788	18.6788	1583

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
synovial joint	UBERON:0002217	98.80	gold quality
gall bladder	UBERON:0002110	95.79	gold quality
mucosa of urinary bladder	UBERON:0001259	94.67	gold quality
omental fat pad	UBERON:0010414	94.44	gold quality
peritoneum	UBERON:0002358	94.40	gold quality
lower lobe of lung	UBERON:0008949	94.11	gold quality
layer of synovial tissue	UBERON:0007616	92.75	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.43	gold quality
upper lobe of left lung	UBERON:0008952	91.73	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.59	gold quality
pericardium	UBERON:0002407	91.52	gold quality
upper lobe of lung	UBERON:0008948	91.41	gold quality
upper leg skin	UBERON:0004262	91.40	gold quality
cervix squamous epithelium	UBERON:0006922	90.35	silver quality
apex of heart	UBERON:0002098	89.75	gold quality
right atrium auricular region	UBERON:0006631	89.65	gold quality
body of stomach	UBERON:0001161	89.49	gold quality
lung	UBERON:0002048	89.47	gold quality
tibial nerve	UBERON:0001323	89.37	gold quality
cervix epithelium	UBERON:0004801	89.35	gold quality
heart left ventricle	UBERON:0002084	89.31	gold quality
cardiac ventricle	UBERON:0002082	89.14	gold quality
vena cava	UBERON:0004087	88.99	gold quality
cardiac atrium	UBERON:0002081	88.91	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.81	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.70	gold quality
lower esophagus mucosa	UBERON:0035834	88.61	gold quality
right lung	UBERON:0002167	88.31	gold quality
ventricular zone	UBERON:0003053	88.01	gold quality
esophagus mucosa	UBERON:0002469	87.83	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6075	no	222.97
E-MTAB-6142	no	128.61
E-MTAB-10137	no	6.74
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CDX2, EGR1, ETS2, FOS, HIF1A, JUN, MYOD1, NFKB1, PDX1, PPARD, RELA, RUNX2, SNAI1, SP1, SP3, SP4, SSRP1, TP53, WT1, ZHX2

miRNA regulators (miRDB)

133 targeting HBEGF, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AQ-3P	99.93	72.66	4867

Literature-anchored findings (GeneRIF, showing 40)

• Heparin-binding EGF-like growth factor decreases inducible nitric oxide synthase and nitric oxide production after intestinal ischemia/reperfusion injury. (PMID:11761337)
• Site-directed mutagenesis of heparin-binding EGF-like growth factor (HB-EGF): analysis of O-glycosylation sites and properties (PMID:11769972)
• HB-EGF mRNA and protein levels in gastric cancers were elevated, compared with normal gastric tissues, especially in the intestinal type. (PMID:11920609)
• The current study reveals that HB-EGF mRNA is abundantly expressed in human and mouse adipose tissue, plasma HB-EGF levels increase in parallel with fat accumulation in human, and subjects with coronary artery disease have higher plasma HB-EGF levels. (PMID:11922634)
• Bronchial epithelial compression regulates MAP kinase signaling and HB-EGF-like growth factor expression. (PMID:11943653)
• Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate epoxygenase metabolites in epithelial cells (PMID:11983897)
• nardilysin (NRDc) is potently inhibited by heparin-binding epidermal growth factor-like growth factor (HB-EGF) (PMID:12095415)
• Helicobacter pylori-stimulated EGF receptor transactivation requires metalloprotease cleavage of HB-EGF (PMID:12099696)
• data suggest that uterine receptivity may be regulated in part by the stromal-derived HB-EGF (PMID:12112577)
• HB-EGF cytoprotection is due, in part, to its ability to decrease reactive oxygen species production (PMID:12230876)
• Review. The mode of activation of EGFR in response to bacterial lipoteichoic acid involves cleavage of the transmembrane ligand HBEGF by ADAM 10. (PMID:12568494)
• Transgenic expression of HB-EGF accelerates the proliferation of hepatocytes after partial hepatectomy (PMID:12612909)
• the effect of N- and C-terminal residues of the EGF-like domain of HB-EGF in the binding affinity to the EGF receptor on A431 cells (PMID:12725245)
• Diffusely expressed throughout normal and psoriatic epidermis and sparsely colocalized with EGFr in all viable epidermal layers, with increased colocalization in psoriatic epidermis. (PMID:12768307)
• HB-EGF has an important role in the early pathogenesis of psoriasis. (PMID:12835543)
• HB-EGF and FGF-2 act in concert to regulate the synthesis of elastin in injury/repair situations in pulmonary fibroblasts. (PMID:12882762)
• proHB-EGF shedding induced by TPA and angiotensin II requires PACSIN3 as an upregulator (PMID:12952982)
• Heparin-binding EGF-like growth factor has a role in Angiopoietin-mediated recruitment of vascular smooth muscle cells. (PMID:12958167)
• GnRH-induced transactivation of the EGF-R and the subsequent ERK1/2 phosphorylation result from ectodomain shedding of HBEGF. (PMID:14573593)
• HB-EGF blocks cytokine-induced NF-kappaB activation and decreases nitric oxide production, interferes with cytokine-induced IkappaB kinase activity, inhibits phosphorylation and degradation of IkappaBalpha, and suppresses release of proinflammatory IL-8. (PMID:14634113)
• Results suggest that epidermal growth factor receptor HER-mediated autocrine and paracrine signaling by heparin-binding EGF-like growth factor or other EGF family members induces cytotrophoblast differentiation to an invasive phenotype. (PMID:14738873)
• 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. (PMID:14764442)
• The spatial and temporal pattern of HB-EGF expression suggest that HB-EGF may an important local regulator of ovarian function and structure. (PMID:15062539)
• relevance of a p38-ADAM-HB-EGF-EGFR-dependent pathway and its potential significance for tumor cells in evasion of chemotherapeutic agent-induced apoptosis (PMID:15169883)
• HB-EGF might be a more important tumor growth regulator of malignant fibrous histiocytoma through autocrine or paracrine pathways, when compared with betacellulin. (PMID:15274392)
• HB-EGF is a potent inducer of tumor growth and angiogenesis (PMID:15289334)
• the heparin-binding domain serves as a negative regulator of heparin-binding EGF-like Growth Factor (PMID:15331606)
• Results indicate that pro-heparin-binding EGF-like growth factor (pro-HB-EGF) shedding and subsequent HB-EGF C terminal fragment signaling are related with progression of the cell cycle. (PMID:15389565)
• ADAM12m is highly expressed in human glioblastomas and may play a role in the prominent proliferation of the glioblastomas through shedding of heparin-binding epidermal growth factor (PMID:15509542)
• HB-EGF has a function in endometrial maturation in mediating decidualization and attenuating TNF alpha- and TGF beta-induced apoptosis of endometrial stromal cells. (PMID:15562026)
• HB-EGF/HER-1 signaling is relevant to mesenchymal stem cell biology, by regulating both proliferation and differentiation (PMID:15755902)
• These results suggested that HB-EGF in peritoneal fluid might play a key role in cell survival and in the proliferation of OVCA. (PMID:15827558)
• HB-EGF may play a vital role in regulating luteal growth in a juxtacrine manner and through activating HER4 signalling (PMID:15979989)
• HB-EGF is one of the factors that are significantly upregulated in PVR (proliferative vitreoretinopathy) retinas. (PMID:15988409)
• Recombinant HB-EGF decreases proinflammatory cytokine-stimulated NF-kappa B activation and nitric oxide production via activation of the phosphoinositide-3-kinase signaling pathway. (PMID:16034135)
• A post-transcriptional mechanism induced in trophoblasts by low O(2) rapidly amplifies HBEGF signaling to inhibit apoptosis. (PMID:16407398)
• HB-EGF and amphiregulin mediate retinoic-acid induced epidermal hyperplasia (PMID:16470170)
• results suggest a novel role for the cytoplasmic domain of HB-EGF that is regulated by phosphorylation (PMID:16557002)
• lysophosphatidic acid-induced IL-8 secretion is partly dependent on EGFR transactivation regulated by PKCdelta-dependent activation of Lyn kinase and MMPs and proHB-EGF (PMID:16687414)
• Inward potassium current in bladder urothelial cells(BUC) can be modulated by EGF and HB-EGF. Changes in BUC membrane potassium conductance caused by altered levels of EGF and HB-EGF may therefore play role in pathophysiology of interstitial cystitis. (PMID:16837648)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hbegfb	ENSDARG00000031246
danio_rerio	hbegfa	ENSDARG00000075121
mus_musculus	Hbegf	ENSMUSG00000024486
rattus_norvegicus	Hbegf	ENSRNOG00000018646

Paralogs (5): AREG (ENSG00000109321), EREG (ENSG00000124882), TGFA (ENSG00000163235), BTC (ENSG00000174808), EPGN (ENSG00000182585)

Protein

Protein identifiers

Proheparin-binding EGF-like growth factor — Q99075 (reviewed: Q99075)

All UniProt accessions (1): Q99075

UniProt curated annotations — full annotation on UniProt →

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 / interactions. Interacts with FBLN1. Interacts with EGFR and ERBB4.

Subcellular location. Secreted. Extracellular space Cell membrane.

Post-translational modifications. 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.

RefSeq proteins (1): NP_001936* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain

UniProt features (29 total): glycosylation site 6, strand 4, disulfide bond 3, chain 2, region of interest 2, compositionally biased region 2, propeptide 2, turn 2, topological domain 2, signal peptide 1, site 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1XDT	X-RAY DIFFRACTION	2.65
2M8S	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99075-F1	66.75	0.15

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 141 (plays a critical role in diphtheria toxin binding and toxin sensitivity)

Disulfide bonds (3): 108–121, 116–132, 134–143

Glycosylation sites (6): 37, 38, 44, 47, 75, 85

Function

Pathways and Gene Ontology

Reactome pathways

31 pathways

ID	Pathway
R-HSA-1227986	Signaling by ERBB2
R-HSA-1236394	Signaling by ERBB4
R-HSA-1250196	SHC1 events in ERBB2 signaling
R-HSA-1250342	PI3K events in ERBB4 signaling
R-HSA-1250347	SHC1 events in ERBB4 signaling
R-HSA-1251985	Nuclear signaling by ERBB4
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-177929	Signaling by EGFR
R-HSA-179812	GRB2 events in EGFR signaling
R-HSA-180292	GAB1 signalosome
R-HSA-180336	SHC1 events in EGFR signaling
R-HSA-182971	EGFR downregulation
R-HSA-1963640	GRB2 events in ERBB2 signaling
R-HSA-1963642	PI3K events in ERBB2 signaling
R-HSA-212718	EGFR interacts with phospholipase C-gamma
R-HSA-2179392	EGFR Transactivation by Gastrin
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5336415	Uptake and function of diphtheria toxin
R-HSA-5638303	Inhibition of Signaling by Overexpressed EGFR
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6785631	ERBB2 Regulates Cell Motility
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8847993	ERBB2 Activates PTK6 Signaling
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-8857538	PTK6 promotes HIF1A stabilization
R-HSA-8863795	Downregulation of ERBB2 signaling
R-HSA-9009391	Extra-nuclear estrogen signaling
R-HSA-9634638	Estrogen-dependent nuclear events downstream of ESR-membrane signaling
R-HSA-9664565	Signaling by ERBB2 KD Mutants

MSigDB gene sets: 602 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, AP1_01, GOBP_EPITHELIUM_DEVELOPMENT, CHIBA_RESPONSE_TO_TSA_UP, WWTAAGGC_UNKNOWN, REACTOME_GAB1_SIGNALOSOME, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, ENK_UV_RESPONSE_KERATINOCYTE_UP, MODULE_64, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GTCTACC_MIR379, GOBP_REGULATION_OF_EPITHELIAL_CELL_MIGRATION

GO Biological Process (17): signal transduction (GO:0007165), epidermal growth factor receptor signaling pathway (GO:0007173), muscle organ development (GO:0007517), regulation of heart contraction (GO:0008016), positive regulation of cell population proliferation (GO:0008284), negative regulation of glycoprotein biosynthetic process (GO:0010561), positive regulation of cell growth (GO:0030307), positive regulation of cell migration (GO:0030335), wound healing, spreading of epidermal cells (GO:0035313), ERBB2-EGFR signaling pathway (GO:0038134), ERBB2-ERBB4 signaling pathway (GO:0038135), positive regulation of smooth muscle cell proliferation (GO:0048661), positive regulation of keratinocyte migration (GO:0051549), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cell chemotaxis (GO:0060326), positive regulation of wound healing (GO:0090303), cell migration (GO:0016477)

GO Molecular Function (6): epidermal growth factor receptor binding (GO:0005154), growth factor activity (GO:0008083), heparin binding (GO:0008201), transmembrane receptor protein tyrosine kinase activator activity (GO:0030297), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), cell surface (GO:0009986), endocytic vesicle membrane (GO:0030666), clathrin-coated endocytic vesicle membrane (GO:0030669), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Signaling by EGFR	5
Signaling by Receptor Tyrosine Kinases	3
Signaling by ERBB2	3
Signaling by ERBB4	3
Intracellular signaling by second messengers	1
Gastrin-CREB signalling pathway via PKC and MAPK	1
PI3K/AKT Signaling in Cancer	1
Uptake and actions of bacterial toxins	1
Signaling by Overexpressed Wild-Type EGFR in Cancer	1
MAPK1/MAPK3 signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
positive regulation of cellular process	2
cell migration	2
ERBB2 signaling pathway	2
signaling receptor activator activity	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
ERBB signaling pathway	1
animal organ development	1
muscle structure development	1
heart contraction	1
regulation of blood circulation	1
cell population proliferation	1
regulation of cell population proliferation	1
glycoprotein biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
regulation of glycoprotein biosynthetic process	1
negative regulation of glycoprotein metabolic process	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
regulation of cell migration	1
positive regulation of cell motility	1
wound healing, spreading of cells	1
epidermal growth factor receptor signaling pathway	1
ERBB4 signaling pathway	1
positive regulation of cell population proliferation	1
smooth muscle cell proliferation	1
regulation of smooth muscle cell proliferation	1
positive regulation of epithelial cell migration	1
keratinocyte migration	1
regulation of keratinocyte migration	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
chemotaxis	1
cellular response to chemical stimulus	1

Protein interactions and networks

STRING

2453 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HBEGF	EGFR	P00533	998
HBEGF	ERBB4	Q15303	995
HBEGF	EGF	P01133	989
HBEGF	ERBB3	P21860	986
HBEGF	CD44	P16070	984
HBEGF	CD9	P21926	980
HBEGF	NRDC	O43847	948
HBEGF	EREG	O14944	928
HBEGF	ERBB2	P04626	911
HBEGF	BTC	P35070	897
HBEGF	TGFA	P01135	864
HBEGF	EPGN	Q6UW88	857
HBEGF	FGF2	P09038	829
HBEGF	PTGS2	P35354	785
HBEGF	ADIPOQ	Q15848	767

IntAct

14 interactions, top by confidence:

A	B	Type	Score
HBEGF	EGFR	psi-mi:“MI:0915”(physical association)	0.610
EGFR	HBEGF	psi-mi:“MI:0407”(direct interaction)	0.610
HBEGF	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
HBEGF	GSN	psi-mi:“MI:0915”(physical association)	0.560
HBEGF	S100A4	psi-mi:“MI:0407”(direct interaction)	0.440
HBEGF	ERBB4	psi-mi:“MI:0915”(physical association)	0.400
HBEGF	GPC4	psi-mi:“MI:0914”(association)	0.350

BioGRID (25): HBEGF (Reconstituted Complex), ZBTB16 (Reconstituted Complex), ZBTB16 (Affinity Capture-Western), ZBTB16 (Reconstituted Complex), HBEGF (Affinity Capture-MS), EGFR (Affinity Capture-Western), HBEGF (Affinity Capture-Western), HBEGF (Affinity Capture-Western), HBEGF (Reconstituted Complex), BAG1 (Two-hybrid), BAG1 (Affinity Capture-Western), HBEGF (Affinity Capture-Western), HBEGF (Proximity Label-MS), HBEGF (Two-hybrid), HBEGF (Affinity Capture-Western)

ESM2 similar proteins: A2BD09, A3KNS2, A5GFQ5, P15943, P24338, Q01580, Q06175, Q06186, Q06335, Q06481, Q08AE8, Q08DX0, Q09118, Q0P5N1, Q0VCT2, Q0VDN7, Q13438, Q2L6K8, Q3MHX6, Q3SWX1, Q58D79, Q58T08, Q5HZV5, Q5MJS3, Q5RKH6, Q68BL7, Q6GN40, Q701R2, Q86VZ4, Q8BHP7, Q8BQ47, Q8CB67, Q8CD91, Q8K2C7, Q8N129, Q8TEQ0, Q92563, Q96C34, Q96KC8, Q99075

Diamond homologs: A0A8U0LTM5, A0A8U0LTT7, P01133, P01134, P01135, P07522, P0DQX9, P0DSL4, P35070, P48030, P55244, P98135, P98138, Q00968, Q01580, Q05928, Q06186, Q06922, Q09118, Q17QD6, Q5EG71, Q6UW88, Q924X1, Q95ND4, Q99075, Q9BEA0, Q9J524, Q9QYM9, Q9TTC5, Q9UIK5, Q9W7C5, A0A6G9KJM3, O14944, P15514, P24338, P31955, Q06175, Q61521, Q6PFE7, Q8IYR6

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
HBEGF	up-regulates	EGFR	binding
ADAM17	“up-regulates activity”	HBEGF	cleavage
MMP1	“up-regulates activity”	HBEGF	cleavage
HBEGF	up-regulates	ERBB4	binding
MMP3	up-regulates	HBEGF	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

19 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

604 predictions. Top by Δscore:

Variant	Effect	Δscore
5:140334280:CCTAA:C	acceptor_loss	1.0000
5:140335867:CTCA:C	donor_loss	1.0000
5:140335868:TCA:T	donor_loss	1.0000
5:140335869:CA:C	donor_loss	1.0000
5:140335870:A:AC	donor_gain	1.0000
5:140335870:ACC:A	donor_loss	1.0000
5:140335871:C:CC	donor_gain	1.0000
5:140336023:GGCAG:G	acceptor_gain	1.0000
5:140336024:GCAG:G	acceptor_gain	1.0000
5:140336025:CAG:C	acceptor_gain	1.0000
5:140336025:CAGC:C	acceptor_gain	1.0000
5:140336026:AG:A	acceptor_gain	1.0000
5:140336027:GCTAG:G	acceptor_loss	1.0000
5:140336028:C:CC	acceptor_gain	1.0000
5:140336034:C:CT	acceptor_gain	1.0000
5:140336035:A:T	acceptor_gain	1.0000
5:140336039:C:CT	acceptor_gain	1.0000
5:140336040:A:T	acceptor_gain	1.0000
5:140342629:ACTT:A	donor_loss	1.0000
5:140342630:CTTA:C	donor_loss	1.0000
5:140342631:TTA:T	donor_loss	1.0000
5:140342632:T:TG	donor_loss	1.0000
5:140342633:A:AC	donor_gain	1.0000
5:140342633:ACATG:A	donor_gain	1.0000
5:140342634:C:CC	donor_gain	1.0000
5:140342634:CA:C	donor_gain	1.0000
5:140342634:CAT:C	donor_gain	1.0000
5:140342634:CATG:C	donor_gain	1.0000
5:140342634:CATGC:C	donor_gain	1.0000
5:140342808:AGTGA:A	acceptor_gain	1.0000

AlphaMissense

1319 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:140335998:C:G	C143S	0.998
5:140335999:A:T	C143S	0.998
5:140342671:C:G	C121S	0.998
5:140342672:A:T	C121S	0.998
5:140342686:C:G	C116S	0.998
5:140342687:A:T	C116S	0.998
5:140335906:A:G	C174R	0.997
5:140335997:A:C	C143W	0.997
5:140335999:A:G	C143R	0.997
5:140342677:C:T	G119E	0.997
5:140342685:G:C	C116W	0.997
5:140342686:C:T	C116Y	0.997
5:140342687:A:G	C116R	0.997
5:140342710:C:G	C108S	0.997
5:140342711:A:T	C108S	0.997
5:140335998:C:T	C143Y	0.996
5:140342637:G:C	C132W	0.996
5:140342638:C:G	C132S	0.996
5:140342638:C:T	C132Y	0.996
5:140342639:A:T	C132S	0.996
5:140342672:A:G	C121R	0.996
5:140342677:C:A	G119V	0.996
5:140335998:C:A	C143F	0.995
5:140342639:A:G	C132R	0.995
5:140342711:A:G	C108R	0.995
5:140342670:G:C	C121W	0.994
5:140342686:C:A	C116F	0.994
5:140342709:A:C	C108W	0.994
5:140342710:C:T	C108Y	0.994
5:140335926:G:T	A167D	0.993

dbSNP variants (sampled 300 via entrez): RS1000131839 (5:140333966 A>G,T), RS1000239516 (5:140340714 C>A,T), RS1001034570 (5:140344807 G>A), RS1001208670 (5:140344685 G>A), RS1001323275 (5:140344401 C>T), RS1001486782 (5:140337769 G>T), RS1001543163 (5:140335557 C>A,T), RS1001642447 (5:140334312 G>A), RS1001792493 (5:140341259 G>GCC), RS1001933767 (5:140332570 A>G), RS1002096244 (5:140334002 A>T), RS1003013729 (5:140348427 T>G), RS1003654273 (5:140337408 C>A), RS1003671222 (5:140343024 C>A), RS1004029658 (5:140333101 T>A)

Disease associations

OMIM: gene MIM:126150 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002817_7	Alzheimer’s disease in APOE e4- carriers	3.000000e-07
GCST004246_1	Alzheimer’s disease	7.000000e-09
GCST004373_10	Atrial fibrillation	2.000000e-07
GCST005316_410	Intelligence (MTAG)	1.000000e-08
GCST005316_641	Intelligence (MTAG)	5.000000e-09
GCST006014_9	Creatine kinase levels	3.000000e-09
GCST006269_822	General cognitive ability	1.000000e-08
GCST008103_180	Bipolar disorder	9.000000e-06
GCST008115_56	Bipolar I disorder	8.000000e-07
GCST010102_5	White matter integrity (fractional anisotropy)	1.000000e-09
GCST010103_2	White matter integrity (mean diffusivity)	4.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0004534	creatine kinase measurement
EFO:0009963	bipolar I disorder
EFO:0004641	white matter integrity

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3286070 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

179 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression, increases reaction, affects reaction (+2 more)	11
Tobacco Smoke Pollution	increases expression, affects expression	6
Benzo(a)pyrene	increases expression, increases methylation	5
Tretinoin	increases expression	5
Particulate Matter	affects cotreatment, affects reaction, increases secretion, increases abundance, increases expression	5
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases expression	4
Air Pollutants	increases abundance, increases expression, affects cotreatment, decreases expression	4
Hydrogen Peroxide	decreases reaction, increases expression	4
Smoke	decreases expression, decreases nitrosation, increases abundance, increases expression	4
Valproic Acid	affects expression, increases expression	4
Cyclosporine	decreases expression, increases expression	4
vanadium pentoxide	decreases reaction, increases expression	3
SB 203580	decreases reaction, increases expression	3
Doxorubicin	decreases expression, affects response to substance, decreases response to substance	3
Estradiol	affects cotreatment, increases expression, increases abundance	3
Zinc	affects reaction, increases phosphorylation, decreases reaction, increases secretion, affects cotreatment (+2 more)	3
Aflatoxin B1	affects expression, increases expression	3
potassium chromate(VI)	affects cotreatment, increases expression, decreases expression	2
epigallocatechin gallate	affects reaction, increases expression, affects cotreatment	2
RTKI cpd	decreases reaction, increases expression	2
monomethylarsonous acid	decreases expression, increases expression	2
pyrazolanthrone	increases activity, increases reaction, increases expression, decreases reaction	2
dimethylarsinous acid	decreases expression, increases expression	2
Arsenic Trioxide	increases expression	2
Acetaminophen	increases expression	2
Ethanol	affects cotreatment, increases abundance, increases expression, decreases expression, decreases reaction (+1 more)	2
Arsenic	affects cotreatment, increases abundance, increases expression, decreases expression	2
Vehicle Emissions	increases expression, affects cotreatment, affects reaction, increases secretion	2
Calcitriol	increases expression, affects cotreatment	2
Cannabidiol	increases expression	2

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3293890	Binding	Binding affinity to human recombinant HBEGF by surface plasmon resonance assay	Synthesis and biological evaluation of a unique heparin mimetic hexasaccharide for structure-activity relationship studies. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SQ94	HAP1 HBEGF (-) 1	Cancer cell line	Male
CVCL_SQ95	HAP1 HBEGF (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.