HGF

Summary

HGF (hepatocyte growth factor, HGNC:4893) is a protein-coding gene on chromosome 7q21.11, encoding Hepatocyte growth factor (P14210). Potent mitogen for mature parenchymal hepatocyte cells, seems to be a hepatotrophic factor, and acts as a growth factor for a broad spectrum of tissues and cell types.

This gene encodes a protein that binds to the hepatocyte growth factor receptor to regulate cell growth, cell motility and morphogenesis in numerous cell and tissue types. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate alpha and beta chains, which form the mature heterodimer. This protein is secreted by mesenchymal cells and acts as a multi-functional cytokine on cells of mainly epithelial origin. This protein also plays a role in angiogenesis, tumorogenesis, and tissue regeneration. Although the encoded protein is a member of the peptidase S1 family of serine proteases, it lacks peptidase activity. Mutations in this gene are associated with nonsyndromic hearing loss.

Source: NCBI Gene 3082 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive nonsyndromic hearing loss 39 (Strong, GenCC) — +3 more curated relationships
• Clinical variants (ClinVar): 328 total — 6 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes
• MANE Select transcript: NM_000601

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4893
Approved symbol	HGF
Name	hepatocyte growth factor
Location	7q21.11
Locus type	gene with protein product
Status	Approved
Aliases	SF, F-TCF, HGFB, HPTA
Ensembl gene	ENSG00000019991
Ensembl biotype	protein_coding
OMIM	142409
Entrez	3082

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 10 protein_coding, 1 retained_intron

ENST00000222390, ENST00000354224, ENST00000412881, ENST00000421558, ENST00000423064, ENST00000444829, ENST00000453018, ENST00000453411, ENST00000457544, ENST00000465234, ENST00000643024

RefSeq mRNA: 5 — MANE Select: NM_000601 NM_000601, NM_001010931, NM_001010932, NM_001010933, NM_001010934

CCDS: CCDS47626, CCDS47627, CCDS47628, CCDS47629, CCDS5597

Canonical transcript exons

ENST00000222390 — 18 exons

Exon	Start	End
ENSE00000698655	81705390	81705535
ENSE00000698657	81705647	81705753
ENSE00000698658	81706287	81706427
ENSE00000698659	81707290	81707364
ENSE00000698660	81710147	81710243
ENSE00000698661	81711481	81711519
ENSE00000698662	81717232	81717365
ENSE00000698663	81720745	81720847
ENSE00000698665	81725890	81726017
ENSE00000698668	81729605	81729779
ENSE00000698671	81743353	81743471
ENSE00000698721	81745000	81745120
ENSE00000698723	81752120	81752262
ENSE00001724324	81769884	81770047
ENSE00003490651	81758692	81758804
ENSE00003590166	81762707	81762872
ENSE00003637724	81757189	81757303
ENSE00003850244	81699010	81702757

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 95.47.

FANTOM5 (CAGE): breadth broad, TPM avg 14.4541 / max 2724.0260, expressed in 888 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84562	7.0491	595
84565	1.6068	330
84561	1.4234	359
84564	1.1354	349
84563	0.9898	331
84560	0.8506	269
84568	0.6071	175
84567	0.3095	164
204507	0.2870	141
84566	0.1705	93

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	95.47	gold quality
stromal cell of endometrium	CL:0002255	91.15	gold quality
visceral pleura	UBERON:0002401	90.54	gold quality
buccal mucosa cell	CL:0002336	90.11	gold quality
monocyte	CL:0000576	87.87	gold quality
mononuclear cell	CL:0000842	87.73	gold quality
epithelial cell of pancreas	CL:0000083	87.49	gold quality
leukocyte	CL:0000738	86.98	gold quality
gall bladder	UBERON:0002110	86.03	gold quality
choroid plexus epithelium	UBERON:0003911	85.51	gold quality
pleura	UBERON:0000977	85.36	gold quality
liver	UBERON:0002107	85.23	gold quality
right coronary artery	UBERON:0001625	85.07	gold quality
left adrenal gland cortex	UBERON:0035825	84.12	gold quality
right lobe of liver	UBERON:0001114	84.04	gold quality
adrenal cortex	UBERON:0001235	84.04	gold quality
left adrenal gland	UBERON:0001234	83.88	gold quality
upper lobe of left lung	UBERON:0008952	83.41	gold quality
adrenal gland	UBERON:0002369	83.25	gold quality
upper lobe of lung	UBERON:0008948	83.13	gold quality
right lung	UBERON:0002167	82.47	gold quality
parietal pleura	UBERON:0002400	82.46	gold quality
left coronary artery	UBERON:0001626	82.28	gold quality
lung	UBERON:0002048	82.08	gold quality
coronary artery	UBERON:0001621	81.61	gold quality
ventricular zone	UBERON:0003053	81.49	gold quality
right adrenal gland cortex	UBERON:0035827	81.42	gold quality
tendon of biceps brachii	UBERON:0008188	81.24	silver quality
calcaneal tendon	UBERON:0003701	81.16	gold quality
right adrenal gland	UBERON:0001233	80.99	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-HCAD-23	yes	2607.77
E-GEOD-76312	yes	1116.12
E-HCAD-24	yes	673.65
E-MTAB-6701	yes	73.55
E-MTAB-9067	yes	14.09
E-ANND-3	yes	7.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

183 targeting HGF, 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-3163	100.00	77.23	8605
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753

Literature-anchored findings (GeneRIF, showing 40)

• hepatocyte growth factor Downregulates E-cadherin and Desmoglein 1 during melanoma development (PMID:11781826)
• Hepatocyte growth factor (PMID:11799124)
• Hepatocyte growth factor/scatter factor inhibits UVB-induced apoptosis of human keratinocytes but not of keratinocyte-derived cell lines via the phosphatidylinositol 3-kinase/AKT pathway. (PMID:11821397)
• Hepatocyte growth factor is essential for migration of myogenic cells and promotes their proliferation during the early periods of tongue morphogenesis in mouse embryos. (PMID:11836782)
• Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer (PMID:11839685)
• Polymorphonuclear neutrophils are a source of hepatocyte growth factor in patients with severe alcoholic hepatitis. (PMID:11867177)
• Scatter factor/hepatocyte growth factor stimulation of glioblastoma cell cycle progression through G(1) is c-Myc dependent and independent of p27 suppression, Cdk2 activation, or E2F1-dependent transcription. (PMID:11909963)
• Unlike other growth factors, HGF did not show any activity on the fibrinolytic system in both normal and dystrophic myoblasts. (PMID:11928807)
• regulation of production, subcellular localization and molecular form in neutrophils (PMID:11929792)
• play important roles in lung development, lung inflammation, and repair. (PMID:11943656)
• role in inhibiting anoikis in head and neck squamous cell carcinoma cells by activation of ERK and Akt signaling independent of NFkappa B (PMID:11994287)
• a diagnostic marker of thrombus formation in patients with cerebral infarction. (PMID:11999653)
• A new crystal form of the NK1 splice variant of HGF/SF demonstrates extensive hinge movement and suggests that the NK1 dimer originates by domain swapping. (PMID:12051906)
• HGF/SF decreased transendothelial resistance (TER) and increased paracellular permeability in human vascular endothelial cells (PMID:12124772)
• HGF in combination with vitamin D3 may have an autocrine and/or paracrine effect on the osteogenic maturation of bone marrow stromal cells, as well as on bone repair and remodeling. (PMID:12151078)
• These results suggest that hepatocyte growth factor and interleukin-6 upregulate each other’s receptors, and thus cooperatively enhance tissue invasion. (PMID:12151314)
• Data show that thymosin beta4 was differentially expressed in HGF-treated HUVECs compared with control. (PMID:12163032)
• HGF and HGFR have an alternative role activating the via STAT3 transdution and operating on placental tissues, overall in organogenesis alteration conditions (PMID:12168776)
• Hepatocyte growth factor as cardiovascular hormone: role of HGF in the pathogenesis of cardiovascular disease. Review. (PMID:12201209)
• The serum level of HGF represents the degree of the carcinogenic state in the liver of patients with C-viral chronic hepatitis and cirrhosis. (PMID:12209727)
• Overexpression of HGF/c-met appears to be a biological feedback response to the fibrotic process of systemic sclerosis. (PMID:12233882)
• HGF induces a strong and transient tyrosine phosphorylation of c-Cbl, resulting in an increased association with Fyn, Lyn, PI-3K, and CrkL. (PMID:12244174)
• aberrant signaling involvement in rhabdomyosarcomagenesis (PMID:12368906)
• plasma kallikrein and FXIa activate pro-HGF in vitro (PMID:12372819)
• NK4-transfected clone showed significant inhibition of pancreatic tumor progression in both the orthotopic implantation and liver metastasis models (PMID:12374695)
• Hepatocyte growth factor triggers signaling cascades mediating vascular smooth muscle cell migration. (PMID:12379223)
• HGF may stimulate the progression and growth of tumor cells in vivo by induction of Cox-2 (PMID:12393863)
• Increased expression of HGF and KGF by buccal mucosal fibroblasts may partly be responsible for the faster wound healing with less scar formation in the oral cavity compared with normal skin. (PMID:12413766)
• HGF, but not VEGF, serum levels in the coronary circulation correlated with left ventricular remodeling, suggesting HGF interaction in the wound-healing process associated with inflammation after AMI (PMID:12419930)
• in human tumor cells, HGF and M-CSF stimulate osteopontin production (which is subsequently used as a substrate for cell adhesion) (PMID:12456016)
• The production of this factor in kidney increases after unilateral nephrectomy. (PMID:12493396)
• immunoexpression of hepatocyte growth factor and c-Met in the eutopic endometrium of patients with pelvic endometrioisis is possibly useful to predict greater activity of the ectopic endometrium (PMID:12524084)
• These results argue for growth factor-dependent hepatocellular carcinoma development and provide novel and combined prognosis markers after HCC surgery. (PMID:12619035)
• In the presence of keratinocytes, fibroblasts from buccal mucosa, periodontal ligament, & skin increased increased HGF and KGF production 2-3 times. This may influence the proliferation & migration of junctional epithelium and affect periodontal disease. (PMID:12645668)
• The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma. (PMID:12682635)
• Tetranectin binds to this protein and TTPA. (PMID:12694198)
• Post-myocardial infarction human HGF gene therapy improved LV remodeling and dysfunction through hypertrophy of cardiomyocytes, infarct wall thickening, preservation of vessels, and antifibrosis in a mouse model (PMID:12695295)
• Autocrine and paracrine support of HGF-c-Met system attenuates degeneration of anterior horn cells in amyotrophic lateral sclerosis. Disruption of neuronal HGF-c-Met system at advanced stage accelerates cellular degeneration and cell death. (PMID:12707786)
• HGF and VEGF modulate the expression of cell adhesion and migration molecules and induce proliferation in endothelial cells, which may contribute to chronic hepatitis C-associated liver angiogenesis. (PMID:12713878)
• stimulates eNOS activity by a PI3K/Akt-dependent phosphorylation in a Ca(2+)-sensitive manner in vascular endothelial cells (PMID:12757411)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	hgfa	ENSDARG00000045544
danio_rerio	hgfb	ENSDARG00000079076
mus_musculus	Hgf	ENSMUSG00000028864
rattus_norvegicus	Hgf	ENSRNOG00000007027
drosophila_melanogaster	CG14780	FBGN0025383
drosophila_melanogaster	CG14227	FBGN0031058
drosophila_melanogaster	CG11664	FBGN0040341
drosophila_melanogaster	CG30287	FBGN0050287
drosophila_melanogaster	CG30288	FBGN0050288
drosophila_melanogaster	CG30289	FBGN0050289
drosophila_melanogaster	CG30414	FBGN0050414
drosophila_melanogaster	CG31205	FBGN0051205
drosophila_melanogaster	CG33225	FBGN0053225
drosophila_melanogaster	CG33226	FBGN0069056
drosophila_melanogaster	CG30283	FBGN0260477

Paralogs (5): PIK3IP1 (ENSG00000100100), GZMK (ENSG00000113088), GZMA (ENSG00000145649), HABP2 (ENSG00000148702), MST1 (ENSG00000173531)

Protein

Protein identifiers

Hepatocyte growth factor — P14210 (reviewed: P14210)

Alternative names: Hepatopoietin-A, Scatter factor

All UniProt accessions (6): A0A2R8YEI1, C9JDP4, C9JS80, C9WSJ3, C9WSJ4, P14210

UniProt curated annotations — full annotation on UniProt →

Function. Potent mitogen for mature parenchymal hepatocyte cells, seems to be a hepatotrophic factor, and acts as a growth factor for a broad spectrum of tissues and cell types. Activating ligand for the receptor tyrosine kinase MET by binding to it and promoting its dimerization. Activates MAPK signaling following TMPRSS13 cleavage and activation.

Subunit / interactions. Dimer of an alpha chain and a beta chain linked by a disulfide bond. Interacts with SRPX2; the interaction increases HGF mitogenic activity.

Post-translational modifications. The single-chain precursor undergoes proteolytic processing by TMPRSS13 resulting in an active two-chain form. The single-chain precursor undergoes proteolytic processing by HGFAC resulting in an active two-chain form.

Disease relevance. Deafness, autosomal recessive, 39 (DFNB39) [MIM:608265] A form of profound prelingual sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Acts as a competitive antagonist in MET-signaling.

Similarity. Belongs to the peptidase S1 family. Plasminogen subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
P14210-1	1	yes
P14210-2	2
P14210-3	3
P14210-4	4, HGF/NK2
P14210-5	5
P14210-6	6, HGF/NK1

RefSeq proteins (5): NP_000592, NP_001010931, NP_001010932, NP_001010933, NP_001010934 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000001	Kringle	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR003609	Pan_app	Domain
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR013806	Kringle-like	Homologous_superfamily
IPR018056	Kringle_CS	Conserved_site
IPR024174	HGF/MST1	Family
IPR027284	Hepatocyte_GF	Family
IPR038178	Kringle_sf	Homologous_superfamily
IPR043504
IPR050759	Serine_protease_kringle	Family

Pfam: PF00024, PF00051, PF00089

UniProt features (109 total): strand 33, disulfide bond 19, sequence conflict 15, helix 10, turn 7, splice variant 7, domain 6, glycosylation site 5, chain 2, sequence variant 2, signal peptide 1, mutagenesis site 1, modified residue 1

Structure

Experimental structures (PDB)

36 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3HMS	X-RAY DIFFRACTION	1.7
7OCM	X-RAY DIFFRACTION	1.7
7OCL	X-RAY DIFFRACTION	1.8
2QJ2	X-RAY DIFFRACTION	1.81
3SP8	X-RAY DIFFRACTION	1.86
5CP9	X-RAY DIFFRACTION	1.9
5CS5	X-RAY DIFFRACTION	1.9
5CSQ	X-RAY DIFFRACTION	1.95
1BHT	X-RAY DIFFRACTION	2
3HMT	X-RAY DIFFRACTION	2
5CS1	X-RAY DIFFRACTION	2
5CS9	X-RAY DIFFRACTION	2
5CT1	X-RAY DIFFRACTION	2
5CT2	X-RAY DIFFRACTION	2
5CT3	X-RAY DIFFRACTION	2
5COE	X-RAY DIFFRACTION	2.18
1GMN	X-RAY DIFFRACTION	2.3
1GP9	X-RAY DIFFRACTION	2.5
1NK1	X-RAY DIFFRACTION	2.5
5CS3	X-RAY DIFFRACTION	2.5
1SI5	X-RAY DIFFRACTION	2.53
3HN4	X-RAY DIFFRACTION	2.6
4D3C	X-RAY DIFFRACTION	2.62
4K3J	X-RAY DIFFRACTION	2.8
6LZ9	X-RAY DIFFRACTION	2.8
3MKP	X-RAY DIFFRACTION	2.81
4O3T	X-RAY DIFFRACTION	2.99
1GMO	X-RAY DIFFRACTION	3
4O3U	X-RAY DIFFRACTION	3.04
1SHY	X-RAY DIFFRACTION	3.22

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P14210-F1	83.76	0.52

Antibody-complex structures (SAbDab): 3 — 4D3C, 4K3J, 6LZ9

Functional residue map

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

Post-translational modifications (1): 32

Disulfide bonds (19): 70–96, 74–84, 128–206, 149–189, 177–201, 211–288, 232–271, 260–283, 305–383, 326–365, 354–377, 391–469, 412–452, 440–464, 487–604, 519–535, 612–679, 642–658, 669–697

Glycosylation sites (5): 294, 402, 476, 566, 653

Mutagenesis-validated functional residues (1):

Position	Phenotype
494	loss of activity due to absence of proteolytic cleavage.

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1266695	Interleukin-7 signaling
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-6806942	MET Receptor Activation
R-HSA-6807004	Negative regulation of MET activity
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8851805	MET activates RAS signaling
R-HSA-8851907	MET activates PI3K/AKT signaling
R-HSA-8865999	MET activates PTPN11
R-HSA-8874081	MET activates PTK2 signaling
R-HSA-8875513	MET interacts with TNS proteins
R-HSA-8875555	MET activates RAP1 and RAC1
R-HSA-8875656	MET receptor recycling
R-HSA-8875791	MET activates STAT3
R-HSA-9734091	Drug-mediated inhibition of MET activation

MSigDB gene sets: 416 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, VERHAAK_AML_WITH_NPM1_MUTATED_DN, CREL_01, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_GLAND_MORPHOGENESIS, GOBP_POSITIVE_REGULATION_OF_DNA_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_MORPHOGENESIS_OF_A_BRANCHING_STRUCTURE, HARRIS_HYPOXIA, GOBP_CELL_CHEMOTAXIS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_SALIVARY_GLAND_DEVELOPMENT

GO Biological Process (32): mitotic cell cycle (GO:0000278), cell morphogenesis (GO:0000902), epithelial to mesenchymal transition (GO:0001837), liver development (GO:0001889), negative regulation of autophagy (GO:0010507), skeletal muscle cell proliferation (GO:0014856), positive regulation of cell migration (GO:0030335), negative regulation of interleukin-6 production (GO:0032715), positive regulation of interleukin-10 production (GO:0032733), cellular response to hepatocyte growth factor stimulus (GO:0035729), negative regulation of apoptotic process (GO:0043066), positive regulation of MAPK cascade (GO:0043410), positive regulation of osteoblast differentiation (GO:0045669), positive regulation of transcription by RNA polymerase II (GO:0045944), hepatocyte growth factor receptor signaling pathway (GO:0048012), epithelial cell proliferation (GO:0050673), negative regulation of inflammatory response (GO:0050728), myoblast proliferation (GO:0051450), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cell chemotaxis (GO:0060326), regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling (GO:0060665), negative regulation of release of cytochrome c from mitochondria (GO:0090201), regulation of p38MAPK cascade (GO:1900744), negative regulation of hydrogen peroxide-mediated programmed cell death (GO:1901299), negative regulation of extrinsic apoptotic signaling pathway via death domain receptors (GO:1902042), positive regulation of DNA biosynthetic process (GO:2000573), proteolysis (GO:0006508), signal transduction (GO:0007165), regulation of anatomical structure morphogenesis (GO:0022603), animal organ development (GO:0048513), positive chemotaxis (GO:0050918), regulation of multicellular organismal process (GO:0051239)

GO Molecular Function (6): signaling receptor binding (GO:0005102), growth factor activity (GO:0008083), chemoattractant activity (GO:0042056), identical protein binding (GO:0042802), serine-type endopeptidase activity (GO:0004252), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), membrane (GO:0016020), platelet alpha granule lumen (GO:0031093)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Signaling by MET	7
MET promotes cell motility	3
Signaling by Interleukins	2
Response to elevated platelet cytosolic Ca2+	1
Intracellular signaling by second messengers	1
PI3K/AKT Signaling in Cancer	1
MAPK1/MAPK3 signaling	1
Negative regulation of the PI3K/AKT network	1
Negative regulation of MET activity	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell migration	2
positive regulation of intracellular signal transduction	2
cell population proliferation	2
protein binding	2
receptor ligand activity	2
cellular anatomical structure	2
cell cycle	1
mitotic nuclear division	1
anatomical structure morphogenesis	1
mesenchymal cell differentiation	1
gland development	1
hepaticobiliary system development	1
autophagy	1
negative regulation of catabolic process	1
regulation of autophagy	1
striated muscle cell proliferation	1
regulation of cell migration	1
positive regulation of cell motility	1
negative regulation of cytokine production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
positive regulation of cytokine production	1
interleukin-10 production	1
regulation of interleukin-10 production	1
response to hepatocyte growth factor	1
cellular response to growth factor stimulus	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
MAPK cascade	1
regulation of MAPK cascade	1
osteoblast differentiation	1
positive regulation of cell differentiation	1
regulation of osteoblast differentiation	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cell surface receptor protein tyrosine kinase signaling pathway	1
inflammatory response	1
negative regulation of defense response	1

Protein interactions and networks

STRING

3749 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HGF	MET	P08581	999
HGF	NTRK1	P04629	993
HGF	NRP1	O14786	952
HGF	FN1	P02751	948
HGF	EGFR	P00533	947
HGF	CD44	P16070	946
HGF	FGF2	P09038	928
HGF	MST1R	Q04912	926
HGF	IL7	P13232	922
HGF	KDR	P35968	908
HGF	FGF7	P21781	890
HGF	FGF10	O15520	886
HGF	FGF4	P08620	884
HGF	FGF22	Q9HCT0	881
HGF	FGF6	P10767	876

IntAct

46 interactions, top by confidence:

A	B	Type	Score
HGF	MET	psi-mi:“MI:0407”(direct interaction)	0.850
MET	HGF	psi-mi:“MI:0407”(direct interaction)	0.850
MET	HGF	psi-mi:“MI:0915”(physical association)	0.850
HGF	HGF	psi-mi:“MI:0407”(direct interaction)	0.620
MEOX2	HGF	psi-mi:“MI:0915”(physical association)	0.560
ADAMTSL4	HGF	psi-mi:“MI:0915”(physical association)	0.560
HGF	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
HGF	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.560
HGF	Met	psi-mi:“MI:0407”(direct interaction)	0.560
Met	HGF	psi-mi:“MI:0407”(direct interaction)	0.560
HGF	HGFAC	psi-mi:“MI:0194”(cleavage reaction)	0.440
HGF	Hgf	psi-mi:“MI:0407”(direct interaction)	0.440
HGF	SRPX2	psi-mi:“MI:0407”(direct interaction)	0.440
HGF	FKBP7	psi-mi:“MI:0915”(physical association)	0.400
CD44	MET	psi-mi:“MI:0915”(physical association)	0.400
HGF	ZZEF1	psi-mi:“MI:0914”(association)	0.350
	NFIB	psi-mi:“MI:0914”(association)	0.350
AKT1	HGF	psi-mi:“MI:2364”(proximity)	0.270
HGF	FBXW7	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	HGF	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (49): MEOX2 (Two-hybrid), ADAMTSL4 (Two-hybrid), BRCA1 (Two-hybrid), FKBP7 (Affinity Capture-MS), FN1 (Co-localization), FKBP7 (Affinity Capture-MS), MET (Protein-peptide), HGF (Reconstituted Complex), HGF (Synthetic Lethality), HGF (Synthetic Lethality), EPHA2 (FRET), LATS2 (FRET), MYC (FRET), STK11 (FRET), HGF (FRET)

ESM2 similar proteins: A1L1V4, A6H737, B4F6N6, B5DF27, B8A4W9, E1C3U7, F1QQC3, F1RD85, M9PE65, O08762, O35548, O73798, O97827, P05156, P14210, P16264, P51512, P51559, P56730, P58022, P58215, P86091, Q08B63, Q17800, Q20911, Q5G265, Q5G266, Q5G267, Q5G268, Q5G269, Q5G270, Q5G271, Q5R5A4, Q5RDI1, Q5RFQ6, Q5W7F4, Q61129, Q7RTY8, Q7TQN3, Q80TS3

Diamond homologs: A0A7J6K144, O18783, P00734, P06868, P08519, P12545, P14210, P14417, P17945, P20918, P26927, P26928, P80010, Q01177, Q01973, Q08048, Q16609, Q24K22, Q29485, Q2TV78, Q5R537, Q5R8X6, Q76BS1, Q7M323, Q867B7, Q9BH09, Q9V6K3, Q9Z139, D3ZTE0, O35453, P00735, P00747, P00750, P00774, P04813, P05208, P05981, P06867, P06869, P08001

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
TWIST1	“up-regulates quantity by expression”	HGF	“transcriptional regulation”
TMPRSS2	“up-regulates quantity by expression”	HGF	“transcriptional regulation”
SP1	“up-regulates quantity by expression”	HGF	“transcriptional regulation”
HGF	up-regulates	MET	binding
SP3	“up-regulates quantity by expression”	HGF	“transcriptional regulation”
STAT3	“up-regulates quantity by expression”	HGF	“transcriptional regulation”
KLKB1	“up-regulates activity”	HGF	cleavage
F11	“up-regulates activity”	HGF	cleavage
HGF	“up-regulates activity”	MET	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	2
Uncertain significance	141
Likely benign	114
Benign	33

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
14949	NM_000601.6(HGF):c.495G>A (p.Ser165=)	Pathogenic
14951	NM_000601.6(HGF):c.482+1991_482+2000del	Pathogenic
2044269	NM_000601.6(HGF):c.1953_1954insGAATGAGT (p.Leu652delinsGluTer)	Pathogenic
2821398	NM_000601.6(HGF):c.1048C>T (p.Arg350Ter)	Pathogenic
4691870	NM_000601.6(HGF):c.1091G>A (p.Trp364Ter)	Pathogenic
4728122	NM_000601.6(HGF):c.6G>A (p.Trp2Ter)	Pathogenic
2507239	NM_000601.6(HGF):c.84T>G (p.Tyr28Ter)	Likely pathogenic
4773543	NM_000601.6(HGF):c.1616+1G>A	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

4808 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:81705660:C:A	W617C	1.000
7:81705660:C:G	W617C	1.000
7:81720771:C:A	W415C	1.000
7:81720771:C:G	W415C	1.000
7:81729658:C:A	W329C	1.000
7:81729658:C:G	W329C	1.000
7:81745041:C:A	W235C	1.000
7:81745041:C:G	W235C	1.000
7:81702623:C:A	W715C	0.999
7:81702623:C:G	W715C	0.999
7:81702625:A:G	W715R	0.999
7:81702625:A:T	W715R	0.999
7:81702678:C:G	C697S	0.999
7:81702679:A:T	C697S	0.999
7:81702738:A:G	L677P	0.999
7:81705427:C:G	C658S	0.999
7:81705428:A:T	C658S	0.999
7:81705475:C:G	C642S	0.999
7:81705476:A:T	C642S	0.999
7:81705662:A:G	W617R	0.999
7:81705662:A:T	W617R	0.999
7:81705675:G:C	C612W	0.999
7:81707317:A:G	L530P	0.999
7:81707350:C:G	C519S	0.999
7:81707351:A:T	C519S	0.999
7:81717246:C:G	C464S	0.999
7:81717247:A:T	C464S	0.999
7:81717254:C:A	W461C	0.999
7:81717254:C:G	W461C	0.999
7:81717281:G:C	C452W	0.999

dbSNP variants (sampled 300 via entrez): RS1000094473 (7:81732405 C>A,T), RS1000129891 (7:81742385 C>T), RS1000159435 (7:81756139 G>A,C), RS1000207363 (7:81760092 C>T), RS1000246826 (7:81701200 A>G), RS1000303357 (7:81728973 A>G), RS1000339624 (7:81762934 A>G), RS1000352910 (7:81748161 T>C), RS1000374358 (7:81724705 T>C,G), RS1000398510 (7:81771673 T>C), RS1000449384 (7:81710414 C>T), RS1000508628 (7:81743763 G>A), RS1000573717 (7:81737259 C>T), RS1000696540 (7:81735659 T>G), RS1000769416 (7:81771996 C>A,G,T)

Disease associations

OMIM: gene MIM:142409 | disease phenotypes: MIM:608265

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive nonsyndromic hearing loss 39	Strong	Autosomal recessive
lymphedema	Strong	Autosomal dominant
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Moderate	AR

Mondo (5): hearing loss disorder (MONDO:0005365), autosomal recessive nonsyndromic hearing loss 39 (MONDO:0012003), sensorineural hearing loss disorder (MONDO:0020678), hearing loss, autosomal recessive (MONDO:0019588), lymphedema (MONDO:0019297)

Orphanet (1): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000407	Sensorineural hearing impairment

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008209	Lymphedema	C15.604.496
C564609	Deafness, Autosomal Recessive (supp.)
C564265	Deafness, Autosomal Recessive 39 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5479 (SINGLE PROTEIN)

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

ChEMBL bioactivities

9 potent at pChembl≥5 of 9 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.23	IC50	59	nM	CHEMBL447602
7.19	IC50	64	nM	CHEMBL453737
7.16	IC50	69	nM	CHEMBL447602
7.09	IC50	82	nM	CHEMBL453737
6.79	IC50	161	nM	CHEMBL444560
6.71	IC50	196	nM	CHEMBL444560
6.50	IC50	313	nM	CHEMBL461648
6.43	IC50	368	nM	CHEMBL461648
5.71	Kd	1950	nM	CHEMBL2337901

PubChem BioAssay actives

9 with measured affinity, of 10 total; 5 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-(4-fluoroanilino)-5-[5-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxy-2-pyridinyl]-3-methylpyrimidin-4-one	364262: Inhibition of human recombinant HGF-mediated cMet phosphorylation in mouse CT26 cells	ic50	0.0590	uM
2-(4-fluoroanilino)-5-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-3-methylpyrimidin-4-one	364261: Inhibition of human recombinant HGF-mediated cMet phosphorylation in human PC3 cells	ic50	0.0640	uM
5-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-2-[(4-fluorophenyl)methyl]-3-methylpyrimidin-4-one	364261: Inhibition of human recombinant HGF-mediated cMet phosphorylation in human PC3 cells	ic50	0.1610	uM
2-benzyl-5-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-3-methylpyrimidin-4-one	364261: Inhibition of human recombinant HGF-mediated cMet phosphorylation in human PC3 cells	ic50	0.3130	uM
disodium;1-amino-4-[4-[4-[(4-amino-9,10-dioxo-3-sulfonatoanthracen-1-yl)amino]phenyl]anilino]-9,10-dioxoanthracene-2-sulfonate	733888: Binding affinity to immobilized HGF (unknown origin) by surface plasmon resonance analysis	kd	1.9500	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
trichostatin A	affects cotreatment, increases expression	4
Tretinoin	increases secretion, decreases reaction, increases expression, decreases expression, decreases secretion	4
Doxorubicin	decreases expression, decreases response to substance	3
Cyclosporine	decreases expression, increases expression, affects cotreatment	3
perfluorooctanoic acid	decreases expression	2
perfluorooctane sulfonic acid	decreases expression	2
N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide	increases activity, increases expression, decreases expression, decreases reaction	2
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	increases phosphorylation, affects localization, decreases reaction, increases expression	2
5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one	increases activity, increases phosphorylation, decreases reaction	2
Arsenic Trioxide	decreases expression, increases expression	2
Alitretinoin	increases secretion, decreases expression, decreases secretion, increases expression	2
Arsenic	affects methylation, increases expression	2
Chenodeoxycholic Acid	decreases reaction, increases expression, affects cotreatment, decreases expression	2
Deoxycholic Acid	affects cotreatment, decreases expression, decreases reaction, increases expression	2
Dexamethasone	decreases reaction, increases expression, decreases expression	2
Estradiol	decreases expression, affects cotreatment	2
Glycochenodeoxycholic Acid	increases expression, affects cotreatment, decreases expression, decreases reaction	2
Heparin	increases reaction, increases expression, affects binding, increases activity	2
Hydrogen Peroxide	increases phosphorylation, decreases expression, decreases reaction, increases cleavage, increases expression	2
Lipopolysaccharides	decreases reaction, increases expression, affects cotreatment, decreases expression	2
Progesterone	affects cotreatment, decreases expression	2
Quercetin	affects binding, decreases reaction, increases reaction, increases expression, increases phosphorylation (+1 more)	2
Thalidomide	affects expression, affects secretion, decreases activity	2
Sodium Selenite	decreases reaction, increases expression, decreases expression	2
2-methoxy-6-undecyl-1,4-benzoquinone	decreases expression	1
A-1155463	affects reaction, affects response to substance, decreases reaction, increases response to substance	1
securinine	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2340053	Binding	Binding affinity to immobilized HGF (unknown origin) by surface plasmon resonance analysis	Anthraquinone Derivatives as Potent Inhibitors of c-Met Kinase and the Extracellular Signaling Pathway. — ACS Med Chem Lett

Cellosaurus cell lines

19 cell lines: 8 transformed cell line, 7 cancer cell line, 3 embryonic stem cell, 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_6684	MDA-MB-435HGF	Cancer cell line	Male
CVCL_A2P9	SEES3-1V human HGF, clone1	Embryonic stem cell	Male
CVCL_A2Q0	SEES3-1V human HGF, clone2	Embryonic stem cell	Male
CVCL_A2Q1	SEES3-1V human HGF, clone3	Embryonic stem cell	Male
CVCL_B1TL	Abcam HeLa HGF KO	Cancer cell line	Female
CVCL_B7N2	HCC827-HGF1	Cancer cell line	Female
CVCL_B7N3	HCC827-HGF2	Cancer cell line	Female
CVCL_B8HE	Abcam HCT 116 HGF KO	Cancer cell line	Male
CVCL_B8WS	Abcam MCF-7 HGF KO	Cancer cell line	Female
CVCL_B9JN	Abcam A-549 HGF KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00852930	PHASE4	COMPLETED	Low Level Laser Treatment and Breast Cancer Related Lymphedema
NCT01068431	PHASE4	COMPLETED	Short Term Effectiveness Study of Juxta-Fit Versus Trico Bandages in the Treatment of Leg Lymphedema
NCT02257970	PHASE4	COMPLETED	Lymphedema Study for Arm or Leg Lymphedema
NCT02375945	PHASE4	COMPLETED	Comparison Between a Non-elastic Falcro Device and Current Method After Total Knee Arthroplasty
NCT03584633	PHASE4	COMPLETED	Effect of Exercise on Indocyanine Green (ICG) Lymphography Imaging
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT00028951	PHASE3	COMPLETED	Fibrin Sealant in Decreasing Lymphedema Following Surgery to Remove Lymph Nodes in Patients With Cancer of the Vulva
NCT00201890	PHASE3	COMPLETED	Trial of Decongestive Lymphatic Therapy for Lymphedema in Women With Breast Cancer DELTA STUDY
NCT00577317	PHASE3	TERMINATED	Flexitouch® Home Maintenance Therapy or Standard Home Maintenance Therapy in Treating Patients With Lower-Extremity Lymphedema Caused by Treatment for Cervical Cancer, Vulvar Cancer, or Endometrial Cancer
NCT02927496	PHASE3	COMPLETED	A 24 Month Study, to Compare the Efficacy of Doxycycline vs. Placebo for Improving Filarial Lymphedema in Mali
NCT02929121	PHASE3	COMPLETED	A 24 Month Study to Compare Efficacy of Doxycycline vs Placebo for Improving Filarial Lymphedema in India
NCT02929134	PHASE3	COMPLETED	A 24 Month Study to Compare Efficacy of Doxycycline vs Placebo for Improving Filarial Lymphedema in Sri Lanka
NCT04228991	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated LocoRegional Radiotherapy in Breast Cancer
NCT06144164	PHASE3	RECRUITING	A Study of a Comprehensive Prevention Program to Reduce Lymphedema After Axillary Lymph Node Dissection in People With Breast Cancer
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00022204	PHASE2	COMPLETED	Vitamin E and Pentoxifylline in Treating Women With Lymphedema After Radiation Therapy for Breast Cancer
NCT00058851	PHASE2	COMPLETED	Massage Therapy for Breast Cancer Treatment-Related Swelling of the Arms
NCT00064857	PHASE2	COMPLETED	Pycnogenol for the Treatment of Lymphedema of the Arm in Breast Cancer Survivors
NCT00077090	PHASE2	UNKNOWN	Hyperbaric Oxygen Therapy Compared With Standard Therapy in Treating Chronic Arm Lymphedema in Patients Who Have Undergone Radiation Therapy for Cancer
NCT00155220	PHASE2	UNKNOWN	Treatment of Lymphedema: Application of the Kinesio Taping
NCT00188604	PHASE2	COMPLETED	The Use of Selenium to Treat Secondary Lymphedema - Breast Cancer
NCT00214032	PHASE2	COMPLETED	Pycnogenol for the Treatment of Lymphedema
NCT00589121	PHASE2	COMPLETED	Image-Guided Radiation Therapy in Treating Patients With Primary Soft Tissue Sarcoma of the Shoulder, Arm, Hip, or Leg
NCT00827372	PHASE2	COMPLETED	A Study of Vascular Endothelial Growth Factor (VEGF) Inhibition in Patients With Unilateral Upper Extremity Lymphedema Following Treatment for Cancer
NCT01003951	PHASE2	COMPLETED	Acupuncture for the Treatment of Chronic Lymphedema
NCT01276054	PHASE2	TERMINATED	Sentinel and/or Axillary Lymph Node Biopsy With or Without Axillary Reverse Mapping in Reducing Incidence and Severity of Arm Lymphedema in Stage 0-2 Patients.
NCT01318785	PHASE2	UNKNOWN	Therapeutical Assessment of Compression Armsleeves for Lymphatic Indications
NCT01406769	PHASE2	COMPLETED	Bioimpedance Spectroscopy in Detecting Lower-Extremity Lymphedema in Patients With Stage I, Stage II, Stage III, or Stage IV Vulvar Cancer Undergoing Surgery and Lymphadenectomy
NCT02700529	PHASE2	COMPLETED	Ubenimex in Adult Patients With Lymphedema of The Lower Limb (ULTRA)
NCT02895724	PHASE2	UNKNOWN	Hyperbaric Oxygen Therapy to Reduce Lymphedema After Breast Cancer -an Explorative Clinical Trial
NCT03658967	PHASE2	COMPLETED	Clinical Study With Lymfactin® in the Treatment of Patients With Secondary Lymphedema (AdeLE)
NCT03776721	PHASE2	COMPLETED	Treatment of Breast Cancer-related Lymphedema With Stem Cells and Fat Grafting
NCT06494111	PHASE2	RECRUITING	Systemic Therapy of Open-label Prophylactic Pravastatin or Pentoxifylline/Tocopherol Prevention of Lymphedema Advancing to Eventual Fibrosis: an Interventional Registry-embedded Bayesian Randomized Trial for Radiation Sequelae (STOP4-LATE-FIBROSE)