HDGF

Summary

HDGF (heparin binding growth factor, HGNC:4856) is a protein-coding gene on chromosome 1q23.1, encoding Hepatoma-derived growth factor (P51858). Acts as a transcriptional repressor.

This gene encodes a member of the hepatoma-derived growth factor family. The encoded protein has mitogenic and DNA-binding activity and may play a role in cellular proliferation and differentiation. High levels of expression of this gene enhance the growth of many tumors. This gene was thought initially to be located on chromosome X; however, that location has been determined to correspond to a related pseudogene. Alternatively spliced transcript variants encoding distinct isoforms have been described.

Source: NCBI Gene 3068 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 42 total
• GTEx eGene: eQTL in 13 tissues, sQTL in 15 (q < 0.05)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.40 (moderately constrained)
• MANE Select transcript: NM_004494

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4856
Approved symbol	HDGF
Name	heparin binding growth factor
Location	1q23.1
Locus type	gene with protein product
Status	Approved
Aliases	HMG1L2
Ensembl gene	ENSG00000143321
Ensembl biotype	protein_coding
OMIM	600339
Entrez	3068

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding_CDS_not_defined, 4 protein_coding

MANE Select: ENST00000357325

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 3, TSL 3: 3, TSL 5: 1

ENST00000357325, ENST00000368206, ENST00000368209, ENST00000465180, ENST00000469145, ENST00000471377, ENST00000477306, ENST00000482651, ENST00000495212, ENST00000710272

RefSeq mRNA: 6 — MANE Select: NM_004494 NM_001126050, NM_001126051, NM_001319186, NM_001319187, NM_001319188, NM_004494

CCDS: CCDS1156, CCDS44247, CCDS44248

Canonical transcript exons

ENST00000357325 — 6 exons

Exon	Start	End
ENSE00001425593	156751343	156751675
ENSE00001922574	156742109	156743455
ENSE00003510666	156744163	156744348
ENSE00003530257	156743652	156743878
ENSE00003587600	156745008	156745146
ENSE00003591248	156745297	156745373

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 186.0566 / max 1415.8164, expressed in 1828 samples.

Highest expression (Bgee): endometrium epithelium, ventricular zone, ganglionic eminence, ileal mucosa, olfactory segment of nasal mucosa.

Genetic regulation across tissues (GTEx eQTL / sQTL)

HDGF is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 13 tissues and its splicing (sQTL) in 15 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 28 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Sun Exposed Lower leg	eqtl	3.2e-22	-0.15	1:156752632:G:C
Brain Frontal Cortex BA9	sqtl	1.3e-19	+1.81	1:156755530:AC:A
Brain Nucleus accumbens basal ganglia	sqtl	2.9e-17	+1.82	1:156755530:AC:A
Brain Putamen basal ganglia	sqtl	1.1e-15	+1.67	1:156755530:AC:A
Brain Cortex	sqtl	4.0e-15	+1.63	1:156755530:AC:A
Brain Caudate basal ganglia	sqtl	9.0e-15	+1.61	1:156755530:AC:A
Brain Anterior cingulate cortex BA24	sqtl	7.2e-14	+1.77	1:156755530:AC:A
Brain Spinal cord cervical c-1	sqtl	2.2e-10	+1.56	1:156755530:AC:A
Brain Cerebellar Hemisphere	sqtl	1.2e-09	+1.46	1:156755530:AC:A
Brain Hippocampus	sqtl	1.5e-08	+1.54	1:156755530:AC:A
Skin Not Sun Exposed Suprapubic	eqtl	2.1e-08	-0.11	1:156748656:G:C
Brain Cerebellum	sqtl	2.4e-08	+1.38	1:156755530:AC:A
Brain Amygdala	sqtl	2.2e-07	+1.55	1:156755530:AC:A
Testis	eqtl	4.2e-06	-0.41	1:156751115:C:T
Brain Hypothalamus	sqtl	2.5e-05	+1.30	1:156755530:AC:A
Cells EBV-transformed lymphocytes	eqtl	1.4e-04	-0.12	1:156730859:T:G
Muscle Skeletal	eqtl	2.9e-04	-0.09	1:156748656:G:C
Adrenal Gland	eqtl	5.6e-03	-0.69	1:157046154:A:G
Testis	sqtl	6.0e-03	+0.74	1:156755534:C:T
Pituitary	eqtl	6.6e-03	-0.42	1:157204073:A:AATTTT

FANTOM5 promoters

showing 10 of 16 alternative TSS:

Promoter ID	TPM avg	Samples expressed
15212	155.3059	1828
15211	8.0529	1733
15213	5.2482	1718
15210	3.1834	1411
201759	2.6746	1367
15208	2.6245	1428
15209	2.3497	1302
15218	1.5223	757
15215	1.4206	997
15203	1.4137	836

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	99.47	gold quality
ventricular zone	UBERON:0003053	98.98	gold quality
ganglionic eminence	UBERON:0004023	98.69	gold quality
ileal mucosa	UBERON:0000331	98.68	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.64	gold quality
mucosa of transverse colon	UBERON:0004991	98.62	gold quality
right uterine tube	UBERON:0001302	98.60	gold quality
tongue squamous epithelium	UBERON:0006919	98.60	gold quality
lower esophagus mucosa	UBERON:0035834	98.58	gold quality
rectum	UBERON:0001052	98.49	gold quality
skin of leg	UBERON:0001511	98.42	gold quality
esophagus mucosa	UBERON:0002469	98.41	gold quality
gastrocnemius	UBERON:0001388	98.37	gold quality
skin of abdomen	UBERON:0001416	98.37	gold quality
metanephros cortex	UBERON:0010533	98.36	gold quality
monocyte	CL:0000576	98.31	gold quality
pancreatic ductal cell	CL:0002079	98.28	gold quality
muscle of leg	UBERON:0001383	98.27	gold quality
mononuclear cell	CL:0000842	98.18	gold quality
embryo	UBERON:0000922	98.15	gold quality
leukocyte	CL:0000738	98.12	gold quality
right lobe of liver	UBERON:0001114	98.05	gold quality
esophagus	UBERON:0001043	98.01	gold quality
zone of skin	UBERON:0000014	97.99	gold quality
gall bladder	UBERON:0002110	97.98	gold quality
duodenum	UBERON:0002114	97.95	gold quality
nasal cavity epithelium	UBERON:0005384	97.93	gold quality
nipple	UBERON:0002030	97.92	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.90	gold quality
stromal cell of endometrium	CL:0002255	97.84	gold quality
transverse colon	UBERON:0001157	97.83	gold quality
small intestine	UBERON:0002108	97.83	gold quality
muscle organ	UBERON:0001630	97.82	gold quality
cartilage tissue	UBERON:0002418	97.82	gold quality
islet of Langerhans	UBERON:0000006	97.81	gold quality
vermiform appendix	UBERON:0001154	97.81	gold quality
bone marrow	UBERON:0002371	97.79	gold quality
adult mammalian kidney	UBERON:0000082	97.75	gold quality
trabecular bone tissue	UBERON:0002483	97.73	gold quality
left lobe of thyroid gland	UBERON:0001120	97.72	gold quality
cortical plate	UBERON:0005343	97.70	gold quality
apex of heart	UBERON:0002098	97.69	gold quality
thymus	UBERON:0002370	97.68	gold quality
caecum	UBERON:0001153	97.67	gold quality
body of stomach	UBERON:0001161	97.66	gold quality
upper lobe of left lung	UBERON:0008952	97.66	gold quality
smooth muscle tissue	UBERON:0001135	97.62	gold quality
endocervix	UBERON:0000458	97.60	gold quality
minor salivary gland	UBERON:0001830	97.58	gold quality
lower esophagus	UBERON:0013473	97.57	gold quality
sural nerve	UBERON:0015488	97.57	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.57	gold quality
thyroid gland	UBERON:0002046	97.56	gold quality
upper lobe of lung	UBERON:0008948	97.54	gold quality
ectocervix	UBERON:0012249	97.54	gold quality
mucosa of stomach	UBERON:0001199	97.53	gold quality
cerebellar cortex	UBERON:0002129	97.52	gold quality
cerebellar hemisphere	UBERON:0002245	97.52	gold quality
mouth mucosa	UBERON:0003729	97.51	gold quality
bone marrow cell	CL:0002092	97.48	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.46	gold quality
liver	UBERON:0002107	97.44	gold quality
stomach	UBERON:0000945	97.41	gold quality
vagina	UBERON:0000996	97.41	gold quality
tibial nerve	UBERON:0001323	97.41	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.41	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.41	gold quality
intestine	UBERON:0000160	97.40	gold quality
pharyngeal mucosa	UBERON:0000355	97.40	gold quality
right lobe of thyroid gland	UBERON:0001119	97.40	gold quality
colon	UBERON:0001155	97.39	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.39	gold quality
granulocyte	CL:0000094	97.38	gold quality
body of uterus	UBERON:0009853	97.38	gold quality
left uterine tube	UBERON:0001303	97.30	gold quality
right atrium auricular region	UBERON:0006631	97.30	gold quality
large intestine	UBERON:0000059	97.28	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.28	gold quality
paraflocculus	UBERON:0005351	97.27	gold quality
heart left ventricle	UBERON:0002084	97.26	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.24	gold quality
pylorus	UBERON:0001166	97.22	gold quality
epithelium of bronchus	UBERON:0002031	97.22	gold quality
cardiac ventricle	UBERON:0002082	97.22	gold quality
body of pancreas	UBERON:0001150	97.21	gold quality
left adrenal gland	UBERON:0001234	97.21	gold quality
blood	UBERON:0000178	97.20	gold quality
bronchus	UBERON:0002185	97.19	gold quality
right adrenal gland cortex	UBERON:0035827	97.19	gold quality
pancreas	UBERON:0001264	97.18	gold quality
cerebellum	UBERON:0002037	97.18	gold quality
type B pancreatic cell	CL:0000169	97.17	gold quality
left adrenal gland cortex	UBERON:0035825	97.16	gold quality
diaphragm	UBERON:0001103	97.15	gold quality
right adrenal gland	UBERON:0001233	97.14	gold quality
cardiac atrium	UBERON:0002081	97.14	gold quality
omental fat pad	UBERON:0010414	97.13	gold quality
left ovary	UBERON:0002119	97.12	gold quality
peritoneum	UBERON:0002358	97.12	gold quality
right coronary artery	UBERON:0001625	97.10	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	158.03
E-GEOD-76312	yes	155.93
E-ANND-3	yes	11.77
E-MTAB-8271	yes	6.54

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	288.0	high
Liver	tissue	207.9	medium
Skeletal muscle	tissue	185.0	high
Thymus	tissue	146.5
Frontal cortex	tissue	129.0
Tongue	tissue	123.8
Duodenum	tissue	122.6	high
Small intestine	tissue	121.0	high
Caudate putamen	tissue	121.0
Corpus callosum	tissue	118.6
Rectum	tissue	111.0	high
Kidney	tissue	110.3	high
Spinal cord	tissue	109.8
Tonsil	tissue	107.7	high
Fallopian tube	tissue	106.2	high
Skin 1	tissue	104.7	high
Colon	tissue	101.0	high
Urinary bladder	tissue	99.5	high
Vagina	tissue	98.9	high
Midbrain	tissue	97.9
Medulla oblongata	tissue	96.0
Thalamus	tissue	95.7
Superior colliculi	tissue	95.0
Cerebellum	tissue	94.0	high
Putamen	tissue	91.9
Cerebral cortex	tissue	90.6	medium
Somatosensory cortex	tissue	90.6
Parathyroid gland	tissue	87.3	medium
Occipital cortex	tissue	85.6
Pons	tissue	83.6
Basal ganglia	tissue	83.2	medium
Hippocampal formation	tissue	83.1
Substantia nigra	tissue	82.9
Ventral forebrain	tissue	81.3
Breast	tissue	79.7	high
Motor cortex	tissue	79.3
Esophagus	tissue	78.7	high
Stomach 1	tissue	77.0	low
Prefrontal cortex	tissue	76.1
Temporal cortex	tissue	73.6
Entorhinal cortex	tissue	73.5
Periaqueductal gray	tissue	73.5
Septum	tissue	72.5
Hypothalamus	tissue	70.5
Choroid plexus	tissue	69.6
Appendix	tissue	68.7	high
Ovary	tissue	67.7	medium
Placenta	tissue	67.5	high
Retrosplenial cortex	tissue	67.5
Retrosplenial and cingulate cortex	tissue	67.4
Cervix	tissue	67.0	high
Epididymis	tissue	66.2	high
Thyroid gland	tissue	66.1	high
Olfactory bulb	tissue	65.9
Smooth muscle	tissue	65.8	high
Adipose tissue	tissue	65.6	medium
Insular cortex	tissue	64.6
Pituitary gland	tissue	64.1
Retina	tissue	63.9
Endometrium 1	tissue	63.6	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — White matter (118.6), Ventral spinal cord (109.8), Dorsal spinal cord (97.2), Area postrema (88.1), Blood vessel (85.8).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets:

Target	Regulation
CDH1	Repression
FAS	Activation
SMYD1	Repression
TP53
VEGFA	Activation
VEGFB	Activation
VIM	Activation

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

Targeting HDGF by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 70 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-1255A	99.74	68.09	744
HSA-MIR-1255B-5P	99.74	68.16	741
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3685	99.62	68.83	1621
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-6871-3P	99.43	68.85	741
HSA-MIR-4506	99.34	67.47	526
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-5100	99.11	67.52	1098

Functional genomics

gnomAD constraint: pLI 0.998, LOEUF 0.396, missense Z 1.94 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000357325 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
1:156,743,452–156,745,100	176 / 211.7	0.83	no
1:156,745,101–156,751,429	38 / 91.1	0.42	no

Literature-anchored findings (GeneRIF, showing 40)

• Hepatoma-derived growth factor stimulates cell growth after translocation to the nucleus (PMID:11751870)
• may be involved in lung remodeling after injury (PMID:12972397)
• HDGF is a highly expressed vascular endothelial cell protein in vivo and is a potent endothelial mitogen and regulator of endothelial cell migration by mechanisms distinct from VEGF. (PMID:14751852)
• NMR analysis of the hath-domain of human hepatoma-derived growth factor (PMID:15017145)
• HDGF may be a novel prognostic factor for pancreatic ductal carcinoma. (PMID:17062679)
• Hepatoma-derived growth factor expression level was shown to be associated with recurrence and prognosis of squamous cell carcinoma of the esophagus. (PMID:17473954)
• The N-terminal PWWP domain of HDGF is required for DNA binding. HDGF exerts its transcription repressive effect through binding to a conserved DNA element in the promoter of target genes. (PMID:17974029)
• HDGF serves as a template for small ubiquitin-related modifier 1 (SUMO-1) conjugation, although it does not contain a suitable consensus site for SUMOylation. (PMID:18331345)
• HDGF expression is upgraded in postoperative stage I non-small cell lung cancer patients, and is a significantly independent predictive factor. (PMID:18478933)
• HDGF knock-down was found to induce the expression of the pro-apoptotic protein Bad and also inactivate ERK and Akt, which in turn led to dephosphorylation of Bad at Ser-112, Ser-136, and activation of the intrinsic apoptotic pathway. (PMID:18651222)
• Quantitative RT-PCR to study the expression levels of the most interesting gene, HDGF, confirmed that its expression was higher in Ewing sarcoma than in control samples. (PMID:19144156)
• HDGF functions as a transcriptional repressor of the SMYD1 gene through interaction with the transcriptional corepressor CtBP. (PMID:19162039)
• The present study is aimed at examining the role of HDGF in keloid pathogenesis. (PMID:19432814)
• Mechanistic study on growth suppression and apoptosis induction by targeting HDGF in human hepatocellular carcinoma HepG2 cells is reported. (PMID:19710540)
• High hepatoma-derived growth factor is associated with colorectal carcinoma. (PMID:19924574)
• High HDGF expression is associated with poor overall survival in patients with hepatocellular carcinoma. Down-regulation of HDGF inhibits the growth, anchorage-independent growth, migration and invasion of HepG2 cells. (PMID:20846397)
• High HDGF is associated with hilar cholangiocarcinoma. (PMID:20848225)
• Increased nuclear expression of HDGF is a potential unfavourable prognostic factor for patients with hepatoma-derived growth factor (PMID:21255068)
• results suggest that HDGF is involved in cell growth, cell invasion, and apoptosis (PMID:21302807)
• HDGF was highly expressed in 158 non-small cell lung cancer tissues compared with normal control. (PMID:21426662)
• The interactome suggests that HDGF is a multifunctional protein and participates in many cellular events, including ribosome biogenesis, RNA processing, DNA damage repair and transcriptional regulation. (PMID:21907836)
• found that HDGF was overexpressed also in primary gastric, breast, and lung cancer tissues harboring mutant p53 genes (PMID:22006999)
• High hepatoma-derived growth factor is associated with gliomas. (PMID:22037800)
• Hepatoma-derived growth factor regulates breast cancer cell invasion by modulating epithelial–mesenchymal transition. (PMID:22247069)
• Differential proteomic analysis of human glioblastoma and neural stem cells reveals HDGF as a novel angiogenic secreted factor (PMID:22331796)
• Hepatoma-derived growth factor overexpression contributes to the oncogenic processes in oral cancer cells (PMID:22361040)
• Expression of a cytosolic variant of hepatoma-derived growth factor causes a redistribution of nucleolin into the cytoplasm. (PMID:23305559)
• Together, these results indicate that HDGF downregulation participates in POMC-induced suppression of metastasis and EMT in melanoma. (PMID:23468531)
• Up-regulation of hepatoma-derived growth factor facilities tumor progression in malignant melanoma. (PMID:23536873)
• Studied HDGF in gallbladder cancer (GBC).Patients with nuclear HDGF-pos tumors had worse survival than patients with HDGF-negative tumors. Treatment of GBC-SD and SGC-996 lines with HDGF-siRNA significantly reduced the proliferation of GBC cell lines. (PMID:23609195)
• Tumor samples from non-small cell lung cancers show an inverse relationship between microRNA-497 and HDGF levels, and ectopic expression of miR-497 significantly inhibited tumor growth and angiogenesis in a xenograft model (PMID:23673296)
• Patients with higher HDGF and CD31 expression level had poorer overall survival rates. (PMID:23771798)
• Positive expression of HDGF was detected in 46.2 % of patients with extrahepatic cholangiocarcinoma and correlated with poor tumor differentiation. The HDGF expression group had lower survival than the negative HDGF expression group. (PMID:23793608)
• Suggest that HDGF exhibits oncogenic properties and may be a novel prognostic factor in Ewing’s sarcoma. (PMID:23878072)
• The suppressive effect of miR-16 on cell proliferation, colony formation, migration, and invasion is partially mediated by inhibiting HDGF expression. (PMID:23954293)
• Combining p53 expression and HDGF expression significantly improved prognostic stratification for patients with Ewing family tumor. (PMID:24072730)
• expression of HDGF was negatively correlated with miR-141 in gastric cancer tissues: the suppressive effects of miR-141 on GC cell proliferation, colony formation, in vitro migration, and invasion were partially mediated by suppressing HDGF expression. (PMID:24276755)
• HDGF is a potential unfavorable factor for the progression and prognosis of endometrial carcinoma. (PMID:24692842)
• ADAM9 high expression is correlated positively and significantly with HDGF high expression in non-small cell lung cancer. (PMID:24770635)
• Data indicate that hepatoma-derived growth factor (HDGF) was a target of miR-195 in non-small cell lung cancer (NSCLC) cells. (PMID:24891187)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hdgf	ENSMUSG00000004897
rattus_norvegicus	Hdgf	ENSRNOG00000042261

Paralogs (4): HDGFL1 (ENSG00000112273), PSIP1 (ENSG00000164985), HDGFL3 (ENSG00000166503), HDGFL2 (ENSG00000167674)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1194494) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased vertical activity	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5R7T2	99.5%	Diamond
Bos taurus	A4FUF0	98.4%	Diamond
Gallus gallus	Q5ZLS7	96.6%	Diamond
Felis catus	Q66T72	94.7%	Diamond
Xenopus tropicalis	Q6P4K1	84.4%	Diamond
Xenopus laevis	Q32N87	84.3%	Diamond
Drosophila pseudoobscura pseudoobscura	Q29NG1	82.7%	Diamond
Drosophila melanogaster	Q8T079	81.9%	Diamond
Aedes aegypti	Q175F8	74.6%	Diamond
Anopheles gambiae	Q7Q161	74.6%	Diamond
Danio rerio	Q5XXA7	72.6%	Diamond
Arabidopsis thaliana	F4IN78	60.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
INSRR	protein-coding	3645
NTRK1	protein-coding	4914
METTL25B	protein-coding	51093
PRCC	protein-coding	5546
MRPL24	protein-coding	79590
ISG20L2	protein-coding	81875
SH2D2A	protein-coding	9047
NES	protein-coding	10763
BCAN-AS2	ncRNA	126568844
CRABP2	protein-coding	1382
BCAN	protein-coding	63827
PEAR1	protein-coding	375033
LRRC71	protein-coding	149499
MIR765	ncRNA	768220
ARHGEF11	protein-coding	9826

Protein

Protein identifiers

Hepatoma-derived growth factor — P51858 (reviewed: P51858)

Alternative names: High mobility group protein 1-like 2

All UniProt accessions (3): A0A384NPW1, A0AA34QVG5, P51858

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional repressor. Has mitogenic activity for fibroblasts. Heparin-binding protein. Does not have mitogenic activity for fibroblasts. Does not bind heparin. Has mitogenic activity for fibroblasts. Heparin-binding protein.

Subunit / interactions. Monomer, and domain-swapped homodimer. Interacts with nuclear proteins NCL and YBX1/YB1. Interacts with cytoskeletal proteins such as actin, dynein, tubulin and vimentin. Interacts with cytoskeletal proteins such as dynein and tubulin but does not interact with actin or vimentin.

Subcellular location. Nucleus. Cytoplasm. Secreted. Extracellular exosome Nucleus. Extracellular exosome.

Tissue specificity. Ubiquitous.

Post-translational modifications. Sumoylated with SUMO1. Sumoylation prevents binding to chromatin. Phosphorylation at Ser-165 is likely to be required for secretion.

Domain organisation. The PWWP domain harbors the heparin-binding sites and is responsible for DNA-binding, while the C-terminal region is essentially unstructured. The N-terminal region does not contain a typical signal sequence but is required for secretion. It also determines exosomal location.

Similarity. Belongs to the HDGF family.

Isoforms (3)

UniProt ID	Names	Canonical?
P51858-1	1, HDFG-A	yes
P51858-2	2, HDGF-C
P51858-3	3, HDGF-B

RefSeq proteins (6): NP_001119522, NP_001119523, NP_001306115, NP_001306116, NP_001306117, NP_004485* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000313	PWWP_dom	Domain

Pfam: PF00855

UniProt features (45 total): modified residue 10, compositionally biased region 6, binding site 6, strand 6, helix 3, cross-link 2, short sequence motif 2, splice variant 2, chain 1, domain 1, region of interest 1, disulfide bond 1, sequence variant 1, mutagenesis site 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
1RI0	NMR structure of the N-terminal hath domain of human HDGF	SOLUTION NMR
2NLU	Domain-Swapped Dimer of the PWWP Module of Human Hepatoma-derived Growth Factor	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51858-F1	67.83	0.31

Human Protein Atlas

Protein class: Predicted secreted proteins, Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IH enhanced · IF enhanced

Functional residue map

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

Ligand- & substrate-binding residues (6)

Position	Role
19	heparin
21	heparin
72	heparin
75	heparin
79	heparin
80	heparin

Post-translational modifications (12)

Type	Positions
N6-acetyllysine	44
Phosphoserine	132, 133, 165, 199, 202, 206, 239
Phosphothreonine	184, 200
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo)	80
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	80

Disulfide bonds (1)

Type	Positions
Disulfide bond	12–108

Mutagenesis-validated functional residues (1)

Position	Phenotype
165	abolishes secretion and alters location of the protein from inside the exosome to the exosomal surface.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-381038	XBP1(S) activates chaperone genes	curated
R-HSA-8953897	Cellular responses to stimuli	—
R-HSA-2262752	Cellular responses to stress	—
R-HSA-381070	IRE1alpha activates chaperones	—
R-HSA-381119	Unfolded Protein Response (UPR)	—

MSigDB gene sets: 305 (showing top): BORCZUK_MALIGNANT_MESOTHELIOMA_UP, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GNF2_PRDX2, KAAB_FAILED_HEART_ATRIUM_DN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GCANCTGNY_MYOD_Q6, MORF_UBE2I, MORF_HDAC1, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOMF_GROWTH_FACTOR_ACTIVITY, GGGTGGRR_PAX4_03, PUJANA_CHEK2_PCC_NETWORK, CTAGGAA_MIR384, MORF_SKP1A, WANG_RESPONSE_TO_BEXAROTENE_UP

GO Biological Process (7): negative regulation of transcription by RNA polymerase II (GO:0000122), chromatin remodeling (GO:0006338), DNA-templated transcription (GO:0006351), signal transduction (GO:0007165), protein localization to nucleus (GO:0034504), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of cell division (GO:0051781)

GO Molecular Function (12): nucleotide binding (GO:0000166), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), transcription corepressor binding (GO:0001222), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), transcription corepressor activity (GO:0003714), RNA binding (GO:0003723), actin binding (GO:0003779), growth factor activity (GO:0008083), heparin binding (GO:0008201), tubulin binding (GO:0015631), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), transcription repressor complex (GO:0017053)

Reactome top-level categories

4 top-level categories:

Category	Pathways
IRE1alpha activates chaperones	1
Cellular responses to stimuli	1
Unfolded Protein Response (UPR)	1
Cellular responses to stress	1

GO top-level categories

36 GO namespaces:

Category	Terms
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
nucleic acid binding	2
cytoskeletal protein binding	2
chromatin organization	1
gene expression	1
RNA biosynthetic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
protein localization to organelle	1
positive regulation of DNA-templated transcription	1
positive regulation of cellular process	1
cell division	1
regulation of cell division	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
cis-regulatory region sequence-specific DNA binding	1
transcription coregulator binding	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
transcription coregulator activity	1
receptor ligand activity	1
glycosaminoglycan binding	1
sulfur compound binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
transcription regulator complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 13 of 25 annotations. The rest are phylogenetic / computational / electronic (IEA).

13 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of transcription by RNA polymerase II	BP	direct assay
positive regulation of cell division	BP	direct assay
cytoplasm	CC	direct assay
extracellular region	CC	high-throughput assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
transcription repressor complex	CC	direct assay
RNA binding	MF	high-throughput assay
actin binding	MF	direct assay
heparin binding	MF	direct assay
transcription corepressor activity	MF	direct assay
transcription corepressor binding	MF	physical interaction
tubulin binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,640 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HDGF	MDK	P21741	908
HDGF	NUDT6	P53370	755
HDGF	FGF2	P09038	748
HDGF	PTN	P21246	736
HDGF	AZU1	P20160	715
HDGF	FGF4	P08620	640
HDGF	FGF13	Q92913	638
HDGF	FGF17	O60258	628
HDGF	FGF1	P05230	604
HDGF	IGF2BP3	O00425	556
HDGF	FGF6	P10767	551
HDGF	METTL3	Q86U44	547
HDGF	FGF8	P55075	526
HDGF	FGF9	P31371	520
HDGF	FGF19	O95750	510

IntAct

Human interaction partners of HDGF in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

9 partners by confidence:

Partner	Interaction type	MIscore	Records
DDX5	colocalization	0.510	1
HDAC1	colocalization	0.510	1
SRSF1	colocalization	0.510	1
SSRP1	colocalization	0.510	1
PARP1	association	0.460	1
GPR37	physical association	0.370	1
JUN	physical association	0.370	1
XBP1	physical association	0.370	1
KIF2A	association	0.350	2

BioGRID (377 interactions; top human partners by supporting records): HIST1H3A (Proximity Label-MS; 4 records), PSIP1 (Cross-Linking-MS (XL-MS); 4 records), DDX5 (Co-fractionation; 3 records), HDGFRP2 (Affinity Capture-MS; 3 records), HIST1H2BG (Proximity Label-MS; 3 records), PARP1 (Proximity Label-MS; 3 records), AHCY (Co-fractionation; 2 records), BRD4 (Affinity Capture-MS; 2 records), CBX3 (Proximity Label-MS; 2 records), CPNE2 (Affinity Capture-MS; 2 records), EFTUD2 (Affinity Capture-MS; 2 records), EGFL6 (Affinity Capture-MS; 2 records), EIF2S2 (Affinity Capture-RNA; 2 records), EMD (Affinity Capture-MS; 2 records), HDAC1 (Affinity Capture-MS; 2 records)

Protein complexes (CORUM) (2)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

2 complexes by size:

Complex	Subunits	Members
★ Emerin complex 52	23	DDX39A, ILF3, LEMD3, RBL2, H1-1, HNRNPK, HNRNPU, IQGAP1, NMI, PDCD4, SNRPD1, THRA, API5, CKB, EMD, HDGF, LSM8, YWHAQ, ACTB, C1QBP, HNRNPL, LMNB1, YWHAE
CTNNB1-DDX5-HDGF complex	3	CTNNB1, DDX5, HDGF

Disease & clinical

Genetic variants

Variant evidence for HDGF: 42 ClinVar records (0 pathogenic / likely pathogenic); 4 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	1
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 27 predictions of 719):

Position(s)	Effect	Δscore	Sites
1:156743879–156743880	acceptor_loss	1.0000	3
1:156743885	acceptor_gain	1.0000
1:156743891	acceptor_gain	1.0000
1:156744161–156744162	donor_loss	1.0000	4
1:156744183	donor_gain	1.0000
1:156744196	donor_gain	1.0000
1:156744349–156744350	acceptor_loss	1.0000	6
1:156744353	acceptor_gain	1.0000
1:156745006–156745007	donor_loss	1.0000	4
1:156745147–156745148	acceptor_loss	1.0000	5

AlphaMissense

588 missense substitutions predicted likely pathogenic (of 1,593 scored), across 112 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M20	9	0.981	1.000
F49	8	0.998	1.000
F17	8	0.997	1.000
F82	8	0.994	1.000
F48	8	0.983	1.000
H53	8	0.982	1.000
D62	8	0.982	0.997
D14	8	0.979	0.997
F50	8	0.973	1.000
H25	8	0.962	1.000
D31	8	0.950	0.989
D142	8	0.708	0.814
W26	7	1.000	1.000
E54	7	0.998	1.000
F73	7	0.997	0.999
E88	7	0.997	0.999
R79	7	0.993	1.000
W87	7	0.992	0.997
F57	7	0.981	0.997
K19	7	0.976	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	2.91e-08
Liver Hepatocellular Carcinoma (validation)	unfavorable	0.000285

Disease associations

OMIM: gene MIM:600339 | disease phenotypes:

GWAS associations

4 associations:

Study	Trait	p-value
GCST010002_29	Refractive error	7e-38
GCST006585_2660	Blood protein levels	3e-23
GCST002223_10	HDL cholesterol	2e-8
GCST004232_51	HDL cholesterol levels	3e-8

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724677 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.31	Kd	4.901	nM	CHEMBL3752910
8.31	ED50	4.901	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 10 total; 1 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148498: Binding affinity to human HDGF incubated for 45 mins by Kinobead based pull down assay	kd	0.0049	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	5
sodium arsenite	decreases expression, increases abundance, increases expression	4
Cadmium Chloride	decreases expression, increases expression	3
bisphenol A	decreases expression, increases expression	2
Resveratrol	decreases expression, increases expression	2
Acetaminophen	decreases expression	2
Copper	affects binding	2
Doxorubicin	decreases expression, affects expression	2
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
bufotalin	increases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects localization, increases expression, affects cotreatment	1
trichostatin A	affects expression	1
beta-lapachone	increases expression	1
sodium bichromate	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
afimoxifene	increases expression	1
nickel subsulfide	decreases expression	1
cupric oxide	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
quinocetone	increases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651540	Binding	Binding affinity to human HDGF incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — *ChemMedChem*

Cellosaurus cell lines

7 cell lines: 4 cancer cell line, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2N1	SEES3-1V human HDGF, clone1	Embryonic stem cell	Male
CVCL_A2N2	SEES3-1V human HDGF, clone2	Embryonic stem cell	Male
CVCL_A2N3	SEES3-1V human HDGF, clone3	Embryonic stem cell	Male
CVCL_D1N1	Abcam K-562 HDGF KO	Cancer cell line	Female
CVCL_D2JL	Abcam Raji HDGF KO	Cancer cell line	Male
CVCL_D9WI	Ubigene HT-29 HDGF KO	Cancer cell line	Female
CVCL_UQ68	Abcam Jurkat HDGF KO	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for HDGF across ~30M SureChEMBL compounds — explore on Sugi Predict.