TGFA

Summary

TGFA (transforming growth factor alpha, HGNC:11765) is a protein-coding gene on chromosome 2p13.3, encoding Protransforming growth factor alpha (P01135). TGF alpha is a mitogenic polypeptide that is able to bind to the EGF receptor/EGFR and to act synergistically with TGF beta to promote anchorage-independent cell proliferation in soft agar.

This gene encodes a growth factor that is a ligand for the epidermal growth factor receptor, which activates a signaling pathway for cell proliferation, differentiation and development. This protein may act as either a transmembrane-bound ligand or a soluble ligand. This gene has been associated with many types of cancers, and it may also be involved in some cases of cleft lip/palate. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 7039 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tooth agenesis (Supportive, GenCC)
• GWAS associations: 19
• Clinical variants (ClinVar): 36 total
• Phenotypes (HPO): 23
• Druggable target: yes
• MANE Select transcript: NM_003236

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11765
Approved symbol	TGFA
Name	transforming growth factor alpha
Location	2p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000163235
Ensembl biotype	protein_coding
OMIM	190170
Entrez	7039

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 10 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000295400, ENST00000394241, ENST00000418333, ENST00000419940, ENST00000444975, ENST00000445399, ENST00000450929, ENST00000460808, ENST00000474101, ENST00000869601, ENST00000869602, ENST00000869603

RefSeq mRNA: 4 — MANE Select: NM_003236 NM_001099691, NM_001308158, NM_001308159, NM_003236

CCDS: CCDS1905, CCDS46316, CCDS77419, CCDS77420

Canonical transcript exons

ENST00000295400 — 6 exons

Exon	Start	End
ENSE00001129787	70453218	70453327
ENSE00001849780	70447284	70450866
ENSE00003508184	70465616	70465736
ENSE00003610312	70514859	70514912
ENSE00003648674	70553728	70553826
ENSE00003787828	70456339	70456488

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 92.29.

FANTOM5 (CAGE): breadth broad, TPM avg 5.4566 / max 282.0771, expressed in 873 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29034	4.8002	807
29035	0.4066	208
29036	0.1530	55
29032	0.0567	17
29033	0.0400	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	92.29	gold quality
epithelium of esophagus	UBERON:0001976	90.22	gold quality
squamous epithelium	UBERON:0006914	89.01	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.93	gold quality
upper leg skin	UBERON:0004262	88.62	gold quality
spinal cord	UBERON:0002240	88.30	gold quality
pancreatic ductal cell	CL:0002079	87.67	silver quality
islet of Langerhans	UBERON:0000006	87.56	gold quality
amniotic fluid	UBERON:0000173	87.12	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.50	gold quality
epithelium of nasopharynx	UBERON:0001951	86.33	gold quality
esophagus mucosa	UBERON:0002469	86.01	gold quality
buccal mucosa cell	CL:0002336	85.44	gold quality
nasal cavity epithelium	UBERON:0005384	85.31	gold quality
corpus callosum	UBERON:0002336	85.17	gold quality
periodontal ligament	UBERON:0008266	85.12	gold quality
lower esophagus mucosa	UBERON:0035834	84.90	gold quality
gall bladder	UBERON:0002110	84.52	gold quality
pharyngeal mucosa	UBERON:0000355	84.44	gold quality
gingiva	UBERON:0001828	84.35	gold quality
gingival epithelium	UBERON:0001949	84.34	gold quality
oral cavity	UBERON:0000167	84.30	gold quality
inferior olivary complex	UBERON:0002127	84.21	gold quality
tongue squamous epithelium	UBERON:0006919	83.70	gold quality
secondary oocyte	CL:0000655	83.66	gold quality
epithelial cell of pancreas	CL:0000083	83.05	gold quality
inferior vagus X ganglion	UBERON:0005363	82.28	gold quality
palpebral conjunctiva	UBERON:0001812	82.14	gold quality
cervix squamous epithelium	UBERON:0006922	82.09	silver quality
blood	UBERON:0000178	82.06	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, BCL11B, CEBPB, EGR1, ESR1, ESR2, FOSL1, GCFC2, GLI2, GLI3, HNF4A, HR, IRF6, MYC, NFKB, NR2E1, ONECUT1, POU2F2, SP1, STAT1, STAT2, TCF3, TEAD1, TFAP2A, TP53, TTF1, ZNF410

miRNA regulators (miRDB)

118 targeting TGFA, 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-7110-3P	100.00	73.18	2486
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3148	99.97	75.06	6478
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-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734

Literature-anchored findings (GeneRIF, showing 40)

• expression in pancreatic endocrine tumors (PMID:11727256)
• mRNA expression in atrophic gastritis before and after Helicobacter pylori eradication (PMID:11859273)
• Activation of the human transforming growth factor alpha (TGF-alpha) gene by the hepatitis B viral X protein (HBx) through AP-2 sites. (PMID:11952158)
• if overexpressed in the pancreas causes the development of tubular structures and fibrosis (PMID:12120215)
• expression and role of TGFA in fat cells and insulin resistance in humans (PMID:12138086)
• findings suggest an increase in functional TGF-alpha and activation of the EGFr in response to IFN-gamma (PMID:12223352)
• TGF-alpha is released from epithelial cells in the upper compartment of the crypt into the adjacent lamina propria and then diffuses to the epithelial cells in the lower part of the crypt, resulting in expansion of the proliferative compartment. (PMID:12468378)
• bile acids activate EGFR via a TGF-alpha-dependent mechanism, and this EGFR activation promotes cellular growth. (PMID:12606307)
• Comparative study in the expression of p53, EGFR, TGF-alpha, and cyclin D1 in verrucous carcinoma, verrucous hyperplasia, and squamous cell carcinoma of head and neck region. (PMID:12607604)
• These results argue for growth factor-dependent hepatocellular carcinoma development and provide novel and combined prognosis markers after HCC surgery. (PMID:12619035)
• role in activating extracellular signal-regulated/mitogen-activated protein kinase and implication in metastatic spread of colon cancer cells (PMID:12657625)
• role in mediating proliferation into differentiation in neuroblastoma cells controlled by estrogen receptor alpha (PMID:12709435)
• TGF-alpha has a role in epidermal tissue regeneration (PMID:12771184)
• Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing human transforming growth factor-alpha (PMID:12896876)
• The growth factor independence of HCT116 cells was shown to be dependent on autocrine transforming growth factor (TGF)-alpha activity. (PMID:12907656)
• Western blot analysis showed increased TGF-alpha protein expression in ethanol-treated HepG2 cells. TGF-alpha in conditioned medium from ethanol-exposed HepG2 cells stimulated type-I collagen messenger RNA expression in rat hepatic stellate cells. (PMID:12960509)
• The immunophenotype of colorectal neuroendocrine tumours regarding hormone markers is heterogeneous. The expression of TGF-alpha corresponds to the immunohistological profile of normal neuroendocrine L-cells. (PMID:14616544)
• Overexpression of TGF-alpha in liver may be associated with regeneration of hepatocytes injured by HBsAg. Continued expression of TGF-alpha might lead to dysplasia of liver cells and development of hepatocellular carcinoma. (PMID:15040026)
• not a relevant modifier locus for the occurrence of cleft lip/cleft palate (PMID:15222785)
• autocrine TGFalpha regulates cell adhesion function by multiple signaling pathways via specific phosphorylation sites of S6K in cancer cells (PMID:15304500)
• TGF-alpha up-regulates keratinocyte toll-like receptor (TLR)5 and TLR9 expression and function, augmenting host defense mechanisms at epithelial surfaces. (PMID:15879109)
• Production of IL-15 and/or TGF-alpha was also associated with amphoterin mRNA expression in colon cancer tissues with tumor-associated macrophages depletion (PMID:15943034)
• TGFA is probably a genetic modifier of clefting in humans, which is consistent with the oligogenic model suggested for nonsyndromic oral clefts. (PMID:16495466)
• TGFalpha is the physiologic human keratinocyte pro-motility factor in human serum (PMID:16691197)
• findings did not suggest an association between offspring TGFalpha TaqI variant and the increased risk of nsCL/P in Chinese population. (PMID:16792897)
• the production of TGF-alpha by HRCC cells leads to the activation of EGFR on tumor-associated endothelial cells that serve as an essential target for therapy with tyrosine kinase inhibitors (PMID:16820093)
• TGFA is up-regulated in tumor cells of SCC but not BCC of the skin. TGFA is also overexpressed in asymptomatic epidermis adjacent to both SCC and BCC, relative to normal skin. (PMID:17525275)
• Naked2 acts as a cargo recognition and targeting (CaRT) protein to ensure proper delivery, tethering, and fusion of TGF-alpha-containing vesicles to a distinct region at the basolateral surface of polarized epithelial cells. (PMID:17553928)
• The overexpression rates of EGFR and TGF-alpha were significantly higher in recurrence group than in non-recurrence group of Dukes’A and B colorectal carcinoma. (PMID:17562274)
• Inhibition of Ski through RNA interference restored TGF-beta signaling and growth inhibition in vitro, and decreased tumor growth in vivo. (PMID:17592292)
• the tumorigenic growth effects of MYC in TGFalpha-expressing liver progenitor cells are not solely dependent on its apoptotic activity. (PMID:17698969)
• The presence of neuroendocrine cells may have an effect on the expression of TGF-alpha and EGFR in gastric adenocarcinoma, and the autocrine mechanism between TGF-alpha and EGFR plays an important role in the prognosis of gastric carcinoma. (PMID:17922051)
• High expression is related to the biological aggressiveness of breast cancer. TGFA is preferentially expressed in tumours co-expressing EGFR/HER3. (PMID:17962208)
• decreasingly expressed in unaffected, cleft of the lip, alveolus with or without cleft palate, and patient with cleft palate only and thus further strength has been given to its role in the onset of the disease (PMID:17993868)
• The transforming growth factor-alpha (TGF-alpha)is a members of the polypeptide growth factor family. The moderate immunoreactivity of TGF-alpha was detected in serous-mucinous adenocarcinoma of the ovary. (PMID:18054376)
• Subsequently, ROS generation by PA-LPS releases transforming growth factor-alpha (TGF-alpha), which in turn, leads to up-regulate MUC5AC expression. (PMID:18073139)
• At early stages, immunoreactivity to TGF-alpha was detected in all metanephric structures and from the 7th week onward, it decreased in differentiating nephrons. (PMID:18080773)
• PRL expands the pool of cells susceptible to tumorigenesis, which is then facilitated by PRL and TGF-alpha cross talk (PMID:18156207)
• Silibinin impairs constitutively active TGFalpha-EGFR autocrine loop in advanced human prostate carcinoma cells. (PMID:18253818)
• Although large differences were found between Amphiregulin and both EGF and TGFalpha in follicular fluid, no significant difference was detected in the levels of the three EGF receptor ligands in sera. (PMID:18325497)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tgfa	ENSDARG00000053939
mus_musculus	Tgfa	ENSMUSG00000029999
rattus_norvegicus	Tgfa	ENSRNOG00000016182

Paralogs (5): AREG (ENSG00000109321), HBEGF (ENSG00000113070), EREG (ENSG00000124882), BTC (ENSG00000174808), EPGN (ENSG00000182585)

Protein

Protein identifiers

Protransforming growth factor alpha — P01135 (reviewed: P01135)

All UniProt accessions (5): E7EPT6, P01135, F8VNR3, F8WA74, H0Y6S5

UniProt curated annotations — full annotation on UniProt →

Function. TGF alpha is a mitogenic polypeptide that is able to bind to the EGF receptor/EGFR and to act synergistically with TGF beta to promote anchorage-independent cell proliferation in soft agar.

Subunit / interactions. Interacts with the PDZ domains of MAGI3, SDCBP and SNTA1. The interaction with SDCBP, is required for the targeting to the cell surface. In the endoplasmic reticulum, in its immature form (i.e. with a prosegment and lacking full N-glycosylation), interacts with CNIH. In the Golgi apparatus, may form a complex with CNIH and GORASP2. Interacts (via cytoplasmic C-terminal domain) with NKD2.

Subcellular location. Secreted. Extracellular space Cell membrane.

Tissue specificity. Isoform 1, isoform 3 and isoform 4 are expressed in keratinocytes and tumor-derived cell lines.

Isoforms (5)

UniProt ID	Names	Canonical?
P01135-1	1	yes
P01135-2	2
P01135-3	3, VaII
P01135-4	4, VaI
P01135-5	5, VaIM

RefSeq proteins (4): NP_001093161, NP_001295087, NP_001295088, NP_003227* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain

UniProt features (29 total): strand 5, disulfide bond 3, splice variant 3, sequence conflict 3, chain 2, lipid moiety-binding region 2, propeptide 2, topological domain 2, signal peptide 1, glycosylation site 1, sequence variant 1, helix 1, turn 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
3E50	X-RAY DIFFRACTION	2.3
1MOX	X-RAY DIFFRACTION	2.5
5KN5	X-RAY DIFFRACTION	2.8
7SZ7	ELECTRON MICROSCOPY	3.4
7SZ5	ELECTRON MICROSCOPY	3.6
1GK5	SOLUTION NMR
1YUF	SOLUTION NMR
1YUG	SOLUTION NMR
2TGF	SOLUTION NMR
3TGF	SOLUTION NMR
4TGF	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01135-F1	66.42	0.00

Antibody-complex structures (SAbDab): 1 — 5KN5

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 (2): 154, 153

Disulfide bonds (3): 47–60, 55–71, 73–82

Glycosylation sites (1): 25

Function

Pathways and Gene Ontology

Reactome pathways

45 pathways

ID	Pathway
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-204005	COPII-mediated vesicle transport
R-HSA-212718	EGFR interacts with phospholipase C-gamma
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5638303	Inhibition of Signaling by Overexpressed EGFR
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-5694530	Cargo concentration in the ER
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-8866910	TFAP2 (AP-2) family regulates transcription of growth factors and their receptors
R-HSA-9009391	Extra-nuclear estrogen signaling
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-9634638	Estrogen-dependent nuclear events downstream of ESR-membrane signaling
R-HSA-9927418	Developmental Lineage of Mammary Gland Luminal Epithelial Cells
R-HSA-9927432	Developmental Lineage of Mammary Gland Myoepithelial Cells
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-1643713	Signaling by EGFR in Cancer
R-HSA-199418	Negative regulation of the PI3K/AKT network
R-HSA-199977	ER to Golgi Anterograde Transport
R-HSA-199991	Membrane Trafficking
R-HSA-212436	Generic Transcription Pathway
R-HSA-2219528	PI3K/AKT Signaling in Cancer
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 376 (showing top): GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, MODULE_92, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_GLAND_MORPHOGENESIS, REACTOME_GAB1_SIGNALOSOME, HARRIS_HYPOXIA, GOBP_REGULATION_OF_NUCLEAR_DIVISION, MODULE_522, MODULE_64, GOZGIT_ESR1_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOCC_CELL_SURFACE, TATTATA_MIR374, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN

GO Biological Process (13): angiogenesis (GO:0001525), cell surface receptor signaling pathway (GO:0007166), epidermal growth factor receptor signaling pathway (GO:0007173), positive regulation of cell population proliferation (GO:0008284), intracellular signal transduction (GO:0035556), ERBB2-EGFR signaling pathway (GO:0038134), positive regulation of MAPK cascade (GO:0043410), positive regulation of mitotic nuclear division (GO:0045840), positive regulation of epithelial cell proliferation (GO:0050679), positive regulation of cell division (GO:0051781), mammary gland alveolus development (GO:0060749), hepatocyte proliferation (GO:0072574), signal transduction (GO:0007165)

GO Molecular Function (6): epidermal growth factor receptor binding (GO:0005154), growth factor activity (GO:0008083), transmembrane receptor protein tyrosine kinase activator activity (GO:0030297), receptor ligand activity (GO:0048018), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (12): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), cell surface (GO:0009986), ER to Golgi transport vesicle membrane (GO:0012507), basolateral plasma membrane (GO:0016323), clathrin-coated endocytic vesicle membrane (GO:0030669), cytoplasmic vesicle (GO:0031410), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), perinuclear region of cytoplasm (GO:0048471), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Signaling by EGFR	5
ER to Golgi Anterograde Transport	2
ESR-mediated signaling	2
Intracellular signaling by second messengers	1
Signaling by Receptor Tyrosine Kinases	1
PI3K/AKT Signaling in Cancer	1
Signaling by Overexpressed Wild-Type EGFR in Cancer	1
MAPK1/MAPK3 signaling	1
Negative regulation of the PI3K/AKT network	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1
Extra-nuclear estrogen signaling	1
Developmental Lineages of the Mammary Gland	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
signal transduction	3
positive regulation of cellular process	2
epithelial cell proliferation	2
signaling receptor activator activity	2
cytoplasm	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
ERBB signaling pathway	1
cell population proliferation	1
regulation of cell population proliferation	1
intracellular anatomical structure	1
epidermal growth factor receptor signaling pathway	1
ERBB2 signaling pathway	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
regulation of mitotic nuclear division	1
positive regulation of nuclear division	1
positive regulation of cell cycle process	1
mitotic nuclear division	1
positive regulation of cell population proliferation	1
regulation of epithelial cell proliferation	1
cell division	1
regulation of cell division	1
anatomical structure development	1
mammary gland lobule development	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
growth factor receptor binding	1
receptor ligand activity	1
transmembrane receptor protein tyrosine kinase activity	1
protein tyrosine kinase activator activity	1
signaling receptor binding	1
protein binding	1
binding	1
organelle membrane	1

Protein interactions and networks

STRING

2760 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TGFA	EGFR	P00533	998
TGFA	EGF	P01133	987
TGFA	ERBB3	P21860	982
TGFA	ERBB2	P04626	978
TGFA	ERBB4	Q15303	971
TGFA	AREG	P15514	934
TGFA	EREG	O14944	871
TGFA	HBEGF	Q99075	864
TGFA	TNF	P01375	833
TGFA	FGF2	P09038	822
TGFA	IGF1	P01343	812
TGFA	ADAM17	P78536	803
TGFA	SDCBP	O00560	777
TGFA	AKT1	P31749	764
TGFA	NRG1	P98202	733

IntAct

135 interactions, top by confidence:

A	B	Type	Score
TGFA	EGFR	psi-mi:“MI:0407”(direct interaction)	0.780
EGFR	TGFA	psi-mi:“MI:0915”(physical association)	0.780
EGFR	TGFA	psi-mi:“MI:0407”(direct interaction)	0.780
TGFA	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.620
TGFA	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.620
MAGI2	TGFA	psi-mi:“MI:0407”(direct interaction)	0.620
NKD2	TGFA	psi-mi:“MI:0915”(physical association)	0.570
TGFA	NKD2	psi-mi:“MI:0915”(physical association)	0.570
TGFA	SGTA	psi-mi:“MI:0915”(physical association)	0.560
SGTA	TGFA	psi-mi:“MI:0915”(physical association)	0.560
TGFA	Magi3	psi-mi:“MI:0915”(physical association)	0.540
Magi3	TGFA	psi-mi:“MI:0403”(colocalization)	0.540
Magi3	TGFA	psi-mi:“MI:0915”(physical association)	0.540
SNX27	TGFA	psi-mi:“MI:0407”(direct interaction)	0.440
TGFA	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
TGFA	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
TGFA	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
TGFA	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.440
TGFA	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
TGFA	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
TGFA	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
TGFA	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (91): TGFA (Two-hybrid), TGFA (Two-hybrid), ERBB2 (Co-localization), ADAM17 (Co-localization), TGFA (PCA), TGFA (Co-crystal Structure), DLG1 (Reconstituted Complex), DLG1 (Two-hybrid), DLG1 (Affinity Capture-Western), ADAM17 (Affinity Capture-Western), TGFA (Co-localization), TGFA (Two-hybrid), TGFA (Two-hybrid), TGFA (Two-hybrid), TGFA (Two-hybrid)

ESM2 similar proteins: A2AIG8, A5D7H1, A6H7A0, A6NFX1, A6NJW4, A8MUP2, A8MXK1, B0BMW8, O35393, O54804, O73884, P01135, P35790, P52875, P57791, Q00961, Q01098, Q01134, Q06922, Q08DW9, Q0P5M9, Q0VDI3, Q14728, Q14957, Q15768, Q2M1K6, Q3UGX3, Q4R7M4, Q4V899, Q5E9H2, Q5M7U7, Q5R6I6, Q5RCI5, Q5ZI20, Q7TPB4, Q8BZH0, Q8IVW8, Q8N431, Q8NBA8, Q8R2R5

Diamond homologs: A0A6G9KJM3, A0A8U0LTM5, A0A8U0LTN3, A0A8U0LTT7, A0A8U0LTT9, A0A8U0LU66, P01134, P01135, P35070, P48030, P55244, P98138, Q06922, Q05928, Q9TTC5, C0HL13, G3V928, O42182, O57382, O75095, O75096, O75197, O75581, O88322, O88572, P01132, P01133, P07522, P98070, P98135, P98157, P98163, Q00968, Q04833, Q07954, Q14114, Q6UXH8, Q6X0I2, Q8VI56, Q91VN0

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
SRC	up-regulates	TGFA	cleavage
SRC	“up-regulates activity”	TGFA
ESR1	“up-regulates quantity by expression”	TGFA	“transcriptional regulation”
ESR2	“up-regulates quantity by expression”	TGFA	“transcriptional regulation”
ADAM17	“up-regulates activity”	TGFA	cleavage
TGFA	“up-regulates quantity by stabilization”	NKD2	binding
TGFA	“up-regulates activity”	EGFR	binding
TGFA	up-regulates	Angiogenesis

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 82 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	52.9×	2e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	50.4×	2e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	50.4×	2e-06
Long-term potentiation	5	44.1×	3e-06
Assembly and cell surface presentation of NMDA receptors	9	42.3×	6e-11
Neurexins and neuroligins	10	36.5×	3e-11
Protein-protein interactions at synapses	6	29.5×	2e-06
RAF/MAP kinase cascade	7	7.9×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	74.5×	3e-14
protein localization to synapse	6	58.9×	7e-08
receptor clustering	7	56.0×	8e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	7	44.5×	3e-08
cell-cell adhesion	11	14.3×	4e-08
protein-containing complex assembly	7	10.2×	3e-04
protein localization to plasma membrane	6	8.4×	3e-03
chemical synaptic transmission	7	6.9×	2e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	3
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1580 predictions. Top by Δscore:

Variant	Effect	Δscore
2:70453212:CCTTA:C	donor_loss	1.0000
2:70453213:CTTA:C	donor_loss	1.0000
2:70453214:TTACC:T	donor_loss	1.0000
2:70453215:TACC:T	donor_loss	1.0000
2:70453216:A:AC	donor_gain	1.0000
2:70453217:C:CC	donor_gain	1.0000
2:70453323:AGCAG:A	acceptor_gain	1.0000
2:70453325:CAG:C	acceptor_gain	1.0000
2:70453326:AG:A	acceptor_gain	1.0000
2:70453327:GC:G	acceptor_loss	1.0000
2:70453328:C:CC	acceptor_gain	1.0000
2:70453329:T:C	acceptor_loss	1.0000
2:70456334:CTCA:C	donor_gain	1.0000
2:70456335:TCA:T	donor_loss	1.0000
2:70456337:A:AC	donor_gain	1.0000
2:70456338:C:CA	donor_gain	1.0000
2:70456338:CT:C	donor_gain	1.0000
2:70456338:CTG:C	donor_gain	1.0000
2:70456338:CTGT:C	donor_gain	1.0000
2:70456338:CTGTA:C	donor_gain	1.0000
2:70456484:GGCAG:G	acceptor_gain	1.0000
2:70456486:CAG:C	acceptor_gain	1.0000
2:70456487:AG:A	acceptor_gain	1.0000
2:70456488:GCTG:G	acceptor_loss	1.0000
2:70456489:C:CC	acceptor_gain	1.0000
2:70456489:C:CG	acceptor_loss	1.0000
2:70514858:CCA:C	donor_gain	1.0000
2:70450864:CCA:C	acceptor_gain	0.9900
2:70450865:CAC:C	acceptor_gain	0.9900
2:70453217:CCT:C	donor_gain	0.9900

AlphaMissense

1030 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:70456459:C:G	C82S	1.000
2:70456460:A:T	C82S	1.000
2:70456458:A:C	C82W	0.999
2:70456459:C:A	C82F	0.999
2:70456459:C:T	C82Y	0.999
2:70456460:A:G	C82R	0.999
2:70456468:C:A	G79V	0.999
2:70456469:C:A	G79C	0.999
2:70456486:C:G	C73S	0.999
2:70456487:A:T	C73S	0.999
2:70465646:A:C	F62C	0.999
2:70465651:G:C	C60W	0.999
2:70465652:C:G	C60S	0.999
2:70465652:C:T	C60Y	0.999
2:70465653:A:G	C60R	0.999
2:70465653:A:T	C60S	0.999
2:70465658:C:A	G58V	0.999
2:70465658:C:T	G58E	0.999
2:70465659:C:G	G58R	0.999
2:70465659:C:T	G58R	0.999
2:70465666:G:C	C55W	0.999
2:70465667:C:G	C55S	0.999
2:70465668:A:G	C55R	0.999
2:70465668:A:T	C55S	0.999
2:70456469:C:G	G79R	0.998
2:70456487:A:G	C73R	0.998
2:70465619:C:G	C71S	0.998
2:70465619:C:T	C71Y	0.998
2:70465620:A:G	C71R	0.998
2:70465620:A:T	C71S	0.998

dbSNP variants (sampled 300 via entrez): RS1000010326 (2:70458329 T>C), RS1000011962 (2:70551917 G>A,C), RS1000088676 (2:70506112 G>A), RS1000123469 (2:70545925 G>A), RS1000166490 (2:70455462 C>T), RS1000183315 (2:70539742 A>G), RS1000236660 (2:70452069 G>A), RS1000287112 (2:70499588 C>T), RS1000299384 (2:70539944 C>T), RS1000369040 (2:70534120 A>C), RS1000381311 (2:70528339 A>G), RS1000383752 (2:70486612 C>T), RS1000428414 (2:70464513 A>C), RS1000512399 (2:70501429 A>T), RS1000522431 (2:70541481 A>G)

Disease associations

OMIM: gene MIM:190170 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
tooth agenesis	Supportive	Autosomal dominant

Mondo (1): tooth agenesis (MONDO:0005486)

Orphanet (0):

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000202	Orofacial cleft
HP:0000677	Oligodontia
HP:0000679	Taurodontia
HP:0000684	Delayed eruption of teeth
HP:0000685	Hypoplasia of teeth
HP:0000687	Widely spaced teeth
HP:0000689	Dental malocclusion
HP:0000690	Agenesis of maxillary lateral incisor
HP:0000691	Microdontia
HP:0000696	Delayed eruption of permanent teeth
HP:0005216	Impaired mastication
HP:0006289	Agenesis of central incisor
HP:0006297	Enamel hypoplasia
HP:0006336	Short dental root
HP:0006342	Peg-shaped maxillary lateral incisors
HP:0006344	Abnormal primary molar morphology
HP:0006482	Abnormal dental morphology
HP:0011051	Agenesis of premolar
HP:0011053	Agenesis of mandibular premolar
HP:0011056	Agenesis of first permanent molar tooth
HP:0011078	Abnormality of canine
HP:0011219	Short face
HP:0012472	Eclabion

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000785_16	Longevity	1.000000e-06
GCST001059_3	Neutrophil count	5.000000e-06
GCST001762_75	Obesity-related traits	8.000000e-06
GCST002470_1	Pulse pressure in young-onset hypertension	2.000000e-07
GCST002481_1	Acne (severe)	5.000000e-06
GCST002663_8	Superior frontal gyrus grey matter volume	7.000000e-06
GCST003802_4	Response to citalopram or escitalopram in depression	5.000000e-07
GCST003853_2	Hip minimal joint space width	5.000000e-11
GCST004049_5	Cough in response to angiotensin-converting enzyme inhibitor drugs	9.000000e-07
GCST004998_2	Severe progression in rheumatoid arthritis	8.000000e-06
GCST005191_4	Hair shape	3.000000e-11
GCST005235_9	Hand grip strength	5.000000e-13
GCST005830_20	Hand grip strength	1.000000e-14
GCST006979_11	Heel bone mineral density	7.000000e-16
GCST007093_19	Osteoarthritis	4.000000e-16
GCST007093_35	Osteoarthritis	2.000000e-08
GCST011398_37	Response to esketamine in treatment resistant depression	8.000000e-07
GCST90007526_2	Low hand grip strength (60 years and older) (EWGSOP)	7.000000e-09
GCST90007529_2	Low hand grip strength (60 years and older) (FNIH)	5.000000e-11

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004833	neutrophil count
EFO:0005763	pulse pressure measurement
EFO:0006516	superior frontal gyrus grey matter volume measurement
EFO:0007873	cartilage thickness measurement
EFO:0005325	response to angiotensin-converting enzyme inhibitor
EFO:0008336	disease progression measurement
EFO:0006941	grip strength measurement
EFO:0009270	heel bone mineral density
EFO:0009748	response to ketamine

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4662938 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	increases activity, increases secretion, increases stability, decreases reaction, increases expression (+2 more)	12
Estradiol	affects cotreatment, increases expression, decreases expression, decreases reaction, affects expression	11
sodium arsenite	increases phosphorylation, increases reaction, affects methylation, increases expression, increases stability (+1 more)	8
Particulate Matter	affects cotreatment, decreases reaction, increases abundance, increases expression, increases methylation (+2 more)	6
bisphenol A	decreases reaction, affects expression, increases expression	5
arsenite	increases secretion, decreases reaction, decreases expression, increases methylation, affects reaction (+2 more)	5
Resveratrol	affects cotreatment, increases expression, affects localization, decreases reaction	4
Tobacco Smoke Pollution	increases expression, increases secretion	4
Genistein	decreases reaction, increases expression	4
RTKI cpd	decreases reaction, increases secretion, increases expression, increases activity, increases phosphorylation	3
Gefitinib	decreases response to substance, decreases reaction, increases reaction, increases response to substance, increases secretion	3
Fulvestrant	decreases reaction, increases expression, decreases expression	3
Air Pollutants	increases expression, increases abundance, increases methylation	3
Arsenic	affects cotreatment, decreases expression, increases expression	3
Cisplatin	increases expression, decreases response to substance	3
Quercetin	affects cotreatment, increases expression, decreases reaction, increases phosphorylation	3
Silicon Dioxide	increases secretion, increases expression, increases reaction, decreases reaction	3
Tamoxifen	decreases reaction, increases expression, affects expression, affects cotreatment, decreases expression	3
Valproic Acid	increases expression	3
polydatin	increases expression, affects localization, decreases reaction, affects cotreatment	2
acteoside	increases expression, affects localization, increases reaction, affects cotreatment	2
batimastat	decreases reaction, increases secretion, decreases secretion	2
N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2’-naphthyl)alanylalanine, 2-aminoethylamide	decreases reaction, increases expression, increases secretion	2
(+)-JQ1 compound	affects cotreatment, decreases expression	2
Irinotecan	decreases reaction, increases secretion, decreases response to substance	2
Benzo(a)pyrene	increases expression, increases methylation	2
Cadmium	decreases expression, increases abundance, decreases reaction	2
Ethinyl Estradiol	affects expression, increases expression	2
Methotrexate	decreases expression, increases expression	2
Tretinoin	increases expression, increases secretion	2

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4827255	Binding	Inhibition of TGFA transcriptional activity in human KMS-11 cells assessed as reduction in H3K36 methylation at 10 uM measured after 72 hrs by chip q-PCR analysis	5-Aminonaphthalene derivatives as selective nonnucleoside nuclear receptor binding SET domain-protein 2 (NSD2) inhibitors for the treatment of multiple myeloma. — Eur J Med Chem

Cellosaurus cell lines

18 cell lines: 14 spontaneously immortalized cell line, 3 embryonic stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0140	AML12	Spontaneously immortalized cell line	Male
CVCL_A7I7	SEES3-1V human TGFA, clone1	Embryonic stem cell	Male
CVCL_A7I8	SEES3-1V human TGFA, clone2	Embryonic stem cell	Male
CVCL_A7I9	SEES3-1V human TGFA, clone3	Embryonic stem cell	Male
CVCL_D6AU	HyCyte AML12 KO-mIgf2	Spontaneously immortalized cell line	Male
CVCL_D8C9	Ubigene A-549 TGFA KO	Cancer cell line	Male
CVCL_D8DT	Ubigene AML12 Atp7b KO	Spontaneously immortalized cell line	Male
CVCL_D8DU	Ubigene AML12 Cs KO	Spontaneously immortalized cell line	Male
CVCL_D8DV	Ubigene AML12 Faah KO	Spontaneously immortalized cell line	Male
CVCL_D8DW	Ubigene AML12 Fasn KO	Spontaneously immortalized cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01470235	Not specified	UNKNOWN	Hypodontia and Ovarian Cancer
NCT03445026	Not specified	UNKNOWN	Frequency of Hypodontia After Chemotherapy in Childhood Cancer Survivors Study
NCT05771246	Not specified	COMPLETED	Craniofacial Morphology And Sella Turcica Bridging Associated With Third Molar Agenesis.