Affinage

TGFA

Protransforming growth factor alpha · UniProt P01135

Length
160 aa
Mass
17.0 kDa
Annotated
2026-06-10
48 papers in source corpus 12 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TGFA encodes a secreted ligand for the EGF receptor (EGFR) that drives autocrine and paracrine proliferative signaling across multiple epithelial and cancer contexts (PMID:20877637). Secreted TGFα activates EGFR on target cells, triggering downstream ERK and AKT phosphorylation; in BRAF-mutant papillary thyroid carcinoma cells this stimulates proliferation via PI3K/AKT independently of MEK/ERK (PMID:20877637), and in nasopharyngeal carcinoma cells TGFα-activated EGFR drives tyrosine phosphorylation of substrates including ANXA3, KRT8, and KRT18 (PMID:20049563). TGFA expression is controlled at multiple levels: transcriptionally, T3 induces TGFA in breast cancer cells through PI3K and RNA polymerase II-dependent transcription but not MAPK/ERK (PMID:27094789, PMID:30916164), and IRF6 acts upstream of Tgfa during palatogenesis, where the two genes genetically interact in cleft lip/palate etiology (PMID:23029012); post-transcriptionally, several miRNAs (miR-137, miR-374b, miR-376c) directly target the TGFA 3' UTR to repress its expression and suppress proliferation in lung, breast, and osteosarcoma cells, with TGFA re-expression rescuing the malignant phenotype (PMID:28239819, PMID:33480984, PMID:32020849). In pancreatic tissue, TGFα synergizes with oncogenic Kras(G12D) through EGFR to accelerate progression to metastatic cancer and IPMN-like lesions (PMID:17785207).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2007 Medium

    Established that TGFα-driven EGFR signaling cooperates with oncogenic Kras to promote pancreatic carcinogenesis, defining a genetic synergy in tumor progression.

    Evidence Transgenic mouse genetic epistasis crossing Elastase-Tgfa with p48-Cre;Kras-G12D mice, with histopathology and microarray

    PMID:17785207

    Open questions at the time
    • Does not resolve which EGFR-downstream effectors mediate the synergy
    • No TGFα loss-of-function to test necessity
  2. 2010 Medium

    Showed that TGFα is secreted and activates EGFR on recipient cells to drive ERK/AKT phosphorylation and proliferation, with PI3K/AKT contribution independent of MEK/ERK in thyroid carcinoma.

    Evidence Conditioned-medium EGFR activation assays, kinase readouts, and proliferation assays with pathway inhibitors in PTC cell lines

    PMID:20877637

    Open questions at the time
    • Single lab, in vitro only
    • Relative contributions of ERK vs AKT to proliferation not fully quantified
  3. 2010 Medium

    Identified concrete EGFR substrates downstream of TGFα stimulation, linking ligand activity to specific phosphorylation events.

    Evidence Phosphoproteomics (2-DE, MS) with IP-western validation in TGFα-treated CNE2 nasopharyngeal carcinoma cells

    PMID:20049563

    Open questions at the time
    • Functional consequence of ANXA3/KRT8/KRT18 phosphorylation unknown
    • Single study
  4. 2012 Medium

    Placed IRF6 upstream of TGFA in palatogenesis, providing a developmental transcriptional context and disease relevance for TGFA in cleft lip/palate.

    Evidence Gene-gene interaction analysis across human cohorts plus Tgfa expression analysis in Irf6 knockout mouse palatal tissue

    PMID:23029012

    Open questions at the time
    • Direct transcriptional regulation of TGFA by IRF6 not demonstrated
    • Mechanism connecting TGFA loss to clefting unresolved
  5. 2017 Medium

    Defined miRNA-mediated post-transcriptional repression of TGFA as a tumor-suppressive axis, with direct 3' UTR targeting and functional rescue.

    Evidence Dual-luciferase reporter, western blot, and proliferation/rescue assays for miR-137 (NSCLC), later extended to miR-374b (breast) and miR-376c (osteosarcoma)

    PMID:28239819 PMID:32020849 PMID:33480984

    Open questions at the time
    • Which miRNA dominates in a given tissue is unclear
    • EGFR pathway engagement downstream of TGFA in these rescue settings not directly measured
  6. 2016 Medium

    Demonstrated hormone-driven transcriptional induction of TGFA, showing T3 upregulates TGFA via PI3K and RNA Pol II-dependent transcription, not MAPK/ERK.

    Evidence RT-PCR with actinomycin D, cycloheximide, LY294002, α-amanitin, and PD98059 in T3-treated MCF7 cells (two studies)

    PMID:27094789 PMID:30916164

    Open questions at the time
    • Transcription factor mediating T3/PI3K induction of TGFA not identified
    • Single group
  7. 2017 Low

    Linked inflammatory signaling to TGFA control, showing IL-1β/NF-κB suppresses miR-376c to relieve TGFA repression.

    Evidence NF-κB knockdown, forced miR-376c expression, and western blot in osteosarcoma cells/tissues

    PMID:29441940

    Open questions at the time
    • Pathway inferred without full mechanistic reconstitution
    • Direct NF-κB regulation of the miR-376c locus not shown
  8. 2023 Low

    Extended TGFA regulation to a circRNA-miRNA-TGFA axis in a non-cancer context (retinal pigment epithelium under high glucose).

    Evidence Dual-luciferase and RIP assays, with miR-7-5p/circ_0006667 manipulation in RPE cells

    PMID:36715959

    Open questions at the time
    • Single lab, limited independent replication
    • TGFA effector mechanism in RPE dysfunction not detailed
  9. 2025 Low

    Proposed a non-EGFR partner for TGFA, reporting TGFA-DSG2 binding driving a c-MYC/ADAM17 pathway in cervical cancer.

    Evidence RNA pull-down for TGFA-DSG2 interaction plus phenotypic and xenograft assays

    PMID:42154444

    Open questions at the time
    • RNA pull-down for a protein-protein interaction is unconventional and lacks orthogonal binding validation
    • Relationship between DSG2 axis and canonical EGFR signaling unresolved
  10. 2025 Low

    Implicated Tgfa as one of several EGFR ligands in cholangiocyte proliferation and bile duct regeneration after injury.

    Evidence Transcriptomics, IHC, and biliary organoid assays with EGFR ligands/inhibitors after bile duct ligation in mouse (preprint)

    Open questions at the time
    • Preprint without Tgfa-specific loss-of-function
    • Tgfa contribution not separated from other EGFR ligands

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TGFA processing, secretion, and ligand availability are coordinated with its multiple transcriptional and post-transcriptional inputs across tissues remains unresolved.
  • No structural or biophysical characterization of TGFα-EGFR binding in the corpus
  • Whether non-EGFR partners such as DSG2 are physiologically relevant is unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3
Localization
GO:0005576 extracellular region 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2
Partners
EGFR

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Concomitant pancreatic expression of TGFα (Tgfa) and oncogenic Kras(G12D) accelerates progression of mPanIN lesions to metastatic pancreatic cancer and drives development of cystic papillary lesions resembling human IPMN, indicating that EGFR signaling (activated by TGFα) synergizes with oncogenic Kras in pancreatic carcinogenesis. Genetic epistasis / transgenic mouse model: Elastase-Tgfa mice crossed with p48(+/Cre);Kras(+/LSL-G12D) mice; histopathology and microarray analysis Cancer cell Medium 17785207
2010 TGFA is secreted by papillary thyroid carcinoma (PTC) cell lines into conditioned medium and activates EGFR on target cells, resulting in ERK and AKT phosphorylation; in NIM-1 PTC cells harboring BRAF mutation, TGFA stimulates proliferation and contributes to PI3K/AKT activation independently of MEK/ERK signaling. Biochemical analysis of PTC cell lines: detection of EGFR on cell membrane and TGFA in conditioned media; conditioned medium activation of EGFR on HeLa cells with ERK/AKT phosphorylation readout; proliferation assays with TGFA stimulation and pathway inhibitors PloS one Medium 20877637
2010 TGFα treatment of NPC CNE2 cells triggers EGFR-dependent tyrosine phosphorylation of ANXA3, KRT8, and KRT18, identifying these as novel downstream substrates of EGFR signaling activated by TGFA. Functional proteomics: 2-DE, 2-D western blotting, mass spectrometry, and IP-western blotting of TGFα-treated vs. control CNE2 cells Medical oncology Medium 20049563
2016 Triiodothyronine (T3) upregulates TGFA mRNA expression in MCF7 breast cancer cells via PI3K activation; this upregulation is dependent on active gene transcription (blocked by actinomycin D at early time points) but does not require MAPK/ERK pathway activation. RT-PCR in MCF7 cells treated with T3 in presence/absence of actinomycin D (transcription inhibitor), cycloheximide (translation inhibitor), and LY294002 (PI3K inhibitor) Life sciences Medium 27094789
2019 T3 at physiological concentration increases TGFA mRNA expression in MCF7 cells independently of MAPK/ERK pathway activation; inhibition of RNA polymerase II modulates this T3-induced TGFA expression, confirming transcriptional regulation. RT-PCR with α-amanitin (RNA Pol II inhibitor) and PD98059 (MAPK/ERK inhibitor) in T3-treated MCF7 cells Archives of endocrinology and metabolism Medium 30916164
2017 miR-137 directly targets the 3' UTR of TGFA in non-small cell lung cancer cells; miR-137 overexpression reduces TGFA protein levels and suppresses NSCLC cell proliferation, while TGFA knockdown alone phenocopies this suppression. Dual-luciferase reporter assay (direct 3' UTR targeting), western blot (TGFA protein), MTT assay and flow cytometry (proliferation/cell cycle), qRT-PCR European review for medical and pharmacological sciences Medium 28239819
2021 miR-374b directly targets and negatively regulates TGFA in breast cancer cells; TGFA contributes to malignant behavior (proliferation, invasion, colony formation, tumor growth), and overexpression of TGFA reverses the tumor-suppressive phenotypes caused by miR-374b overexpression. Bioinformatics target prediction, in vitro and in vivo functional assays (2D/3D proliferation, invasion, xenograft), rescue experiments with TGFA overexpression Carcinogenesis Medium 33480984
2021 miR-376c directly targets the 3' UTR of TGFA; miR-376c overexpression suppresses TGFA expression and inhibits osteosarcoma Saos-2 cell growth and proliferation; cisplatin upregulates miR-376c and downregulates TGFA in a concentration-dependent manner, and TGFA overexpression reverses cisplatin-induced growth inhibition. Luciferase reporter assay (3' UTR direct targeting), TGFA-shRNA knockdown, TGFA ORF overexpression, MTT and BrdU proliferation assays, qRT-PCR, western blot Bosnian journal of basic medical sciences Medium 32020849
2017 IL-1β activates NF-κB signaling, which suppresses miR-376c expression, thereby relieving miR-376c-mediated repression of TGFA and promoting osteosarcoma cell growth; NF-κB knockdown suppresses TGFA expression and attenuates the TGFA increase induced by IL-1β. miR-376c/TGFA expression in OS tissues and cells; forced miR-376c expression; NF-κB knockdown; western blot for NF-κB and TGFA protein levels Die Pharmazie Low 29441940
2023 miR-7-5p directly targets TGFA 3' UTR; circ_0006667 sponges miR-7-5p, thereby upregulating TGFA expression in retinal pigment epithelial cells under high-glucose conditions; miR-7-5p overexpression protects cells from high-glucose-induced dysfunction largely by downregulating TGFA. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays, RT-qPCR, western blot, MTT, EdU, flow cytometry International ophthalmology Low 36715959
2012 IRF6 and TGFA genetically interact in the etiology of cleft lip/palate; Tgfa is not expressed in palatal tissues of Irf6 knockout mice, placing IRF6 upstream of TGFA in palatogenesis. Statistical gene-gene interaction analyses in multiple human cohorts; expression analysis of Tgfa and Irf6 in wild-type vs. Irf6 knockout mouse palatal tissues at critical stages of palatogenesis PloS one Medium 23029012
2025 TGFA binds to DSG2 (desmoglein 2) and activates downstream c-MYC/ADAM17 pathway, promoting cervical cancer cell proliferation, metastasis, and autophagy; TGFA knockdown inhibits tumor growth in vivo. RNA pull-down assay (TGFA-DSG2 interaction), western blot, MTT, flow cytometry, Transwell assay, nude mouse xenograft; RT-qPCR Cell cycle Low 42154444
2025 In mouse extrahepatic bile duct, Tgfa is expressed in cholangiocytes at homeostasis and its levels increase after bile duct obstruction along with Egfr upregulation; EGFR activation (to which Tgfa contributes as a ligand) drives cholangiocyte proliferation and bile duct regeneration after injury. Transcriptomic and immunohistochemistry analyses of mouse EHBD at homeostasis and after bile duct ligation; biliary organoid assays with recombinant EGFR ligands and EGFR/ERBB2 inhibitors; in vivo EGFR inhibition after obstruction bioRxiv (preprint)preprint Low

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Concomitant pancreatic activation of Kras(G12D) and Tgfa results in cystic papillary neoplasms reminiscent of human IPMN. Cancer cell 126 17785207
2004 MSX1, PAX9, and TGFA contribute to tooth agenesis in humans. Journal of dental research 125 15329380
1997 Studies of the candidate genes TGFB2, MSX1, TGFA, and TGFB3 in the etiology of cleft lip and palate in the Philippines. The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 115 9003904
2003 Variants of developmental genes (TGFA, TGFB3, and MSX1) and their associations with orofacial clefts: a case-parent triad analysis. Genetic epidemiology 73 12652527
2005 Oral clefts, maternal smoking, and TGFA: a meta-analysis of gene-environment interaction. The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 65 15643916
1997 Testing for interaction between maternal smoking and TGFA genotype among oral cleft cases born in Maryland 1992-1996. The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 65 9345615
2016 MALAT1 promotes osteosarcoma development by targeting TGFA via MIR376A. Oncotarget 56 27458156
1995 Association of transforming growth factor alpha (TGFA) and its precursors with malignant change in Barrett's epithelium: biological and clinical variables. International journal of cancer 55 7814148
2012 Interaction between IRF6 and TGFA genes contribute to the risk of nonsyndromic cleft lip/palate. PloS one 43 23029012
2004 Maternal MTHFR interacts with the offspring's BCL3 genotypes, but not with TGFA, in increasing risk to nonsyndromic cleft lip with or without cleft palate. European journal of human genetics : EJHG 43 15054400
1994 Evidence, from family studies, for linkage disequilibrium between TGFA and a gene for nonsyndromic cleft lip with or without cleft palate. American journal of human genetics 43 7977355
2009 Evidence that TGFA influences risk to cleft lip with/without cleft palate through unconventional genetic mechanisms. Human genetics 42 19444471
1999 Transforming growth factor-alpha (TGFA): genomic structure, boundary sequences, and mutation analysis in nonsyndromic cleft lip/palate and cleft palate only. Genomics 29 10552925
1986 RFLPs for transforming growth factor alpha (TGFA) gene at 2p13. Nucleic acids research 29 2876411
2005 Microsatellite polymorphisms in the epidermal growth factor receptor (EGFR) gene and the transforming growth factor-alpha (TGFA) gene and risk of oral cancer in Puerto Rico. Pharmacogenetics and genomics 27 15864136
2010 MTHFR, TGFB3, and TGFA polymorphisms and their association with the risk of non-syndromic cleft lip and cleft palate in China. American journal of medical genetics. Part A 26 20082468
2021 Circular RNA TAF4B Promotes Bladder Cancer Progression by Sponging miR-1298-5p and Regulating TGFA Expression. Frontiers in oncology 25 34322376
1987 A Taq I polymorphism for the human transforming growth factor alpha gene (TGFA). Nucleic acids research 20 2885813
2017 MiR-137 and its target TGFA modulate cell growth and tumorigenesis of non-small cell lung cancer. European review for medical and pharmacological sciences 18 28239819
2022 LncRNA LASTR promote lung cancer progression through the miR-137/TGFA/PI3K/AKT axis through integration analysis. Journal of Cancer 17 35281858
2020 Novel association between TGFA, TGFB1, IRF1, PTGS2 and IKBKB single-nucleotide polymorphisms and occurrence, severity and treatment response of major depressive disorder. PeerJ 17 32140313
1991 Expression analysis of EGF-R and TGFa in human ovarian carcinomas. Anticancer research 17 1746909
2021 MicroRNA-374b inhibits breast cancer progression through regulating CCND1 and TGFA genes. Carcinogenesis 15 33480984
2016 Triiodothyronine (T3) induces HIF1A and TGFA expression in MCF7 cells by activating PI3K. Life sciences 15 27094789
2010 Identification of tyrosine phosphoproteins in signaling pathway triggered TGF-a by using functional proteomics technology. Medical oncology (Northwood, London, England) 14 20049563
2010 Integrated ligand-receptor bioinformatic and in vitro functional analysis identifies active TGFA/EGFR signaling loop in papillary thyroid carcinomas. PloS one 14 20877637
2013 Relationship between EGF, TGFA, and EGFR Gene Polymorphisms and Traditional Chinese Medicine ZHENG in Gastric Cancer. Evidence-based complementary and alternative medicine : eCAM 13 24454509
2021 LncRNA LINC00857 strengthens the malignancy behaviors of pancreatic adenocarcinoma cells by serving as a competing endogenous RNA for miR-340-5p to upregulate TGFA expression. PloS one 12 33661995
2022 Association of MTHFR, BMP4, TGFA and IRF6 Polymorphisms with Non-Syndromic Cleft lip and Palate in North Indian Patients. Avicenna journal of medical biotechnology 9 35633991
2017 Association between maternal exposure to tobacco, presence of TGFA gene, and the occurrence of oral clefts. A case control study. Clinical oral investigations 9 28303469
2012 TGFA/Taq I polymorphism and environmental factors in non-syndromic oral clefts in Southern Brazil. Brazilian oral research 9 22892881
2008 TGFA/TAQ I polymorphism in nonsyndromic cleft lip and palate patients from Rio Grande Do Sul, Brazil. The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 9 18788876
1995 Epidermal growth factor receptor (EGF-R) and transforming growth factor alpha (TGFA) expression in different endometrial cancers. Anticancer research 9 7654016
2017 Association of Common Variants in TGFA with Increased Risk of Knee Osteoarthritis Susceptibility. Genetic testing and molecular biomarkers 8 28777012
2017 IL-1β-mediated NF-κB signaling augments the osteosarcoma cell growth through modulating miR-376c/TGFA axis. Die Pharmazie 8 29441940
2009 Transforming growth factor-alfa gene (TGFA), human tooth agenesis, and evidence of segmental uniparental isodisomy. European journal of oral sciences 6 19196314
2023 Circ_0006667 contributes to high glucose-induced retinal pigment epithelial cell dysfunction by mediating miR-7-5p/TGFA axis in diabetic retinopathy. International ophthalmology 4 36715959
2022 CircRTN1 acts as a miR-431-5p sponge to promote thyroid cancer progression by upregulating TGFA. Hormones (Athens, Greece) 4 35804263
2021 Cisplatin inhibits the proliferation of Saos-2 osteosarcoma cells via the miR-376c/TGFA pathway. Bosnian journal of basic medical sciences 4 32020849
2021 IRF6, MSX1, TGFA, dental anomalies, and skeletal malocclusion. European journal of orthodontics 4 33200192
1993 [Cleft lip and palate in the Chilean population: association with BamH1 polymorphism of the transforming growth factor alpha (TGFA) gene]. Revista medica de Chile 4 8272608
2019 Triiodothyronine (T3) upregulates the expression of proto-oncogene TGFA independent of MAPK/ERK pathway activation in the human breast adenocarcinoma cell line, MCF7. Archives of endocrinology and metabolism 3 30916164
2025 Integrative multi-omics analysis identifies TGFA as a novel glioma susceptibility gene and therapeutic target. Frontiers in neurology 1 41267963
2020 Genetic variation of IRF6 and TGFA genes in an HIV-exposed newborn with non-syndromic cleft lip palate. Oral diseases 1 32862534
2005 [Possible association due to linkage disequilibrium of TGFA, RARA and BCL3 with nonsyndromic cleft lip with or without cleft palate in the Chilean population]. Revista medica de Chile 1 16311697
2026 TGFA promotes the development of cervical cancer via interacting with DSG2. Cell cycle (Georgetown, Tex.) 0 42154444
2020 Association of rs2862851 in TGFA Gene with Peripheral TGFA Levels and the Severity of Knee Osteoarthritis in the Han Chinese Population. Genetic testing and molecular biomarkers 0 33181041
2016 Associations Between TGFA/TGFB3/MSX1 Gene Polymorphisms and Congenital Non-Syndromic Hearing Impairment in a Chinese Population. Medical science monitor : international medical journal of experimental and clinical research 0 27356075

Missed literature

Know a paper Affinage missed for TGFA? Flag it for the maintainers and the community.

No submissions yet.