Affinage

TGFA

Protransforming growth factor alpha · UniProt P01135

Length
160 aa
Mass
17.0 kDa
Annotated
2026-04-28
47 papers in source corpus 17 papers cited in narrative 18 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TGFA encodes transforming growth factor-alpha, a secreted EGF-family ligand that activates EGFR to drive cell proliferation and survival through PI3K/AKT signaling, functioning as a key mitogenic factor in epithelial tissues during development and in cancer. In pancreatic tumorigenesis, TGFA cooperates with oncogenic KRAS to accelerate progression from preneoplastic lesions to metastatic cancer and intraductal papillary mucinous neoplasm (PMID:17785207), while in BRAF-mutant thyroid cancer cells TGFA-EGFR signaling promotes proliferation through PI3K/AKT independently of MEK/ERK (PMID:20877637). TGFA expression is regulated transcriptionally by IRF6 during palatogenesis and by T3-activated PI3K in breast cancer cells (PMID:23029012, PMID:27094789), and post-transcriptionally by multiple miRNAs (miR-137, miR-376c, miR-374b, miR-340-5p, miR-1298-5p, miR-431-5p, miR-7-5p) whose suppressive effects are antagonized by competing endogenous lncRNAs and circRNAs (PMID:27458156, PMID:29441940, PMID:28239819, PMID:33480984). Variants in TGFA coding and regulatory regions have been identified in individuals with nonsyndromic orofacial clefting, and Tgfa expression in medial edge palatal epithelium at the time of shelf fusion supports a role in craniofacial morphogenesis (PMID:10552925, PMID:23029012).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1999 Medium

    Establishing that TGFA is expressed in the critical palatal epithelium at the time of shelf fusion and harbors rare coding/regulatory variants in cleft patients answered whether TGFA has a direct developmental role in craniofacial morphogenesis.

    Evidence Genomic sequencing of all TGFA exons/regulatory regions in 250 cleft individuals plus mouse palatal expression mapping

    PMID:10552925

    Open questions at the time
    • Functional validation of individual variants not performed
    • Causal mechanism linking TGFA variants to cleft pathogenesis not demonstrated
    • Role of TGFA relative to other EGFR ligands in palatogenesis unclear
  2. 2007 High

    Demonstrating that pancreatic co-expression of Tgfa and oncogenic Kras synergistically accelerates progression to metastatic cancer and IPMN established TGFA-EGFR signaling as a cooperating oncogenic pathway with KRAS in pancreatic tumorigenesis.

    Evidence Genetic cross of Elastase-Tgfa and p48-Cre;KrasG12D transgenic mice with histopathological and transcriptomic analysis

    PMID:17785207

    Open questions at the time
    • Whether TGFA is the critical endogenous EGFR ligand versus other ligands not resolved
    • Downstream effector pathways mediating synergy not dissected
  3. 2010 Medium

    Showing that secreted TGFA activates EGFR to drive PI3K/AKT-dependent proliferation independently of MEK/ERK in BRAF-mutant PTC cells, and identifying novel phosphotyrosine substrates (ANXA3, KRT8, KRT18) in TGFA-treated cells, clarified the signaling branch selectivity and substrate repertoire downstream of TGFA-EGFR.

    Evidence Conditioned-medium transfer with pathway inhibitors in thyroid cancer cells; 2-DE/MS phosphoproteomics in TGFA-treated NPC cells

    PMID:20049563 PMID:20877637

    Open questions at the time
    • In vivo relevance of PI3K/AKT-selective signaling not tested
    • ANXA3/KRT phosphorylation functional consequences unknown
    • Generalizability beyond BRAF-mutant context unclear
  4. 2012 Medium

    Placing IRF6 upstream of TGFA in palatogenesis — Tgfa expression is absent in Irf6-knockout palatal tissue — resolved how TGFA expression is regulated during craniofacial development and explained the genetic interaction between IRF6 and TGFA in orofacial cleft susceptibility.

    Evidence Irf6 knockout mouse palatal tissue expression analysis combined with genetic interaction testing in four human cohorts

    PMID:23029012

    Open questions at the time
    • Whether IRF6 directly binds the TGFA promoter or acts indirectly not determined
    • Other IRF6 targets that may contribute to clefting not excluded
  5. 2016 Medium

    Discovering that T3 induces TGFA transcription through PI3K (blocked by LY294002) independently of MAPK/ERK and that lncRNA MALAT1 sponges miR-376c to de-repress TGFA established that TGFA expression is controlled at both the transcriptional and post-transcriptional levels by distinct regulatory axes.

    Evidence RT-PCR with PI3K/MAPK inhibitors in T3-treated MCF7 cells; RNA pulldown and luciferase assays for MALAT1-miR376A-TGFA axis in osteosarcoma cells

    PMID:27094789 PMID:27458156

    Open questions at the time
    • Identity of the transcription factor linking PI3K to TGFA promoter unknown
    • Whether MALAT1-miR-376c axis operates outside osteosarcoma not tested
  6. 2017 Medium

    Validation that miR-137 and miR-376c directly target the TGFA 3′-UTR, with miR-376c itself regulated by NF-κB/IL-1β signaling, expanded the inventory of TGFA-targeting miRNAs and linked inflammatory signaling to post-transcriptional TGFA de-repression.

    Evidence Luciferase reporter assays confirming direct miRNA binding to TGFA 3′-UTR in NSCLC and osteosarcoma cells; NF-κB inhibitor experiments

    PMID:28239819 PMID:29441940

    Open questions at the time
    • In vivo validation of miR-137 and miR-376c regulation of TGFA lacking
    • Relative contribution of each miRNA to TGFA regulation in any single tissue unknown
  7. 2021 Medium

    Multiple studies converged to show that TGFA is a common effector of diverse ceRNA networks — circTAF4B/miR-1298-5p in bladder cancer, miR-374b in breast cancer, LINC00857/miR-340-5p in PAAD, and cisplatin-induced miR-376c in osteosarcoma — establishing that TGFA upregulation is a recurrent oncogenic output of miRNA sponging across cancer types.

    Evidence Luciferase reporter, RIP, and rescue experiments across bladder cancer, breast cancer, PAAD, and osteosarcoma cell lines with xenograft confirmation

    PMID:32020849 PMID:33480984 PMID:33661995 PMID:34322376

    Open questions at the time
    • No systematic comparison of which ceRNA axis dominates in a given tissue
    • Whether targeting TGFA directly is therapeutically superior to targeting individual ceRNAs unknown
    • Endogenous stoichiometry of ceRNA competition not measured
  8. 2022 Medium

    Further ceRNA axes (circRTN1/miR-431-5p in thyroid cancer, LASTR/miR-137 in lung cancer) converging on TGFA with downstream PI3K/AKT activation reinforced TGFA as a nodal oncogenic target regulated by competing noncoding RNAs.

    Evidence Luciferase, RIP, xenograft assays in thyroid cancer cells; western blot for PI3K/AKT in lung cancer cells

    PMID:35281858 PMID:35804263

    Open questions at the time
    • LASTR/miR-137/TGFA axis is low confidence with pathway placement based only on western blot
    • Direct demonstration that TGFA mediates PI3K/AKT activation in the LASTR axis lacking
  9. 2023 Medium

    Identification of circ_0006667/miR-7-5p/TGFA axis in retinal pigment epithelium under high-glucose conditions extended TGFA's ceRNA-regulated biology beyond cancer into diabetic retinopathy.

    Evidence Luciferase and RIP assays in ARPE-19 cells under high-glucose conditions

    PMID:36715959

    Open questions at the time
    • In vivo diabetic retinopathy model not used
    • Functional contribution of TGFA relative to other high-glucose effectors not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • The precise proteolytic processing mechanism of the TGFA transmembrane precursor, the identity of the metalloprotease(s) principally responsible in each tissue context, and whether TGFA signals in a juxtacrine versus paracrine mode in specific developmental and disease settings remain unresolved.
  • No structural model of TGFA-EGFR complex from these studies
  • Relative contributions of TGFA versus other EGFR ligands in any single in vivo context not delineated
  • Therapeutic targeting of TGFA specifically (versus EGFR) not explored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-1643685 Disease 6 R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 2
Partners
EGFRIRF6KRAS

Evidence

Reading pass · 18 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) synergistically accelerates progression of mPanIN lesions to metastatic pancreatic cancer and drives development of cystic papillary lesions (IPMN), placing EGFR/TGFα signaling upstream of IPMN development in cooperation with Kras Genetic epistasis — transgenic mouse cross (Elastase-Tgfa × p48(+/Cre);Kras(+/LSL-G12D)) with histopathological and microarray analysis Cancer cell High 17785207
2010 TGFα stimulation of NPC cells (via EGFR) triggers tyrosine phosphorylation of downstream substrates including ANXA3, KRT8, and KRT18, identifying these as novel components of the EGFR phosphotyrosine signaling network activated by TGFα Functional proteomics: 2-DE, 2-D western blotting, mass spectrometry, and IP-western blotting of TGFα-treated CNE2 cells Medical oncology Medium 20049563
2010 TGFA is secreted by papillary thyroid carcinoma (PTC) cells and activates EGFR on target cells, stimulating cell proliferation through PI3K/AKT activation independently of MEK/ERK signaling in BRAF-mutant PTC cells Conditioned medium transfer to HeLa cells, biochemical EGFR activation assays (ERK and AKT phosphorylation), cell proliferation assay with TGFA stimulation in NIM-1 PTC cells PloS one Medium 20877637
2016 Triiodothyronine (T3) induces TGFA mRNA expression in MCF7 breast cancer cells through activation of PI3K; this induction is blocked by the PI3K inhibitor LY294002 and requires active gene transcription RT-PCR with pharmacological inhibitors (actinomycin D, cycloheximide, LY294002) in T3-treated MCF7 cells Life sciences Medium 27094789
2019 T3-induced upregulation of TGFA mRNA in MCF7 cells is independent of the MAPK/ERK pathway (PD98059 inhibition does not block it) but requires RNA Polymerase II activity (α-amanitin inhibition modulates the effect) RT-PCR with pharmacological inhibitors (α-amanitin, PD98059) in T3-treated MCF7 cells Archives of endocrinology and metabolism Medium 30916164
2016 MALAT1 lncRNA promotes osteosarcoma cell growth by acting as a competing endogenous RNA (ceRNA) for MIR376A, thereby de-repressing TGFA expression; direct binding between MIR376A and both MALAT1 3'-UTR and TGFA 3'-UTR was demonstrated RNA pulldown, dual-luciferase reporter assay, qRT-PCR, western blot, knockdown/overexpression in OS cell lines Oncotarget Medium 27458156
2017 miR-376c directly targets the 3'-UTR of TGFA and suppresses TGFA expression; IL-1β-driven NF-κB signaling downregulates miR-376c, leading to increased TGFA protein and osteosarcoma cell growth Luciferase reporter assay, western blot, miR-376c mimic/inhibitor transfection, NF-κB inhibition in osteosarcoma cells Die Pharmazie Medium 29441940
2017 miR-137 directly targets TGFA mRNA and suppresses its expression, mediating the tumor-suppressive effect of miR-137 on NSCLC cell proliferation Dual-luciferase reporter assay confirming miR-137 binding to TGFA 3'-UTR; western blot for TGFA protein; MTT and flow cytometry upon miR-137 overexpression/silencing and TGFA knockdown European review for medical and pharmacological sciences Medium 28239819
2021 circTAF4B sponges miR-1298-5p to upregulate TGFA expression, promoting bladder cancer cell proliferation, migration, invasion, and EMT; direct binding between miR-1298-5p and circTAF4B and between miR-1298-5p and TGFA 3'-UTR was validated RNA pull-down, dual-luciferase reporter assay, nuclear/cytoplasmic fractionation, CCK-8, colony formation, wound healing, Transwell, western blot, and mouse xenograft Frontiers in oncology Medium 34322376
2021 miR-374b directly targets and negatively regulates TGFA in breast cancer cells; TGFA knockdown suppresses cell proliferation, 3D growth, invasion, and colony formation, and overexpression of TGFA rescues the phenotype caused by miR-374b overexpression Bioinformatics prediction, luciferase reporter assay, gain/loss-of-function experiments in vitro and in vivo (mouse tumor growth), rescue experiments with TGFA overexpression Carcinogenesis Medium 33480984
2021 LINC00857 functions as a ceRNA to sponge miR-340-5p, thereby upregulating TGFA and promoting PAAD cell proliferation, invasion, and migration; direct interactions between LINC00857/miR-340-5p and miR-340-5p/TGFA were validated Dual-luciferase reporter assay, CCK-8, colony formation, Transwell assay, TCGA database analysis PloS one Medium 33661995
2021 Cisplatin inhibits osteosarcoma (Saos-2) cell proliferation by upregulating miR-376c, which directly targets the TGFA 3'-UTR and suppresses TGFA expression; TGFA overexpression reverses cisplatin-induced growth inhibition Luciferase reporter assay, qRT-PCR, western blot, MTT, BrdU assay, TGFA shRNA and ORF clone transfection, miR-376c mimic/sponge transfection Bosnian journal of basic medical sciences Medium 32020849
2022 circRTN1 sponges miR-431-5p to upregulate TGFA expression, promoting thyroid cancer cell proliferation, migration, and invasion; direct binding between miR-431-5p and circRTN1, and between miR-431-5p and TGFA 3'-UTR were validated Dual-luciferase reporter assay, RIP assay, qRT-PCR, western blot, colony formation, EdU, Transwell, flow cytometry, and xenograft tumor assay Hormones Medium 35804263
2022 LASTR lncRNA promotes lung cancer cell proliferation and metastasis through the miR-137/TGFA axis, activating the PI3K/AKT signaling pathway downstream of TGFA Knockdown of LASTR, qRT-PCR, cell proliferation/metastasis assays, western blotting for PI3K/AKT pathway components, GSEA, bioinformatic analysis Journal of Cancer Low 35281858
2023 circ_0006667 sponges miR-7-5p to upregulate TGFA expression in retinal pigment epithelial cells; this axis promotes high-glucose-induced cell dysfunction (suppressed proliferation, increased apoptosis) in a diabetic retinopathy model Dual-luciferase reporter assay, RIP assay, RT-qPCR, western blot, MTT, EdU, flow cytometry in ARPE-19 cells International ophthalmology Medium 36715959
2012 IRF6 and TGFA interact genetically in orofacial cleft susceptibility; Tgfa expression in murine palatal tissue requires Irf6 (Tgfa was not expressed in Irf6 knockout mice during palatogenesis), placing Irf6 upstream of Tgfa in the palatogenesis pathway Genetic interaction analysis in four human cohorts plus Irf6 knockout mouse model with expression analysis of Tgfa in palatal tissue PloS one Medium 23029012
1999 Human TGFA is composed of six exons; several sequence variants in conserved coding and regulatory segments were identified as rare candidate causes for orofacial clefting, supporting TGFA's role in facial morphogenesis; high-level TGFA expression occurs in medial edge palatal shelf epithelium at the time of shelf fusion in mice Genomic sequencing of TGFA (all exons, splice junctions, conserved 3'-UTR) in 250 individuals with NS-CL/P or NS-CPO; conformational analysis (SSCP) Genomics Medium 10552925
2025 In the extrahepatic bile duct (mouse), Tgfa is expressed by cholangiocytes at homeostasis and is upregulated after bile duct obstruction; increased Tgfa (along with other EGFR ligands) is associated with injury-induced biliary hyperproliferation that is EGFR-dependent Mouse bile duct ligation model, transcriptomic analysis, immunohistochemistry, biliary organoid studies with EGFR ligand stimulation and inhibition bioRxivpreprint Low

Source papers

Stage 0 corpus · 47 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 124 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 72 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
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
2022 LncRNA LASTR promote lung cancer progression through the miR-137/TGFA/PI3K/AKT axis through integration analysis. Journal of Cancer 15 35281858
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 14 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
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
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 7 35633991
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
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