{"gene":"TGFBR2","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2005,"finding":"Heterozygous mutations in TGFBR2 (or TGFBR1) cause a syndrome of cardiovascular, craniofacial, neurocognitive and skeletal abnormalities (Loeys-Dietz syndrome); despite mutant alleles failing to support TGFβ signal propagation in vitro, patient-derived tissues showed increased nuclear phospho-Smad2 and elevated collagen/CTGF expression, indicating paradoxically increased TGFβ signaling in vivo.","method":"Patient-derived cell culture assays of acute TGFβ signaling kinetics; immunostaining of patient tissues for p-Smad2, collagen, and CTGF; genetic mutation analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cell-based signaling assays, tissue immunostaining, genetic analysis) across ten families; replicated in vivo and in vitro","pmids":["15731757"],"is_preprint":false},{"year":2004,"finding":"Heterozygous mutations in TGFBR2 cause Marfan syndrome type 2 (MFS2); identified mutations lead to loss of TGFβ signaling activity on extracellular matrix formation.","method":"Chromosomal breakpoint mapping, DNA sequencing of TGFBR2, functional assessment of TGFβ signaling activity and ECM formation in mutation carriers","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — breakpoint identification plus functional signaling assay, multiple unrelated families","pmids":["15235604"],"is_preprint":false},{"year":2014,"finding":"Postnatal conditional inactivation of Tgfbr2 in smooth muscle cells causes thoracic aortic thickening, dilation, and dissection; loss of TGFBR2 decreases canonical Smad signaling but unexpectedly increases MAPK signaling, and aortic disease results from perturbed contractile apparatus in medial cells and paracrine growth factor production by adventitial cells; treatment with rapamycin prevents dissection.","method":"Smooth-muscle-specific Cre/lox conditional knockout in mice; TGFβ serologic neutralization; Western blot for Smad and MAPK signaling; rapamycin treatment; aortic histology","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple mechanistic readouts (Smad, MAPK signaling, histology, pharmacological rescue), replicated across models","pmids":["24401272"],"is_preprint":false},{"year":2007,"finding":"Conditional endothelial deletion of Tgfbr2 (or Alk5) in mice does not affect vessel morphogenesis and does not produce HHT-like vascular malformations, indicating that neither ALK5 nor TGFBR2 is required for ALK1 signaling pertinent to HHT2 pathogenesis.","method":"Conditional endothelial-specific Cre knockout of Alk1, Alk5, or Tgfbr2 in mice; vascular phenotype analysis; Alk5 inhibitor in zebrafish","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with direct phenotypic comparison across three receptor knockouts in same Cre line; negative result for TGFBR2 is well-controlled","pmids":["17911384"],"is_preprint":false},{"year":2010,"finding":"Heterozygous TGFBR2 mutations in patient-derived aortic smooth muscle cells decrease expression of SMC contractile proteins and impair TGFβ1-induced upregulation of contractile genes; patient-derived fibroblasts also fail to differentiate into mature myofibroblasts upon TGFβ1 stimulation, establishing that TGFBR2 mutations impair SMC contractile differentiation.","method":"Explanted patient aortic SMCs and fibroblasts; TGFβ1 stimulation assays; Western blot and immunostaining for contractile proteins in patient vs. control aortas","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — patient-derived primary cells with functional stimulation assay, confirmed in fixed patient tissue; multiple orthogonal readouts","pmids":["20628007"],"is_preprint":false},{"year":2010,"finding":"Quantitative analysis of nine TGFBR2 patient mutations showed differing effects on protein stability, internalization, Smad phosphorylation, ERK signaling, and transcriptional activity; mutations associated with LDS and MFS2 showed dominant-negative effects; the R460C TAAD-associated mutation retained residual Smad phosphorylation, suggesting that the balance between defective Smad vs. ERK signaling determines phenotypic severity.","method":"Quantitative cell-based assays for TGFBR2 protein expression, turnover (internalization), Smad phosphorylation, ERK activation, and transcriptional reporter activity for nine patient mutations","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple quantitative functional assays across nine alleles in a single systematic study","pmids":["21098638"],"is_preprint":false},{"year":2006,"finding":"Cell-autonomous ablation of Tgfbr2 specifically in palatal epithelial cells causes soft palate cleft; mutant MEE cells fail to undergo programmed cell death and instead continue to proliferate and form cysts/epithelial bridges; Irf6 expression is downregulated in Tgfbr2-mutant MEE cells, placing Irf6 downstream of TGFBR2 in palatal epithelial fate determination.","method":"Cre/lox conditional knockout of Tgfbr2 in palatal epithelial cells; genetic lineage labeling of MEE; immunostaining for Irf6, K14; histological analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with lineage tracing and molecular phenotyping, multiple orthogonal readouts","pmids":["16780827"],"is_preprint":false},{"year":2006,"finding":"Deletion of Tgfbr2 in Col2a-expressing cells disrupts maintenance of boundaries in the axial skeleton; loss of Tgfbr2 expands Pax1/Pax9 expression domains across sclerotome segments and reduces Fibromodulin (intervertebral disc marker) expression, demonstrating that TGFBR2 signaling maintains sclerotome segmental boundaries.","method":"Col2a-Cre conditional knockout of Tgfbr2 in mice; in situ hybridization and immunostaining for Pax1, Pax9, Msx1, Fmod; histological analysis with PNA staining","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple molecular markers across developmental stages","pmids":["16824508"],"is_preprint":false},{"year":2009,"finding":"Conditional loss of Tgfbr2 in Prx1Cre-expressing skull mesenchyme causes open skull defects due to reduced mesenchymal cell proliferation and impaired osteoblast differentiation; in isolated Tgfbr2-deleted osteoprogenitor cultures, mRNA levels of Runx2, Osterix, Dlx5, and Msx2 are downregulated, demonstrating that Tgfbr2 regulates osteoblast differentiation independently of proliferation.","method":"Prx1Cre conditional KO; BrdU proliferation assay; TUNEL apoptosis; immunofluorescence for Runx2/Osterix; Adeno-Cre deletion in cultured osteoprogenitors; RT-PCR","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO plus ex vivo mechanistic dissection with Adeno-Cre deletion; multiple molecular readouts","pmids":["19699732"],"is_preprint":false},{"year":2013,"finding":"Deletion of Tgfbr2 in odontoblast/bone mesenchyme (Osx-Cre) disrupts molar root elongation and HERS formation; odontoblast organization and Dspp expression are reduced, while Dmp1 increases; Tgfbr2 in dental mesenchyme indirectly regulates HERS maintenance.","method":"Osx-Cre conditional KO of Tgfbr2; microCT; immunostaining for K14, Dspp, Dmp1, Nfic; histological analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple molecular and structural readouts across postnatal time points","pmids":["23933490"],"is_preprint":false},{"year":2013,"finding":"Tgfbr2 mutant palatal mesenchymal cells (Tgfbr2fl/fl;Wnt1-Cre) spontaneously accumulate lipid droplets due to reduced lipolysis; these cells fail to respond to Sonic Hedgehog-driven proliferation; inhibition of p38 MAPK or telmisartan treatment restores lipid metabolism and cell proliferation, rescuing cleft palate in vivo.","method":"Cranial neural crest-specific Tgfbr2 conditional KO; lipid droplet staining; lipolysis assay; p38 MAPK inhibitor treatment in vitro and in vivo; rescue of palate fusion","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with pharmacological rescue both in vitro and in vivo; multiple mechanistic readouts including p38 MAPK pathway","pmids":["23975680"],"is_preprint":false},{"year":2014,"finding":"miR-145 directly targets the 3'-UTR of TGFBR2 mRNA in vascular smooth muscle cells; miR-145 overexpression attenuates TGFβ receptor II-dependent extracellular matrix gene expression and fibrosis, while miR-145 knockout mice show increased matrix synthesis and a pronounced fibrotic response to angiotensin II; endothelial cell co-culture induces miR-143/145 expression via Notch signaling.","method":"miR-145 overexpression/knockout in cell culture and mouse models; luciferase 3'-UTR reporter assay; angiotensin II infusion; ECM gene expression analysis","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct 3'-UTR reporter validation plus in vivo KO mouse with phenotypic readout; multiple orthogonal approaches","pmids":["25323858"],"is_preprint":false},{"year":2019,"finding":"NG2 glia-derived TGF-β2 signals through TGFBR2 in microglia to maintain brain immune homeostasis; gain- and loss-of-function of NG2 glia-TGF-β2 or microglial TGFBR2 regulate CX3CR1-mediated immune suppression; ablation of NG2 glia or TGFBR2 deficiency in microglia leads to exaggerated neuroinflammation and dopaminergic neuron loss in MPTP model.","method":"Diphtheria toxin-mediated NG2 glia ablation; RNA sequencing; co-cultures of NG2 glia and microglia; gain/loss-of-function experiments for TGFβ2 and TGFBR2; MPTP mouse model; immunohistochemistry","journal":"BMC medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including cell ablation, RNA-seq, co-culture gain/loss-of-function, and in vivo disease model","pmids":["31727112"],"is_preprint":false},{"year":2013,"finding":"miR-21 suppresses TGFBR2 expression by binding its 3'-UTR; androgen receptor (AR) signaling potentiates this effect, creating a positive feedback loop where miR-21 and AR regulate each other's expression; this miR-21/AR axis attenuates TGFβ-mediated Smad2/3 activation, cell growth inhibition, migration inhibition, and apoptosis in prostate cancer cells.","method":"3'-UTR luciferase reporter assay; AR/miR-21 overexpression and knockdown in prostate epithelial cell lines and xenografts; Western blot for p-Smad2/3; cell growth, migration, and apoptosis assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — 3'-UTR validation plus functional rescue experiments in multiple cell systems and in vivo xenograft","pmids":["24037531"],"is_preprint":false},{"year":2006,"finding":"TGFBR2 frameshift mutations in TGFBR2 exon 3 (polyadenine tract BAT-RII) occur at elevated rates in MLH1-deficient cells; reconstitution of TGFBR2 expression in an MSI colon cancer cell line (HCT116) decreases proliferation and reduces cdk4 expression and kinase activity, establishing that TGFBR2 inactivation drives increased cdk4-dependent proliferation in MSI colorectal cancer.","method":"TGFBR2 reconstitution in HCT116 MSI cell line; proliferation assays; cdk4 immunostaining and kinase activity assay in primary colon cancers with mutant vs. wild-type BAT-RII","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional reconstitution with molecular mechanistic readout (cdk4 expression and kinase activity) plus primary tumor validation","pmids":["16108056"],"is_preprint":false},{"year":2008,"finding":"MLH1 deficiency produces ~11-fold higher TGFBR2 microsatellite mutation rates compared to MSH6 deficiency; TGFBR2 microsatellite mutates ~3× faster than ACVR2 in both hMLH1 and hMSH6 deficient backgrounds, establishing that TGFBR2 frameshift mutation rate is dependent on specific MMR gene background.","method":"EGFP frameshift reporter plasmids containing TGFBR2 or ACVR2 coding microsatellites in MMR-deficient cell lines; flow cytometry; DNA sequencing","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative reporter reconstitution assay with mutation-resistant controls in isogenic MMR backgrounds; clear mechanistic outcome","pmids":["18941508"],"is_preprint":false},{"year":2019,"finding":"Loss of Tgfbr2 in Kras-mutant lung cells promotes lung squamous cell carcinoma (SCC) formation through a Smad-independent ERK1/2 pathway; low pERK1/2 upregulates SOX2 expression (oncogenic SCC driver), and ERK1/2 suppression cooperates with SMAD4 loss to elevate SOX2; Smad4 loss alone does not drive SCC, placing ERK1/2 downstream of Tgfbr2 as a key suppressor of SOX2-driven SCC.","method":"Kras × Tgfbr2 conditional KO mouse model; Kras × Smad4 conditional KO comparison; ERK1/2 inhibitor treatment; SOX2 expression analysis; IHC of mouse and human tumors","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in multiple mouse models plus pharmacological rescue; mechanistic pathway established with orthogonal approaches","pmids":["31209059"],"is_preprint":false},{"year":2019,"finding":"TGFBR2 reconstitution in MSI colorectal cancer cells alters the protein composition of secreted exosomes; TGFBR2 expression status determines a distinct exosomal proteome and modulates cytokine secretion (IL-4, SCF, PDGF-B) in recipient hepatoma cells.","method":"Doxycycline-inducible TGFBR2 reconstitution in HCT116-TGFBR2 cells; exosome isolation and mass spectrometry proteomics; nanoparticle tracking; confocal microscopy; Luminex cytokine profiling","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 2 / Moderate — isogenic inducible model, mass spectrometry, and functional cytokine readout; multiple orthogonal methods","pmids":["28376875"],"is_preprint":false},{"year":2016,"finding":"TGFBR2 reconstitution in HCT116 MSI colorectal cancer cells increases LFNG glycosyltransferase expression in a TGFBR2-dependent manner and enhances N-acetyl-d-glucosamine incorporation into Notch1, linking TGFBR2 signaling to Notch1 glycosylation via LFNG.","method":"Doxycycline-inducible TGFBR2 reconstitution in HCT116; Glyco-Gene Chip array; real-time RT-PCR validation; dual [³H]-GlcNAc/[³⁵S]-methionine metabolic labeling; Notch1 immunoprecipitation","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1 / Moderate — metabolic radiolabeling with immunoprecipitation in isogenic inducible model, direct biochemical demonstration","pmids":["27156840"],"is_preprint":false},{"year":2014,"finding":"Neural-specific deletion of Tgfbr2 (Foxg1-Cre) impairs brain angiogenesis through an altered secretome; VEGFA, IGF1, IGF2, TGFβ, ID1, THBS2, and ADAMTS1 are altered; conditioned medium from Tgfbr2-KO neural cultures causes HUVEC branching and migration defects that are rescued by supplementing VEGFA, FGF2, and IGF1.","method":"Foxg1-Cre conditional KO of Tgfbr2; conditioned medium transfer to HUVECs; HUVEC branching and migration assays; growth factor supplementation rescue experiments; gene expression analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with ex vivo conditioned medium functional rescue; multiple orthogonal assays","pmids":["24990151"],"is_preprint":false},{"year":2023,"finding":"USP33, a deubiquitinating enzyme, interacts with TGFBR2 (identified by mass spectrometry and luciferase complementation), deubiquitinates TGFBR2, prevents its lysosomal degradation, and promotes its accumulation at the cell membrane to sustain TGFβ signaling; TGFβ target gene ZEB1 transcriptionally upregulates USP33, creating a positive feedback loop.","method":"Mass spectrometry interactome; luciferase complementation assay; ubiquitination assay; lysosome inhibitor experiments; ChIP for ZEB1; Western blot; functional proliferation/migration/invasion assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical deubiquitination assay with mechanistic follow-up (lysosome pathway, feedback loop), multiple orthogonal methods","pmids":["37322017"],"is_preprint":false},{"year":2024,"finding":"ITGB5 (integrin β5) promotes TGFBR2 endosomal recycling by acting as a scaffold that interacts with both TGFBR2 and the sorting nexin SNX17, preventing lysosomal degradation of TGFBR2 and maintaining its cell-surface distribution; TGFβ signaling directly upregulates ITGB5, creating a positive feedback loop that enhances TGFβ-mediated EMT and gastric cancer metastasis.","method":"Co-immunoprecipitation of ITGB5/TGFBR2/SNX17; ITGB5 knockdown in vitro and in vivo; endosomal recycling assay; Western blot for TGFBR2 surface and total levels; feedback loop validation","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying trimeric complex, endosomal recycling functional assay, in vivo validation","pmids":["38729557"],"is_preprint":false},{"year":2025,"finding":"PIEZO1 attenuates TGFβ signaling by promoting endocytosis and autophagy of TGFBR2 via Rab GTPase 3C; PIEZO1 knockout in smooth muscle cells of Marfan syndrome mice exacerbates TAA and TGFβ pathway activation by inhibiting TGFBR2 endocytosis/autophagy; pharmacological PIEZO1 activation (Yoda1) prevents TGFβ activation and reverses TAA.","method":"SMC-specific PIEZO1 conditional KO in Marfan syndrome (Fbn1C1041G/+) mice; Yoda1 pharmacological treatment; Rab3C interaction experiments; endocytosis/autophagy assays; aortic histology and TGFβ pathway analysis","journal":"European heart journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with pharmacological rescue in disease model, mechanistic pathway (Rab3C endocytosis) identified; single lab, some mechanistic details only in abstract","pmids":["39585648"],"is_preprint":false},{"year":2021,"finding":"The E3 ubiquitin ligase HUWE1 mediates ubiquitination and degradation of TGFBR2 in gastric cancer cells; HUWE1 overexpression promotes GC cell proliferation, migration, and invasion, and these effects are impaired by TGFBR2 overexpression, placing TGFBR2 downstream of HUWE1-mediated ubiquitin-proteasome degradation.","method":"HUWE1 overexpression/silencing in GC cell lines; ubiquitination assay; Western blot; MTT and Transwell assays; TGFBR2 rescue experiments","journal":"Investigational new drugs","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ubiquitination assay plus rescue experiment, single lab, single study","pmids":["33405091"],"is_preprint":false},{"year":2021,"finding":"CRISPR/Cas9-mediated knockout of TGFBR2 in ovarian cancer tumor-infiltrating lymphocytes renders them resistant to TGFβ-mediated immunosuppression, evidenced by absence of SMAD phosphorylation, preserved proinflammatory cytokine secretion, and improved cytotoxicity in the presence of TGFβ.","method":"CRISPR/Cas9 KO of TGFBR2 in primary patient TILs; Western blot for p-SMAD; cytokine secretion assays; cytotoxicity assay; transcriptome analysis; off-target sequencing","journal":"Journal for immunotherapy of cancer","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct KO in primary patient cells with multiple functional readouts; mechanistic pathway (SMAD phosphorylation) directly confirmed","pmids":["35882447"],"is_preprint":false},{"year":2019,"finding":"TGFBR2 reconstitution in MSI colorectal cancer cells alters miRNA expression profiles in both cells and secreted extracellular vesicles; specific subsets of miRNAs are regulated in a TGFBR2-dependent manner, including downregulation of miR-381-3p in TGFBR2-deficient cells and EVs.","method":"Doxycycline-inducible TGFBR2 reconstitution in HCT116-TGFBR2; small RNA sequencing of cell and EV miRNA profiles; isogenic comparison","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic inducible model with RNA-seq; single lab but two compartments analyzed orthogonally","pmids":["31432155"],"is_preprint":false},{"year":2022,"finding":"The transcription factor GABPA directly activates TGFBR2 transcription (ChIP identified GABPA binding at TGFBR2 locus); GABPA and TGFBR2 phenocopy each other in suppressing renal cell carcinoma proliferation, invasion, and stemness; oncometabolite L-2-HG epigenetically silences GABPA via DNA methylation, disrupting the GABPA-TGFBR2-TGFβ axis.","method":"siRNA/overexpression of GABPA; RNA sequencing to identify TGFBR2 as GABPA target; ChIP assay for GABPA at TGFBR2 locus; L-2-HG treatment with methylation analysis; xenograft mouse model","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct transcriptional regulation, functional rescue experiments, in vivo xenograft validation","pmids":["35549739"],"is_preprint":false},{"year":2021,"finding":"SOX4 directly activates TGFBR2 transcription; SOX4 and the SWI/SNF ATPase SMARCA4 form a complex that maintains open chromatin at TGFBR2 regulatory regions; TGFBR2 is required to mediate SOX4-dependent PI3K/Akt signaling in triple-negative breast cancer.","method":"Genomic/proteomic analyses; ChIP for SOX4/SMARCA4 at TGFBR2 locus; chromatin accessibility assay (ATAC-seq equivalent); TGFBR2 knockdown rescue of SOX4-driven PI3K signaling; Co-IP of SOX4/SMARCA4 complex","journal":"NPJ breast cancer","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP plus chromatin accessibility plus Co-IP plus functional rescue; multiple orthogonal methods, single lab","pmids":["33837205"],"is_preprint":false},{"year":2017,"finding":"YAP-1 promotes TGFBR2 transcription by binding directly to the TGFBR2 promoter through TEAD transcription factors in T cells, thereby promoting Treg differentiation and immunosuppression in hepatocellular carcinoma.","method":"Bioinformatics identification of YAP-1/TEAD binding sites in TGFBR2 promoter; luciferase reporter assay; ChIP/promoter binding assay; overexpression of YAP-1 in T cells; flow cytometry for Treg markers","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter-binding ChIP plus reporter assay; single lab, limited orthogonal methods","pmids":["28472799"],"is_preprint":false},{"year":2020,"finding":"YAP/TAZ represses TGFBR2 both post-transcriptionally through the miR-106b-25 cluster and transcriptionally via EZH2 (identified as a YAP/TAZ transcriptional target); YAP/TAZ and EZH2 cooperate to repress TGFBR2 in NSCLC.","method":"miRNA target validation; EZH2 as YAP/TAZ target gene analysis; reporter assays; Western blot; correlation in clinical NSCLC samples","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mechanistic chain established by reporter assay and expression analysis; single lab, limited direct biochemical validation of YAP-EZH2-TGFBR2 circuit","pmids":["33296708"],"is_preprint":false},{"year":2021,"finding":"MYOCD localizes to the TGFBR2 promoter region and recruits PRMT5/MEP50 complex to epigenetically silence TGFBR2 transcription; loss of MYOCD leads to TGFBR2 hyperactivation, and NSCLC cells deficient in MYOCD are particularly sensitive to TGFBR kinase inhibitors.","method":"ChIP showing MYOCD at TGFBR2 promoter; PRMT5/MEP50 co-recruitment assay; TGFBR2 expression analysis with MYOCD manipulation; sensitivity assays with TGFBRi","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based promoter occupancy plus epigenetic complex recruitment; functional pharmacological validation; single lab","pmids":["33995678"],"is_preprint":false},{"year":2019,"finding":"TGFβ signaling through SMAD2/3 transcriptionally induces miR-520e expression (confirmed by ChIP-PCR), which in turn targets and downregulates TGFBR2, constituting a TGFβ-SMAD-miR-520e-TGFBR2 negative-feedback loop in NSCLC cells.","method":"ChIP-PCR for SMAD2/3 at miR-520e promoter; miR-520e overexpression/inhibition; luciferase 3'-UTR reporter for TGFBR2; Western blot; clinical correlation in NSCLC samples","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-PCR for direct transcriptional regulation plus 3'-UTR reporter; single lab, single study","pmids":["30475986"],"is_preprint":false},{"year":2019,"finding":"GDF15-induced apoptosis, caspase-9/3 activation, and ERK1/2/p38 MAPK inhibition in A549 cells depends on TGFBR2 expression; TGFBR2 silencing blocks all GDF15-induced apoptotic and MAPK effects, placing TGFBR2 as a required mediator of GDF15 signaling in this cell context.","method":"GDF15 overexpression (full and mature forms); siRNA knockdown of TGFBR2; flow cytometry for annexin V/PI; caspase activity assays; ERK1/2 and p38 phosphorylation by Western blot","journal":"Cell biochemistry and function","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — mechanistic rescue experiment with multiple signaling readouts; single lab, single cell line","pmids":["31172564"],"is_preprint":false},{"year":2023,"finding":"NRP1 (neuropilin-1) interacts with TGFBR2 at endothelial adherens junctions (Co-IP), reduces plasma membrane localization of TGFBR2, and suppresses TGFβ signaling; NRP1 knockdown increases TGFBR2 membrane abundance and TGFβ-driven inflammation.","method":"Co-IP of NRP1 with TGFBR2; NRP1 endothelial-specific KO mice; surface TGFBR2 localization analysis; inflammatory marker expression; atherosclerosis model","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo conditional KO with mechanistic localization readout; multiple orthogonal methods","pmids":["37220183"],"is_preprint":false},{"year":2019,"finding":"A super-enhancer (marked by H3K27Ac) at the TGFBR2 locus controls its transcription in pancreatic cancer cells; CRISPR deletion of this super-enhancer (sgTGFBR2-SEΔ) reduces TGFBR2 expression, impairs TGFβ-induced p-SMAD2/3 signaling, and attenuates TGFβ-induced migration and EMT.","method":"H3K27Ac ChIP-seq; BRD4 inhibitor (JQ1) treatment; CRISPR sgRNA-mediated super-enhancer deletion; p-SMAD2/3 Western blot; migration and EMT assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR-based enhancer deletion with functional downstream signaling readout; single lab","pmids":["31730895"],"is_preprint":false},{"year":2021,"finding":"Enzalutamide decreases TGFBR2 protein expression in osteoblasts through PTH1R-mediated endocytosis; PTH1R blockade rescues enzalutamide-mediated TGFBR2 reduction and restores enzalutamide sensitivity in prostate cancer cells co-cultured with osteoblasts.","method":"Co-culture of PCa cells with osteoblasts; PTH1R inhibitor rescue; Western blot for TGFBR2 protein; bone metastasis mouse models; clinical data analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic co-culture rescue experiment with pharmacological inhibitor; in vivo model correlation; single lab","pmids":["34752846"],"is_preprint":false},{"year":2022,"finding":"TGFBR2 reconstitution in MSI/MMR-deficient VCMsh2/Tgfbr2 mice modulates gut microbiota composition; combined loss of Msh2 and Tgfbr2 in intestinal epithelium synergistically promotes inflammation-associated colorectal cancer, and gut microbiota strongly modulates tumor incidence.","method":"Villin-Cre dual conditional KO of Msh2 and Tgfbr2; intestinal tumor analysis; mutational spectra; gene expression profiling; microbiota compositional analysis","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in vivo with microbiota mechanistic component; single lab","pmids":["35688320"],"is_preprint":false},{"year":2016,"finding":"Tgfbr2 deletion in Osx-Cre-expressing immature osteoblasts causes postnatal reduction in bone volume due to decreased osteoblast proliferation (PCNA reduction) and impaired maturation (Bglap/osteocalcin mRNA reduced) without altering Runx2 mRNA or apoptosis.","method":"Osx-Cre conditional KO; microCT; histomorphometry; qRT-PCR for Runx2, Bglap, PCNA, Bax/Bcl2; osteoblast and osteoclast enumeration","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple molecular and histomorphometric readouts; single lab","pmids":["28043895"],"is_preprint":false},{"year":2015,"finding":"Odontoblast-specific loss of Tgfbr2 disrupts odontoblast polarity and matrix secretion after mantle dentin formation, reduces alkaline phosphatase and Dsp expression, increases Dmp1, and causes ectopic fibrous matrix calcification leading to pulpal obliteration.","method":"Odontoblast-specific Cre conditional KO; immunohistochemistry for ALP, Dsp, Dmp1, collagen I, biglycan; microCT","journal":"Journal of dental research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple molecular and structural readouts; single lab","pmids":["25818583"],"is_preprint":false},{"year":2019,"finding":"A TGFBR2/SMAD2/DNMT1/miR-145 negative regulatory loop operates in LPS-induced sepsis: miR-145 directly targets TGFBR2 (confirmed by luciferase reporter and RIP); activated SMAD2 binds the DNMT1 promoter (ChIP), upregulating DNMT1 which methylates the miR-145 promoter, suppressing miR-145 and further increasing TGFBR2 expression.","method":"Luciferase reporter; ChIP for SMAD2 at DNMT1 promoter; RIP assay; miR-145 promoter methylation; TGFBR2 knockdown; LPS sepsis mouse model","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays (ChIP, luciferase, RIP) establishing the full circuit; single lab","pmids":["30784922"],"is_preprint":false},{"year":2020,"finding":"TGFBR2 interacts with PDGFR in GBM cells (Co-immunoprecipitation); concurrent TGFBR2 and PDGFR expression attenuates PDGFRi toxicity and maintains downstream PDGFR signaling under inhibitor treatment, contributing to PDGFRi resistance.","method":"Co-immunoprecipitation of TGFBR2 with PDGFR in GBM cells; PDGFRi toxicity assays; PDGFR downstream signaling Western blot","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP identifying TGFBR2-PDGFR interaction plus functional pharmacological readout; single lab","pmids":["29888103"],"is_preprint":false},{"year":2020,"finding":"Hypoxia-induced EZH2 promotes H3K27me3 at the TGFBR2 promoter, causing hypermethylation and epigenetic silencing of TGFBR2 in prostate cancer; separately, hypoxia upregulates miR-93 which also targets and suppresses TGFBR2.","method":"EZH2 siRNA/inhibitor experiments; methylation-specific PCR; ChIP for H3K27me3 at TGFBR2 promoter; luciferase 3'-UTR reporter for miR-93/TGFBR2; demethylation agent rescue","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for histone modification plus 3'-UTR reporter; two independent mechanisms identified; single lab","pmids":["29699590"],"is_preprint":false},{"year":2017,"finding":"Combined mutation of Apc, Kras, and Tgfbr2 deletion in intestinal epithelial cells cooperates to drive colorectal cancer metastasis; Tgfbr2 deletion combined with Kras mutation induces EMT-like morphology and lymph vessel intravasation; liver metastasis requires Kras combined with either Trp53 or Tgfbr2 deletion, with highest metastasis in the Apc/Kras/Tgfbr2 combination.","method":"Intestinal epithelial conditional KO mouse models with combinations of Apc, Kras, Tgfbr2, Trp53, Fbxw7; tumor-derived organoid splenic transplantation metastasis assay; RNA sequencing","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic genetic epistasis across five driver mutations in vivo with functional metastasis assay and transcriptomics","pmids":["29282223"],"is_preprint":false}],"current_model":"TGFBR2 is a transmembrane serine/threonine kinase receptor that, upon TGFβ ligand binding, canonically activates SMAD2/3 phosphorylation and non-canonically activates ERK/MAPK signaling; its surface abundance is regulated by endosomal recycling (promoted by ITGB5/SNX17 and inhibited by PIEZO1/Rab3C-mediated endocytosis/autophagy) and by ubiquitin-proteasome/lysosomal degradation (mediated by E3 ligase HUWE1 and deubiquitinase USP33); its transcription is activated by GABPA, SOX4/SMARCA4, and YAP-1/TEAD, and repressed by EZH2/YAP/TAZ and MYOCD/PRMT5 as well as a super-enhancer; it is post-transcriptionally repressed by multiple miRNAs (miR-21/AR, miR-145, miR-93, miR-520e) via 3'-UTR binding; in smooth muscle, TGFBR2 signaling is required for contractile differentiation and aortic wall homeostasis; in neural cells it controls a secretome that supports brain angiogenesis; in the immune system NG2-glia-derived TGFβ2 acts through microglial TGFBR2 to suppress neuroinflammation via CX3CR1; loss-of-function TGFBR2 mutations (including microsatellite frameshift mutations in MMR-deficient cancers) abrogate TGFβ tumor-suppressive signaling, deregulate cdk4-driven proliferation, and alter exosome cargo; the balance between impaired SMAD vs. ERK signaling downstream of mutant TGFBR2 alleles determines phenotypic severity in connective tissue disorders."},"narrative":{"mechanistic_narrative":"TGFBR2 is the type II transmembrane serine/threonine kinase receptor for the TGFβ family that, upon ligand binding, drives canonical SMAD2/3 phosphorylation and a parallel non-canonical ERK/p38 MAPK output, governing tissue homeostasis across the cardiovascular, skeletal, craniofacial, neural, and immune systems [PMID:24401272, PMID:20628007]. The relative balance of these two arms is functionally decisive: heterozygous TGFBR2 mutations cause connective-tissue disorders (Loeys-Dietz syndrome and Marfan syndrome type 2) in which mutant alleles fail to support TGFβ signaling in vitro yet paradoxically yield increased phospho-SMAD2 and collagen/CTGF in patient tissue, and the degree of impaired SMAD versus ERK signaling tracks with phenotypic severity [PMID:15731757, PMID:15235604, PMID:21098638]. In smooth muscle, TGFBR2 is required for contractile differentiation and aortic wall integrity, and its postnatal loss lowers SMAD while raising MAPK signaling to produce thoracic aortic dilation and dissection [PMID:24401272, PMID:20628007]. During development TGFBR2 controls programmed cell death and Irf6 expression in palatal epithelium, sclerotome boundary maintenance, osteoblast proliferation and differentiation, and tooth root formation [PMID:16780827, PMID:16824508, PMID:19699732, PMID:28043895]. In the nervous and immune systems, neural TGFBR2 shapes a pro-angiogenic secretome, and NG2-glia-derived TGFβ2 acts through microglial TGFBR2 to suppress neuroinflammation via CX3CR1 [PMID:24990151, PMID:31727112]. In cancer, TGFBR2 is a tumor suppressor inactivated by coding-microsatellite frameshift mutation in mismatch-repair-deficient colorectal cancer, where its loss deregulates cdk4-driven proliferation and cooperates with Apc/Kras to drive metastasis; loss of the Smad-independent ERK1/2 arm downstream of TGFBR2 derepresses SOX2 to promote lung squamous carcinoma [PMID:16108056, PMID:29282223, PMID:31209059]. TGFBR2 surface abundance is set by competing trafficking and degradation inputs—endosomal recycling promoted by an ITGB5/SNX17 scaffold versus PIEZO1/Rab3C-driven endocytosis-autophagy and NRP1-mediated membrane retention—and by ubiquitin-dependent turnover balanced by the E3 ligase HUWE1 and the deubiquitinase USP33 [PMID:38729557, PMID:39585648, PMID:37220183, PMID:33405091, PMID:37322017]. Its transcription is directly activated by GABPA, SOX4/SMARCA4, and YAP-1/TEAD and repressed by EZH2, MYOCD/PRMT5, and a super-enhancer, while multiple miRNAs including miR-21, miR-145, miR-93, and miR-520e silence it through 3'-UTR binding, several within TGFβ-driven feedback loops [PMID:35549739, PMID:33837205, PMID:28472799, PMID:29699590, PMID:33995678, PMID:31730895, PMID:24037531, PMID:25323858, PMID:30475986].","teleology":[{"year":2004,"claim":"Establishing that TGFBR2 loss-of-function causes heritable connective-tissue disease defined the receptor as essential for extracellular matrix homeostasis in humans.","evidence":"Breakpoint mapping and sequencing of TGFBR2 with TGFβ signaling/ECM functional assays in Marfan syndrome type 2 families","pmids":["15235604"],"confidence":"High","gaps":["Did not resolve which downstream arm (SMAD vs MAPK) drives ECM dysregulation","Cellular site of action not pinpointed"]},{"year":2005,"claim":"The paradox that mutant alleles fail to signal in vitro yet show elevated phospho-SMAD2 and collagen in patient tissue reframed disease as dysregulated rather than simply absent TGFβ signaling.","evidence":"Patient-derived signaling kinetics and tissue immunostaining for p-Smad2/collagen/CTGF across Loeys-Dietz families","pmids":["15731757"],"confidence":"High","gaps":["Mechanism reconciling in vitro loss with in vivo gain not established","Did not identify the compensatory pathway raising SMAD output"]},{"year":2010,"claim":"Allelic series quantification linked the SMAD-versus-ERK signaling balance of individual mutations to clinical severity, explaining genotype-phenotype variation.","evidence":"Quantitative cell-based assays of stability, internalization, Smad phosphorylation, ERK, and transcription across nine patient mutations; patient SMC/fibroblast differentiation assays","pmids":["21098638","20628007"],"confidence":"High","gaps":["Causal direction between ERK gain and disease not proven in vivo","Tissue-specific signaling thresholds undefined"]},{"year":2014,"claim":"Conditional smooth-muscle knockout established that postnatal TGFBR2 maintains aortic wall integrity, with disease driven by decreased SMAD and increased MAPK signaling and rescuable by rapamycin.","evidence":"Smooth-muscle Cre/lox Tgfbr2 knockout with Smad/MAPK Westerns, histology, and rapamycin treatment in mice","pmids":["24401272"],"confidence":"High","gaps":["Molecular trigger of MAPK upregulation upon TGFBR2 loss unresolved","Adventitial paracrine factors not fully identified"]},{"year":2009,"claim":"Tissue-specific conditional knockouts mapped distinct developmental requirements for TGFBR2 in palate, sclerotome, skull, bone, and tooth, separating proliferation from differentiation roles.","evidence":"Multiple Cre/lox conditional Tgfbr2 knockouts (palatal epithelium, Col2a, Prx1, Osx, odontoblast) with marker analysis, BrdU, TUNEL, and ex vivo deletion","pmids":["16780827","16824508","19699732","23933490","28043895","25818583"],"confidence":"High","gaps":["Downstream effectors (e.g., Irf6, Runx2) placement only partially mechanistic","Ligand source in each tissue not always defined"]},{"year":2008,"claim":"Microsatellite frameshift inactivation of TGFBR2 in mismatch-repair-deficient cancer, with mutation rate set by the specific MMR background, identified TGFBR2 as a tumor suppressor target and quantified its vulnerability.","evidence":"TGFBR2 reconstitution in MSI HCT116 cells with cdk4 readouts; EGFP frameshift reporters across MLH1/MSH6-deficient backgrounds","pmids":["16108056","18941508"],"confidence":"High","gaps":["Did not address metastatic cooperation","Downstream secretory/microbiota consequences not yet examined"]},{"year":2019,"claim":"Genetic epistasis defined TGFBR2 as a metastasis suppressor and revealed a Smad-independent ERK1/2 arm restraining SOX2-driven squamous carcinoma.","evidence":"Combinatorial Apc/Kras/Tgfbr2/Trp53 intestinal knockouts with organoid metastasis assays; Kras×Tgfbr2 vs Kras×Smad4 lung models with ERK inhibition","pmids":["29282223","31209059"],"confidence":"High","gaps":["How TGFBR2 maintains ERK tone to suppress SOX2 mechanistically incomplete","Relative contribution of SMAD vs ERK loss to metastasis not isolated"]},{"year":2019,"claim":"TGFBR2 status was shown to reprogram secreted exosome/EV cargo, glycosylation of Notch1 via LFNG, and cytokine secretion, extending its tumor-suppressor role to the secretome.","evidence":"Doxycycline-inducible TGFBR2 reconstitution in HCT116 with exosome proteomics, small-RNA sequencing, metabolic GlcNAc labeling, and Luminex cytokine profiling","pmids":["28376875","27156840","31432155"],"confidence":"Medium","gaps":["Functional consequence of altered exosome cargo on tumor progression not established in vivo","Single isogenic model"]},{"year":2019,"claim":"Beyond cell-autonomous signaling, TGFBR2 was shown to coordinate paracrine programs: neural TGFBR2 shapes a pro-angiogenic secretome and microglial TGFBR2 enforces immune homeostasis.","evidence":"Foxg1-Cre Tgfbr2 knockout with conditioned-medium HUVEC rescue; NG2-glia ablation and microglial TGFBR2 gain/loss in MPTP neuroinflammation model","pmids":["24990151","31727112"],"confidence":"High","gaps":["Transcriptional control of the secretome by TGFBR2 not detailed","CX3CR1 coupling mechanism downstream of TGFBR2 unresolved"]},{"year":2024,"claim":"Receptor surface abundance was established as an actively regulated node, with recycling, endocytosis/autophagy, membrane retention, and ubiquitin turnover each tuning TGFβ output.","evidence":"ITGB5/SNX17/TGFBR2 Co-IP and recycling assays; PIEZO1/Rab3C conditional KO and Yoda1 rescue in Marfan mice; NRP1 Co-IP and endothelial KO; HUWE1 ubiquitination and USP33 deubiquitination assays","pmids":["38729557","39585648","37220183","33405091","37322017"],"confidence":"Medium","gaps":["Hierarchy/competition among trafficking regulators not integrated","Several mechanisms rest on single-lab Co-IP or ubiquitination assays"]},{"year":2022,"claim":"Transcriptional and post-transcriptional control of TGFBR2 was mapped to direct activators, repressive epigenetic complexes, and miRNA feedback loops, defining how receptor dosage is set.","evidence":"ChIP for GABPA, SOX4/SMARCA4, YAP-1/TEAD activators; EZH2/H3K27me3, MYOCD/PRMT5, and super-enhancer repression; 3'-UTR reporters for miR-21/AR, miR-145, miR-93, miR-520e feedback circuits","pmids":["35549739","33837205","28472799","29699590","33995678","31730895","24037531","25323858","30475986","33296708"],"confidence":"Medium","gaps":["Context-specific dominance among these regulators not resolved","Many circuits validated in single cancer cell systems"]},{"year":2021,"claim":"Therapeutic engineering of TGFBR2 signaling was demonstrated by knocking it out in tumor-infiltrating lymphocytes to escape TGFβ immunosuppression.","evidence":"CRISPR/Cas9 TGFBR2 knockout in primary patient TILs with p-SMAD, cytokine, and cytotoxicity readouts","pmids":["35882447"],"confidence":"High","gaps":["Durability and in vivo antitumor efficacy not addressed","Effect limited to SMAD-axis readouts"]},{"year":null,"claim":"How the SMAD-versus-MAPK signaling balance is set in a tissue-specific manner—and whether the trafficking/degradation and transcriptional regulators converge to control this balance—remains the central unresolved question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking receptor dosage control to the SMAD/ERK output ratio","Mechanism converting reduced TGFBR2 to increased MAPK/SMAD signaling in vivo undefined","Structural basis of mutation-specific signaling bias not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,4,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,24,32]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[20,21,33]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[21,22]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,7,8,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,14,16,42]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,24,28]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[20,21,22,33]}],"complexes":[],"partners":["ITGB5","SNX17","USP33","HUWE1","NRP1","PIEZO1","PDGFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P37173","full_name":"TGF-beta receptor type-2","aliases":["TGF-beta type II receptor","Transforming growth factor-beta receptor type II","TGF-beta receptor type II","TbetaR-II"],"length_aa":567,"mass_kda":64.6,"function":"Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and thus regulates a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways Has transforming growth factor beta-activated receptor activity Has transforming growth factor beta-activated receptor activity Binds TGFB1, TGFB2 and TGFB3 in the picomolar affinity range without the participation of additional receptors. Blocks activation of SMAD2 and SMAD3 by TGFB1","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P37173/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TGFBR2","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TGFBR2","total_profiled":1310},"omim":[{"mim_id":"620961","title":"SORTING NEXIN 25; SNX25","url":"https://www.omim.org/entry/620961"},{"mim_id":"619656","title":"LOEYS-DIETZ SYNDROME 6; LDS6","url":"https://www.omim.org/entry/619656"},{"mim_id":"618005","title":"CONGENITAL DISORDER OF GLYCOSYLATION WITH DEFECTIVE FUCOSYLATION 1; CDGF1","url":"https://www.omim.org/entry/618005"},{"mim_id":"617168","title":"AORTIC ANEURYSM, FAMILIAL THORACIC 10; AAT10","url":"https://www.omim.org/entry/617168"},{"mim_id":"616914","title":"MARFANOID-PROGEROID-LIPODYSTROPHY SYNDROME; MFLS","url":"https://www.omim.org/entry/616914"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TGFBR2"},"hgnc":{"alias_symbol":["TBRII","TBR-ii"],"prev_symbol":["MFS2"]},"alphafold":{"accession":"P37173","domains":[{"cath_id":"2.10.60.10","chopping":"38-147","consensus_level":"high","plddt":86.8335,"start":38,"end":147},{"cath_id":"3.30.200.20","chopping":"242-327","consensus_level":"medium","plddt":92.9909,"start":242,"end":327},{"cath_id":"1.10.510.10","chopping":"330-550","consensus_level":"high","plddt":94.2041,"start":330,"end":550}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P37173","model_url":"https://alphafold.ebi.ac.uk/files/AF-P37173-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P37173-F1-predicted_aligned_error_v6.png","plddt_mean":81.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TGFBR2","jax_strain_url":"https://www.jax.org/strain/search?query=TGFBR2"},"sequence":{"accession":"P37173","fasta_url":"https://rest.uniprot.org/uniprotkb/P37173.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P37173/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P37173"}},"corpus_meta":[{"pmid":"15731757","id":"PMC_15731757","title":"A 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TGFBR1) cause a syndrome of cardiovascular, craniofacial, neurocognitive and skeletal abnormalities (Loeys-Dietz syndrome); despite mutant alleles failing to support TGFβ signal propagation in vitro, patient-derived tissues showed increased nuclear phospho-Smad2 and elevated collagen/CTGF expression, indicating paradoxically increased TGFβ signaling in vivo.\",\n      \"method\": \"Patient-derived cell culture assays of acute TGFβ signaling kinetics; immunostaining of patient tissues for p-Smad2, collagen, and CTGF; genetic mutation analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cell-based signaling assays, tissue immunostaining, genetic analysis) across ten families; replicated in vivo and in vitro\",\n      \"pmids\": [\"15731757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Heterozygous mutations in TGFBR2 cause Marfan syndrome type 2 (MFS2); identified mutations lead to loss of TGFβ signaling activity on extracellular matrix formation.\",\n      \"method\": \"Chromosomal breakpoint mapping, DNA sequencing of TGFBR2, functional assessment of TGFβ signaling activity and ECM formation in mutation carriers\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — breakpoint identification plus functional signaling assay, multiple unrelated families\",\n      \"pmids\": [\"15235604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Postnatal conditional inactivation of Tgfbr2 in smooth muscle cells causes thoracic aortic thickening, dilation, and dissection; loss of TGFBR2 decreases canonical Smad signaling but unexpectedly increases MAPK signaling, and aortic disease results from perturbed contractile apparatus in medial cells and paracrine growth factor production by adventitial cells; treatment with rapamycin prevents dissection.\",\n      \"method\": \"Smooth-muscle-specific Cre/lox conditional knockout in mice; TGFβ serologic neutralization; Western blot for Smad and MAPK signaling; rapamycin treatment; aortic histology\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple mechanistic readouts (Smad, MAPK signaling, histology, pharmacological rescue), replicated across models\",\n      \"pmids\": [\"24401272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Conditional endothelial deletion of Tgfbr2 (or Alk5) in mice does not affect vessel morphogenesis and does not produce HHT-like vascular malformations, indicating that neither ALK5 nor TGFBR2 is required for ALK1 signaling pertinent to HHT2 pathogenesis.\",\n      \"method\": \"Conditional endothelial-specific Cre knockout of Alk1, Alk5, or Tgfbr2 in mice; vascular phenotype analysis; Alk5 inhibitor in zebrafish\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with direct phenotypic comparison across three receptor knockouts in same Cre line; negative result for TGFBR2 is well-controlled\",\n      \"pmids\": [\"17911384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Heterozygous TGFBR2 mutations in patient-derived aortic smooth muscle cells decrease expression of SMC contractile proteins and impair TGFβ1-induced upregulation of contractile genes; patient-derived fibroblasts also fail to differentiate into mature myofibroblasts upon TGFβ1 stimulation, establishing that TGFBR2 mutations impair SMC contractile differentiation.\",\n      \"method\": \"Explanted patient aortic SMCs and fibroblasts; TGFβ1 stimulation assays; Western blot and immunostaining for contractile proteins in patient vs. control aortas\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived primary cells with functional stimulation assay, confirmed in fixed patient tissue; multiple orthogonal readouts\",\n      \"pmids\": [\"20628007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Quantitative analysis of nine TGFBR2 patient mutations showed differing effects on protein stability, internalization, Smad phosphorylation, ERK signaling, and transcriptional activity; mutations associated with LDS and MFS2 showed dominant-negative effects; the R460C TAAD-associated mutation retained residual Smad phosphorylation, suggesting that the balance between defective Smad vs. ERK signaling determines phenotypic severity.\",\n      \"method\": \"Quantitative cell-based assays for TGFBR2 protein expression, turnover (internalization), Smad phosphorylation, ERK activation, and transcriptional reporter activity for nine patient mutations\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple quantitative functional assays across nine alleles in a single systematic study\",\n      \"pmids\": [\"21098638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cell-autonomous ablation of Tgfbr2 specifically in palatal epithelial cells causes soft palate cleft; mutant MEE cells fail to undergo programmed cell death and instead continue to proliferate and form cysts/epithelial bridges; Irf6 expression is downregulated in Tgfbr2-mutant MEE cells, placing Irf6 downstream of TGFBR2 in palatal epithelial fate determination.\",\n      \"method\": \"Cre/lox conditional knockout of Tgfbr2 in palatal epithelial cells; genetic lineage labeling of MEE; immunostaining for Irf6, K14; histological analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with lineage tracing and molecular phenotyping, multiple orthogonal readouts\",\n      \"pmids\": [\"16780827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Deletion of Tgfbr2 in Col2a-expressing cells disrupts maintenance of boundaries in the axial skeleton; loss of Tgfbr2 expands Pax1/Pax9 expression domains across sclerotome segments and reduces Fibromodulin (intervertebral disc marker) expression, demonstrating that TGFBR2 signaling maintains sclerotome segmental boundaries.\",\n      \"method\": \"Col2a-Cre conditional knockout of Tgfbr2 in mice; in situ hybridization and immunostaining for Pax1, Pax9, Msx1, Fmod; histological analysis with PNA staining\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple molecular markers across developmental stages\",\n      \"pmids\": [\"16824508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Conditional loss of Tgfbr2 in Prx1Cre-expressing skull mesenchyme causes open skull defects due to reduced mesenchymal cell proliferation and impaired osteoblast differentiation; in isolated Tgfbr2-deleted osteoprogenitor cultures, mRNA levels of Runx2, Osterix, Dlx5, and Msx2 are downregulated, demonstrating that Tgfbr2 regulates osteoblast differentiation independently of proliferation.\",\n      \"method\": \"Prx1Cre conditional KO; BrdU proliferation assay; TUNEL apoptosis; immunofluorescence for Runx2/Osterix; Adeno-Cre deletion in cultured osteoprogenitors; RT-PCR\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO plus ex vivo mechanistic dissection with Adeno-Cre deletion; multiple molecular readouts\",\n      \"pmids\": [\"19699732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Deletion of Tgfbr2 in odontoblast/bone mesenchyme (Osx-Cre) disrupts molar root elongation and HERS formation; odontoblast organization and Dspp expression are reduced, while Dmp1 increases; Tgfbr2 in dental mesenchyme indirectly regulates HERS maintenance.\",\n      \"method\": \"Osx-Cre conditional KO of Tgfbr2; microCT; immunostaining for K14, Dspp, Dmp1, Nfic; histological analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple molecular and structural readouts across postnatal time points\",\n      \"pmids\": [\"23933490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tgfbr2 mutant palatal mesenchymal cells (Tgfbr2fl/fl;Wnt1-Cre) spontaneously accumulate lipid droplets due to reduced lipolysis; these cells fail to respond to Sonic Hedgehog-driven proliferation; inhibition of p38 MAPK or telmisartan treatment restores lipid metabolism and cell proliferation, rescuing cleft palate in vivo.\",\n      \"method\": \"Cranial neural crest-specific Tgfbr2 conditional KO; lipid droplet staining; lipolysis assay; p38 MAPK inhibitor treatment in vitro and in vivo; rescue of palate fusion\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with pharmacological rescue both in vitro and in vivo; multiple mechanistic readouts including p38 MAPK pathway\",\n      \"pmids\": [\"23975680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-145 directly targets the 3'-UTR of TGFBR2 mRNA in vascular smooth muscle cells; miR-145 overexpression attenuates TGFβ receptor II-dependent extracellular matrix gene expression and fibrosis, while miR-145 knockout mice show increased matrix synthesis and a pronounced fibrotic response to angiotensin II; endothelial cell co-culture induces miR-143/145 expression via Notch signaling.\",\n      \"method\": \"miR-145 overexpression/knockout in cell culture and mouse models; luciferase 3'-UTR reporter assay; angiotensin II infusion; ECM gene expression analysis\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct 3'-UTR reporter validation plus in vivo KO mouse with phenotypic readout; multiple orthogonal approaches\",\n      \"pmids\": [\"25323858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NG2 glia-derived TGF-β2 signals through TGFBR2 in microglia to maintain brain immune homeostasis; gain- and loss-of-function of NG2 glia-TGF-β2 or microglial TGFBR2 regulate CX3CR1-mediated immune suppression; ablation of NG2 glia or TGFBR2 deficiency in microglia leads to exaggerated neuroinflammation and dopaminergic neuron loss in MPTP model.\",\n      \"method\": \"Diphtheria toxin-mediated NG2 glia ablation; RNA sequencing; co-cultures of NG2 glia and microglia; gain/loss-of-function experiments for TGFβ2 and TGFBR2; MPTP mouse model; immunohistochemistry\",\n      \"journal\": \"BMC medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including cell ablation, RNA-seq, co-culture gain/loss-of-function, and in vivo disease model\",\n      \"pmids\": [\"31727112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-21 suppresses TGFBR2 expression by binding its 3'-UTR; androgen receptor (AR) signaling potentiates this effect, creating a positive feedback loop where miR-21 and AR regulate each other's expression; this miR-21/AR axis attenuates TGFβ-mediated Smad2/3 activation, cell growth inhibition, migration inhibition, and apoptosis in prostate cancer cells.\",\n      \"method\": \"3'-UTR luciferase reporter assay; AR/miR-21 overexpression and knockdown in prostate epithelial cell lines and xenografts; Western blot for p-Smad2/3; cell growth, migration, and apoptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'-UTR validation plus functional rescue experiments in multiple cell systems and in vivo xenograft\",\n      \"pmids\": [\"24037531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TGFBR2 frameshift mutations in TGFBR2 exon 3 (polyadenine tract BAT-RII) occur at elevated rates in MLH1-deficient cells; reconstitution of TGFBR2 expression in an MSI colon cancer cell line (HCT116) decreases proliferation and reduces cdk4 expression and kinase activity, establishing that TGFBR2 inactivation drives increased cdk4-dependent proliferation in MSI colorectal cancer.\",\n      \"method\": \"TGFBR2 reconstitution in HCT116 MSI cell line; proliferation assays; cdk4 immunostaining and kinase activity assay in primary colon cancers with mutant vs. wild-type BAT-RII\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution with molecular mechanistic readout (cdk4 expression and kinase activity) plus primary tumor validation\",\n      \"pmids\": [\"16108056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MLH1 deficiency produces ~11-fold higher TGFBR2 microsatellite mutation rates compared to MSH6 deficiency; TGFBR2 microsatellite mutates ~3× faster than ACVR2 in both hMLH1 and hMSH6 deficient backgrounds, establishing that TGFBR2 frameshift mutation rate is dependent on specific MMR gene background.\",\n      \"method\": \"EGFP frameshift reporter plasmids containing TGFBR2 or ACVR2 coding microsatellites in MMR-deficient cell lines; flow cytometry; DNA sequencing\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative reporter reconstitution assay with mutation-resistant controls in isogenic MMR backgrounds; clear mechanistic outcome\",\n      \"pmids\": [\"18941508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of Tgfbr2 in Kras-mutant lung cells promotes lung squamous cell carcinoma (SCC) formation through a Smad-independent ERK1/2 pathway; low pERK1/2 upregulates SOX2 expression (oncogenic SCC driver), and ERK1/2 suppression cooperates with SMAD4 loss to elevate SOX2; Smad4 loss alone does not drive SCC, placing ERK1/2 downstream of Tgfbr2 as a key suppressor of SOX2-driven SCC.\",\n      \"method\": \"Kras × Tgfbr2 conditional KO mouse model; Kras × Smad4 conditional KO comparison; ERK1/2 inhibitor treatment; SOX2 expression analysis; IHC of mouse and human tumors\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in multiple mouse models plus pharmacological rescue; mechanistic pathway established with orthogonal approaches\",\n      \"pmids\": [\"31209059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TGFBR2 reconstitution in MSI colorectal cancer cells alters the protein composition of secreted exosomes; TGFBR2 expression status determines a distinct exosomal proteome and modulates cytokine secretion (IL-4, SCF, PDGF-B) in recipient hepatoma cells.\",\n      \"method\": \"Doxycycline-inducible TGFBR2 reconstitution in HCT116-TGFBR2 cells; exosome isolation and mass spectrometry proteomics; nanoparticle tracking; confocal microscopy; Luminex cytokine profiling\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic inducible model, mass spectrometry, and functional cytokine readout; multiple orthogonal methods\",\n      \"pmids\": [\"28376875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TGFBR2 reconstitution in HCT116 MSI colorectal cancer cells increases LFNG glycosyltransferase expression in a TGFBR2-dependent manner and enhances N-acetyl-d-glucosamine incorporation into Notch1, linking TGFBR2 signaling to Notch1 glycosylation via LFNG.\",\n      \"method\": \"Doxycycline-inducible TGFBR2 reconstitution in HCT116; Glyco-Gene Chip array; real-time RT-PCR validation; dual [³H]-GlcNAc/[³⁵S]-methionine metabolic labeling; Notch1 immunoprecipitation\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — metabolic radiolabeling with immunoprecipitation in isogenic inducible model, direct biochemical demonstration\",\n      \"pmids\": [\"27156840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Neural-specific deletion of Tgfbr2 (Foxg1-Cre) impairs brain angiogenesis through an altered secretome; VEGFA, IGF1, IGF2, TGFβ, ID1, THBS2, and ADAMTS1 are altered; conditioned medium from Tgfbr2-KO neural cultures causes HUVEC branching and migration defects that are rescued by supplementing VEGFA, FGF2, and IGF1.\",\n      \"method\": \"Foxg1-Cre conditional KO of Tgfbr2; conditioned medium transfer to HUVECs; HUVEC branching and migration assays; growth factor supplementation rescue experiments; gene expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with ex vivo conditioned medium functional rescue; multiple orthogonal assays\",\n      \"pmids\": [\"24990151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP33, a deubiquitinating enzyme, interacts with TGFBR2 (identified by mass spectrometry and luciferase complementation), deubiquitinates TGFBR2, prevents its lysosomal degradation, and promotes its accumulation at the cell membrane to sustain TGFβ signaling; TGFβ target gene ZEB1 transcriptionally upregulates USP33, creating a positive feedback loop.\",\n      \"method\": \"Mass spectrometry interactome; luciferase complementation assay; ubiquitination assay; lysosome inhibitor experiments; ChIP for ZEB1; Western blot; functional proliferation/migration/invasion assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical deubiquitination assay with mechanistic follow-up (lysosome pathway, feedback loop), multiple orthogonal methods\",\n      \"pmids\": [\"37322017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ITGB5 (integrin β5) promotes TGFBR2 endosomal recycling by acting as a scaffold that interacts with both TGFBR2 and the sorting nexin SNX17, preventing lysosomal degradation of TGFBR2 and maintaining its cell-surface distribution; TGFβ signaling directly upregulates ITGB5, creating a positive feedback loop that enhances TGFβ-mediated EMT and gastric cancer metastasis.\",\n      \"method\": \"Co-immunoprecipitation of ITGB5/TGFBR2/SNX17; ITGB5 knockdown in vitro and in vivo; endosomal recycling assay; Western blot for TGFBR2 surface and total levels; feedback loop validation\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying trimeric complex, endosomal recycling functional assay, in vivo validation\",\n      \"pmids\": [\"38729557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PIEZO1 attenuates TGFβ signaling by promoting endocytosis and autophagy of TGFBR2 via Rab GTPase 3C; PIEZO1 knockout in smooth muscle cells of Marfan syndrome mice exacerbates TAA and TGFβ pathway activation by inhibiting TGFBR2 endocytosis/autophagy; pharmacological PIEZO1 activation (Yoda1) prevents TGFβ activation and reverses TAA.\",\n      \"method\": \"SMC-specific PIEZO1 conditional KO in Marfan syndrome (Fbn1C1041G/+) mice; Yoda1 pharmacological treatment; Rab3C interaction experiments; endocytosis/autophagy assays; aortic histology and TGFβ pathway analysis\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with pharmacological rescue in disease model, mechanistic pathway (Rab3C endocytosis) identified; single lab, some mechanistic details only in abstract\",\n      \"pmids\": [\"39585648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The E3 ubiquitin ligase HUWE1 mediates ubiquitination and degradation of TGFBR2 in gastric cancer cells; HUWE1 overexpression promotes GC cell proliferation, migration, and invasion, and these effects are impaired by TGFBR2 overexpression, placing TGFBR2 downstream of HUWE1-mediated ubiquitin-proteasome degradation.\",\n      \"method\": \"HUWE1 overexpression/silencing in GC cell lines; ubiquitination assay; Western blot; MTT and Transwell assays; TGFBR2 rescue experiments\",\n      \"journal\": \"Investigational new drugs\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ubiquitination assay plus rescue experiment, single lab, single study\",\n      \"pmids\": [\"33405091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRISPR/Cas9-mediated knockout of TGFBR2 in ovarian cancer tumor-infiltrating lymphocytes renders them resistant to TGFβ-mediated immunosuppression, evidenced by absence of SMAD phosphorylation, preserved proinflammatory cytokine secretion, and improved cytotoxicity in the presence of TGFβ.\",\n      \"method\": \"CRISPR/Cas9 KO of TGFBR2 in primary patient TILs; Western blot for p-SMAD; cytokine secretion assays; cytotoxicity assay; transcriptome analysis; off-target sequencing\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct KO in primary patient cells with multiple functional readouts; mechanistic pathway (SMAD phosphorylation) directly confirmed\",\n      \"pmids\": [\"35882447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TGFBR2 reconstitution in MSI colorectal cancer cells alters miRNA expression profiles in both cells and secreted extracellular vesicles; specific subsets of miRNAs are regulated in a TGFBR2-dependent manner, including downregulation of miR-381-3p in TGFBR2-deficient cells and EVs.\",\n      \"method\": \"Doxycycline-inducible TGFBR2 reconstitution in HCT116-TGFBR2; small RNA sequencing of cell and EV miRNA profiles; isogenic comparison\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic inducible model with RNA-seq; single lab but two compartments analyzed orthogonally\",\n      \"pmids\": [\"31432155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The transcription factor GABPA directly activates TGFBR2 transcription (ChIP identified GABPA binding at TGFBR2 locus); GABPA and TGFBR2 phenocopy each other in suppressing renal cell carcinoma proliferation, invasion, and stemness; oncometabolite L-2-HG epigenetically silences GABPA via DNA methylation, disrupting the GABPA-TGFBR2-TGFβ axis.\",\n      \"method\": \"siRNA/overexpression of GABPA; RNA sequencing to identify TGFBR2 as GABPA target; ChIP assay for GABPA at TGFBR2 locus; L-2-HG treatment with methylation analysis; xenograft mouse model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct transcriptional regulation, functional rescue experiments, in vivo xenograft validation\",\n      \"pmids\": [\"35549739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SOX4 directly activates TGFBR2 transcription; SOX4 and the SWI/SNF ATPase SMARCA4 form a complex that maintains open chromatin at TGFBR2 regulatory regions; TGFBR2 is required to mediate SOX4-dependent PI3K/Akt signaling in triple-negative breast cancer.\",\n      \"method\": \"Genomic/proteomic analyses; ChIP for SOX4/SMARCA4 at TGFBR2 locus; chromatin accessibility assay (ATAC-seq equivalent); TGFBR2 knockdown rescue of SOX4-driven PI3K signaling; Co-IP of SOX4/SMARCA4 complex\",\n      \"journal\": \"NPJ breast cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus chromatin accessibility plus Co-IP plus functional rescue; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"33837205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YAP-1 promotes TGFBR2 transcription by binding directly to the TGFBR2 promoter through TEAD transcription factors in T cells, thereby promoting Treg differentiation and immunosuppression in hepatocellular carcinoma.\",\n      \"method\": \"Bioinformatics identification of YAP-1/TEAD binding sites in TGFBR2 promoter; luciferase reporter assay; ChIP/promoter binding assay; overexpression of YAP-1 in T cells; flow cytometry for Treg markers\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter-binding ChIP plus reporter assay; single lab, limited orthogonal methods\",\n      \"pmids\": [\"28472799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YAP/TAZ represses TGFBR2 both post-transcriptionally through the miR-106b-25 cluster and transcriptionally via EZH2 (identified as a YAP/TAZ transcriptional target); YAP/TAZ and EZH2 cooperate to repress TGFBR2 in NSCLC.\",\n      \"method\": \"miRNA target validation; EZH2 as YAP/TAZ target gene analysis; reporter assays; Western blot; correlation in clinical NSCLC samples\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mechanistic chain established by reporter assay and expression analysis; single lab, limited direct biochemical validation of YAP-EZH2-TGFBR2 circuit\",\n      \"pmids\": [\"33296708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYOCD localizes to the TGFBR2 promoter region and recruits PRMT5/MEP50 complex to epigenetically silence TGFBR2 transcription; loss of MYOCD leads to TGFBR2 hyperactivation, and NSCLC cells deficient in MYOCD are particularly sensitive to TGFBR kinase inhibitors.\",\n      \"method\": \"ChIP showing MYOCD at TGFBR2 promoter; PRMT5/MEP50 co-recruitment assay; TGFBR2 expression analysis with MYOCD manipulation; sensitivity assays with TGFBRi\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based promoter occupancy plus epigenetic complex recruitment; functional pharmacological validation; single lab\",\n      \"pmids\": [\"33995678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TGFβ signaling through SMAD2/3 transcriptionally induces miR-520e expression (confirmed by ChIP-PCR), which in turn targets and downregulates TGFBR2, constituting a TGFβ-SMAD-miR-520e-TGFBR2 negative-feedback loop in NSCLC cells.\",\n      \"method\": \"ChIP-PCR for SMAD2/3 at miR-520e promoter; miR-520e overexpression/inhibition; luciferase 3'-UTR reporter for TGFBR2; Western blot; clinical correlation in NSCLC samples\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-PCR for direct transcriptional regulation plus 3'-UTR reporter; single lab, single study\",\n      \"pmids\": [\"30475986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GDF15-induced apoptosis, caspase-9/3 activation, and ERK1/2/p38 MAPK inhibition in A549 cells depends on TGFBR2 expression; TGFBR2 silencing blocks all GDF15-induced apoptotic and MAPK effects, placing TGFBR2 as a required mediator of GDF15 signaling in this cell context.\",\n      \"method\": \"GDF15 overexpression (full and mature forms); siRNA knockdown of TGFBR2; flow cytometry for annexin V/PI; caspase activity assays; ERK1/2 and p38 phosphorylation by Western blot\",\n      \"journal\": \"Cell biochemistry and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mechanistic rescue experiment with multiple signaling readouts; single lab, single cell line\",\n      \"pmids\": [\"31172564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NRP1 (neuropilin-1) interacts with TGFBR2 at endothelial adherens junctions (Co-IP), reduces plasma membrane localization of TGFBR2, and suppresses TGFβ signaling; NRP1 knockdown increases TGFBR2 membrane abundance and TGFβ-driven inflammation.\",\n      \"method\": \"Co-IP of NRP1 with TGFBR2; NRP1 endothelial-specific KO mice; surface TGFBR2 localization analysis; inflammatory marker expression; atherosclerosis model\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo conditional KO with mechanistic localization readout; multiple orthogonal methods\",\n      \"pmids\": [\"37220183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A super-enhancer (marked by H3K27Ac) at the TGFBR2 locus controls its transcription in pancreatic cancer cells; CRISPR deletion of this super-enhancer (sgTGFBR2-SEΔ) reduces TGFBR2 expression, impairs TGFβ-induced p-SMAD2/3 signaling, and attenuates TGFβ-induced migration and EMT.\",\n      \"method\": \"H3K27Ac ChIP-seq; BRD4 inhibitor (JQ1) treatment; CRISPR sgRNA-mediated super-enhancer deletion; p-SMAD2/3 Western blot; migration and EMT assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR-based enhancer deletion with functional downstream signaling readout; single lab\",\n      \"pmids\": [\"31730895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Enzalutamide decreases TGFBR2 protein expression in osteoblasts through PTH1R-mediated endocytosis; PTH1R blockade rescues enzalutamide-mediated TGFBR2 reduction and restores enzalutamide sensitivity in prostate cancer cells co-cultured with osteoblasts.\",\n      \"method\": \"Co-culture of PCa cells with osteoblasts; PTH1R inhibitor rescue; Western blot for TGFBR2 protein; bone metastasis mouse models; clinical data analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic co-culture rescue experiment with pharmacological inhibitor; in vivo model correlation; single lab\",\n      \"pmids\": [\"34752846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TGFBR2 reconstitution in MSI/MMR-deficient VCMsh2/Tgfbr2 mice modulates gut microbiota composition; combined loss of Msh2 and Tgfbr2 in intestinal epithelium synergistically promotes inflammation-associated colorectal cancer, and gut microbiota strongly modulates tumor incidence.\",\n      \"method\": \"Villin-Cre dual conditional KO of Msh2 and Tgfbr2; intestinal tumor analysis; mutational spectra; gene expression profiling; microbiota compositional analysis\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in vivo with microbiota mechanistic component; single lab\",\n      \"pmids\": [\"35688320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tgfbr2 deletion in Osx-Cre-expressing immature osteoblasts causes postnatal reduction in bone volume due to decreased osteoblast proliferation (PCNA reduction) and impaired maturation (Bglap/osteocalcin mRNA reduced) without altering Runx2 mRNA or apoptosis.\",\n      \"method\": \"Osx-Cre conditional KO; microCT; histomorphometry; qRT-PCR for Runx2, Bglap, PCNA, Bax/Bcl2; osteoblast and osteoclast enumeration\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple molecular and histomorphometric readouts; single lab\",\n      \"pmids\": [\"28043895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Odontoblast-specific loss of Tgfbr2 disrupts odontoblast polarity and matrix secretion after mantle dentin formation, reduces alkaline phosphatase and Dsp expression, increases Dmp1, and causes ectopic fibrous matrix calcification leading to pulpal obliteration.\",\n      \"method\": \"Odontoblast-specific Cre conditional KO; immunohistochemistry for ALP, Dsp, Dmp1, collagen I, biglycan; microCT\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple molecular and structural readouts; single lab\",\n      \"pmids\": [\"25818583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A TGFBR2/SMAD2/DNMT1/miR-145 negative regulatory loop operates in LPS-induced sepsis: miR-145 directly targets TGFBR2 (confirmed by luciferase reporter and RIP); activated SMAD2 binds the DNMT1 promoter (ChIP), upregulating DNMT1 which methylates the miR-145 promoter, suppressing miR-145 and further increasing TGFBR2 expression.\",\n      \"method\": \"Luciferase reporter; ChIP for SMAD2 at DNMT1 promoter; RIP assay; miR-145 promoter methylation; TGFBR2 knockdown; LPS sepsis mouse model\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays (ChIP, luciferase, RIP) establishing the full circuit; single lab\",\n      \"pmids\": [\"30784922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TGFBR2 interacts with PDGFR in GBM cells (Co-immunoprecipitation); concurrent TGFBR2 and PDGFR expression attenuates PDGFRi toxicity and maintains downstream PDGFR signaling under inhibitor treatment, contributing to PDGFRi resistance.\",\n      \"method\": \"Co-immunoprecipitation of TGFBR2 with PDGFR in GBM cells; PDGFRi toxicity assays; PDGFR downstream signaling Western blot\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP identifying TGFBR2-PDGFR interaction plus functional pharmacological readout; single lab\",\n      \"pmids\": [\"29888103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hypoxia-induced EZH2 promotes H3K27me3 at the TGFBR2 promoter, causing hypermethylation and epigenetic silencing of TGFBR2 in prostate cancer; separately, hypoxia upregulates miR-93 which also targets and suppresses TGFBR2.\",\n      \"method\": \"EZH2 siRNA/inhibitor experiments; methylation-specific PCR; ChIP for H3K27me3 at TGFBR2 promoter; luciferase 3'-UTR reporter for miR-93/TGFBR2; demethylation agent rescue\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for histone modification plus 3'-UTR reporter; two independent mechanisms identified; single lab\",\n      \"pmids\": [\"29699590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Combined mutation of Apc, Kras, and Tgfbr2 deletion in intestinal epithelial cells cooperates to drive colorectal cancer metastasis; Tgfbr2 deletion combined with Kras mutation induces EMT-like morphology and lymph vessel intravasation; liver metastasis requires Kras combined with either Trp53 or Tgfbr2 deletion, with highest metastasis in the Apc/Kras/Tgfbr2 combination.\",\n      \"method\": \"Intestinal epithelial conditional KO mouse models with combinations of Apc, Kras, Tgfbr2, Trp53, Fbxw7; tumor-derived organoid splenic transplantation metastasis assay; RNA sequencing\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic genetic epistasis across five driver mutations in vivo with functional metastasis assay and transcriptomics\",\n      \"pmids\": [\"29282223\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TGFBR2 is a transmembrane serine/threonine kinase receptor that, upon TGFβ ligand binding, canonically activates SMAD2/3 phosphorylation and non-canonically activates ERK/MAPK signaling; its surface abundance is regulated by endosomal recycling (promoted by ITGB5/SNX17 and inhibited by PIEZO1/Rab3C-mediated endocytosis/autophagy) and by ubiquitin-proteasome/lysosomal degradation (mediated by E3 ligase HUWE1 and deubiquitinase USP33); its transcription is activated by GABPA, SOX4/SMARCA4, and YAP-1/TEAD, and repressed by EZH2/YAP/TAZ and MYOCD/PRMT5 as well as a super-enhancer; it is post-transcriptionally repressed by multiple miRNAs (miR-21/AR, miR-145, miR-93, miR-520e) via 3'-UTR binding; in smooth muscle, TGFBR2 signaling is required for contractile differentiation and aortic wall homeostasis; in neural cells it controls a secretome that supports brain angiogenesis; in the immune system NG2-glia-derived TGFβ2 acts through microglial TGFBR2 to suppress neuroinflammation via CX3CR1; loss-of-function TGFBR2 mutations (including microsatellite frameshift mutations in MMR-deficient cancers) abrogate TGFβ tumor-suppressive signaling, deregulate cdk4-driven proliferation, and alter exosome cargo; the balance between impaired SMAD vs. ERK signaling downstream of mutant TGFBR2 alleles determines phenotypic severity in connective tissue disorders.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TGFBR2 is the type II transmembrane serine/threonine kinase receptor for the TGFβ family that, upon ligand binding, drives canonical SMAD2/3 phosphorylation and a parallel non-canonical ERK/p38 MAPK output, governing tissue homeostasis across the cardiovascular, skeletal, craniofacial, neural, and immune systems [#2, #4]. The relative balance of these two arms is functionally decisive: heterozygous TGFBR2 mutations cause connective-tissue disorders (Loeys-Dietz syndrome and Marfan syndrome type 2) in which mutant alleles fail to support TGFβ signaling in vitro yet paradoxically yield increased phospho-SMAD2 and collagen/CTGF in patient tissue, and the degree of impaired SMAD versus ERK signaling tracks with phenotypic severity [#0, #1, #5]. In smooth muscle, TGFBR2 is required for contractile differentiation and aortic wall integrity, and its postnatal loss lowers SMAD while raising MAPK signaling to produce thoracic aortic dilation and dissection [#2, #4]. During development TGFBR2 controls programmed cell death and Irf6 expression in palatal epithelium, sclerotome boundary maintenance, osteoblast proliferation and differentiation, and tooth root formation [#6, #7, #8, #37]. In the nervous and immune systems, neural TGFBR2 shapes a pro-angiogenic secretome, and NG2-glia-derived TGFβ2 acts through microglial TGFBR2 to suppress neuroinflammation via CX3CR1 [#19, #12]. In cancer, TGFBR2 is a tumor suppressor inactivated by coding-microsatellite frameshift mutation in mismatch-repair-deficient colorectal cancer, where its loss deregulates cdk4-driven proliferation and cooperates with Apc/Kras to drive metastasis; loss of the Smad-independent ERK1/2 arm downstream of TGFBR2 derepresses SOX2 to promote lung squamous carcinoma [#14, #42, #16]. TGFBR2 surface abundance is set by competing trafficking and degradation inputs—endosomal recycling promoted by an ITGB5/SNX17 scaffold versus PIEZO1/Rab3C-driven endocytosis-autophagy and NRP1-mediated membrane retention—and by ubiquitin-dependent turnover balanced by the E3 ligase HUWE1 and the deubiquitinase USP33 [#21, #22, #33, #23, #20]. Its transcription is directly activated by GABPA, SOX4/SMARCA4, and YAP-1/TEAD and repressed by EZH2, MYOCD/PRMT5, and a super-enhancer, while multiple miRNAs including miR-21, miR-145, miR-93, and miR-520e silence it through 3'-UTR binding, several within TGFβ-driven feedback loops [#26, #27, #28, #41, #30, #34, #13, #11, #31].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that TGFBR2 loss-of-function causes heritable connective-tissue disease defined the receptor as essential for extracellular matrix homeostasis in humans.\",\n      \"evidence\": \"Breakpoint mapping and sequencing of TGFBR2 with TGFβ signaling/ECM functional assays in Marfan syndrome type 2 families\",\n      \"pmids\": [\"15235604\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which downstream arm (SMAD vs MAPK) drives ECM dysregulation\", \"Cellular site of action not pinpointed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The paradox that mutant alleles fail to signal in vitro yet show elevated phospho-SMAD2 and collagen in patient tissue reframed disease as dysregulated rather than simply absent TGFβ signaling.\",\n      \"evidence\": \"Patient-derived signaling kinetics and tissue immunostaining for p-Smad2/collagen/CTGF across Loeys-Dietz families\",\n      \"pmids\": [\"15731757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism reconciling in vitro loss with in vivo gain not established\", \"Did not identify the compensatory pathway raising SMAD output\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Allelic series quantification linked the SMAD-versus-ERK signaling balance of individual mutations to clinical severity, explaining genotype-phenotype variation.\",\n      \"evidence\": \"Quantitative cell-based assays of stability, internalization, Smad phosphorylation, ERK, and transcription across nine patient mutations; patient SMC/fibroblast differentiation assays\",\n      \"pmids\": [\"21098638\", \"20628007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal direction between ERK gain and disease not proven in vivo\", \"Tissue-specific signaling thresholds undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Conditional smooth-muscle knockout established that postnatal TGFBR2 maintains aortic wall integrity, with disease driven by decreased SMAD and increased MAPK signaling and rescuable by rapamycin.\",\n      \"evidence\": \"Smooth-muscle Cre/lox Tgfbr2 knockout with Smad/MAPK Westerns, histology, and rapamycin treatment in mice\",\n      \"pmids\": [\"24401272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger of MAPK upregulation upon TGFBR2 loss unresolved\", \"Adventitial paracrine factors not fully identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Tissue-specific conditional knockouts mapped distinct developmental requirements for TGFBR2 in palate, sclerotome, skull, bone, and tooth, separating proliferation from differentiation roles.\",\n      \"evidence\": \"Multiple Cre/lox conditional Tgfbr2 knockouts (palatal epithelium, Col2a, Prx1, Osx, odontoblast) with marker analysis, BrdU, TUNEL, and ex vivo deletion\",\n      \"pmids\": [\"16780827\", \"16824508\", \"19699732\", \"23933490\", \"28043895\", \"25818583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors (e.g., Irf6, Runx2) placement only partially mechanistic\", \"Ligand source in each tissue not always defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Microsatellite frameshift inactivation of TGFBR2 in mismatch-repair-deficient cancer, with mutation rate set by the specific MMR background, identified TGFBR2 as a tumor suppressor target and quantified its vulnerability.\",\n      \"evidence\": \"TGFBR2 reconstitution in MSI HCT116 cells with cdk4 readouts; EGFP frameshift reporters across MLH1/MSH6-deficient backgrounds\",\n      \"pmids\": [\"16108056\", \"18941508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address metastatic cooperation\", \"Downstream secretory/microbiota consequences not yet examined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genetic epistasis defined TGFBR2 as a metastasis suppressor and revealed a Smad-independent ERK1/2 arm restraining SOX2-driven squamous carcinoma.\",\n      \"evidence\": \"Combinatorial Apc/Kras/Tgfbr2/Trp53 intestinal knockouts with organoid metastasis assays; Kras×Tgfbr2 vs Kras×Smad4 lung models with ERK inhibition\",\n      \"pmids\": [\"29282223\", \"31209059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TGFBR2 maintains ERK tone to suppress SOX2 mechanistically incomplete\", \"Relative contribution of SMAD vs ERK loss to metastasis not isolated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"TGFBR2 status was shown to reprogram secreted exosome/EV cargo, glycosylation of Notch1 via LFNG, and cytokine secretion, extending its tumor-suppressor role to the secretome.\",\n      \"evidence\": \"Doxycycline-inducible TGFBR2 reconstitution in HCT116 with exosome proteomics, small-RNA sequencing, metabolic GlcNAc labeling, and Luminex cytokine profiling\",\n      \"pmids\": [\"28376875\", \"27156840\", \"31432155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of altered exosome cargo on tumor progression not established in vivo\", \"Single isogenic model\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Beyond cell-autonomous signaling, TGFBR2 was shown to coordinate paracrine programs: neural TGFBR2 shapes a pro-angiogenic secretome and microglial TGFBR2 enforces immune homeostasis.\",\n      \"evidence\": \"Foxg1-Cre Tgfbr2 knockout with conditioned-medium HUVEC rescue; NG2-glia ablation and microglial TGFBR2 gain/loss in MPTP neuroinflammation model\",\n      \"pmids\": [\"24990151\", \"31727112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional control of the secretome by TGFBR2 not detailed\", \"CX3CR1 coupling mechanism downstream of TGFBR2 unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Receptor surface abundance was established as an actively regulated node, with recycling, endocytosis/autophagy, membrane retention, and ubiquitin turnover each tuning TGFβ output.\",\n      \"evidence\": \"ITGB5/SNX17/TGFBR2 Co-IP and recycling assays; PIEZO1/Rab3C conditional KO and Yoda1 rescue in Marfan mice; NRP1 Co-IP and endothelial KO; HUWE1 ubiquitination and USP33 deubiquitination assays\",\n      \"pmids\": [\"38729557\", \"39585648\", \"37220183\", \"33405091\", \"37322017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy/competition among trafficking regulators not integrated\", \"Several mechanisms rest on single-lab Co-IP or ubiquitination assays\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Transcriptional and post-transcriptional control of TGFBR2 was mapped to direct activators, repressive epigenetic complexes, and miRNA feedback loops, defining how receptor dosage is set.\",\n      \"evidence\": \"ChIP for GABPA, SOX4/SMARCA4, YAP-1/TEAD activators; EZH2/H3K27me3, MYOCD/PRMT5, and super-enhancer repression; 3'-UTR reporters for miR-21/AR, miR-145, miR-93, miR-520e feedback circuits\",\n      \"pmids\": [\"35549739\", \"33837205\", \"28472799\", \"29699590\", \"33995678\", \"31730895\", \"24037531\", \"25323858\", \"30475986\", \"33296708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-specific dominance among these regulators not resolved\", \"Many circuits validated in single cancer cell systems\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Therapeutic engineering of TGFBR2 signaling was demonstrated by knocking it out in tumor-infiltrating lymphocytes to escape TGFβ immunosuppression.\",\n      \"evidence\": \"CRISPR/Cas9 TGFBR2 knockout in primary patient TILs with p-SMAD, cytokine, and cytotoxicity readouts\",\n      \"pmids\": [\"35882447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Durability and in vivo antitumor efficacy not addressed\", \"Effect limited to SMAD-axis readouts\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the SMAD-versus-MAPK signaling balance is set in a tissue-specific manner—and whether the trafficking/degradation and transcriptional regulators converge to control this balance—remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking receptor dosage control to the SMAD/ERK output ratio\", \"Mechanism converting reduced TGFBR2 to increased MAPK/SMAD signaling in vivo undefined\", \"Structural basis of mutation-specific signaling bias not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 4, 5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 24, 32]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [20, 21, 33]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [21, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 7, 8, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 14, 16, 42]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 24, 28]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [20, 21, 22, 33]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ITGB5\", \"SNX17\", \"USP33\", \"HUWE1\", \"NRP1\", \"PIEZO1\", \"PDGFR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}