Affinage

TGFBR3

Transforming growth factor beta receptor type 3 · UniProt Q03167

Length
851 aa
Mass
93.5 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TGFBR3 (betaglycan) is a membrane-anchored heparan sulfate/chondroitin sulfate proteoglycan that functions as a multi-ligand co-receptor controlling the access of TGF-β superfamily ligands to their signaling receptors (PMID:8391934, PMID:1657406). It captures TGF-β—including isoforms that bind the signaling receptors poorly—through its N-terminal endoglin-related domain and presents it to the type II receptor (TβRII), forming a high-affinity ternary complex that requires membrane anchorage and equalizes the activity of TGF-β isoforms (PMID:8391934, PMID:8106553, PMID:11278442); subsequent recruitment of TβRI drives displacement of betaglycan to complete the signaling complex, a hand-off mechanism resolved structurally (PMID:27951653, PMID:40011426). High-affinity ligand binding depends on cooperation between its N-terminal endoglin-related and C-terminal zona pellucida (ZP) domains tethered together (PMID:19842711, PMID:21402931). Through the ZP domain it acts as an obligate high-affinity inhibin A co-receptor with ActRII, conferring inhibin sensitivity and enabling inhibin antagonism of activin signaling—a function genetically separable from TGF-β presentation and required in vivo for inhibin A suppression of pituitary FSH (PMID:10746731, PMID:16621788, PMID:19372236, PMID:30364975). Betaglycan's net effect on TGF-β signaling is context-dependent: depending on cell type and GAG composition it either enhances signaling or inhibits it by blocking type I/type II receptor association, the latter requiring intact GAG chains (PMID:11668175, PMID:9830054). Its ectodomain is shed by MT1-MMP/MT3-MMP to yield a soluble TGF-β-neutralizing antagonist, and the residual membrane stub is cleaved by γ-secretase, converting betaglycan from a signaling enhancer into an antagonist (PMID:14672946, PMID:21167215). Independently of TGF-β, betaglycan modulates canonical Wnt signaling via its GAG chains and suppresses NF-κB activity through a β-arrestin 2/IκBα complex (PMID:27784788, PMID:29130787, PMID:23322721). Loss-of-function in mice establishes betaglycan as required for fetal testis cord formation and Leydig cell endocrine function and for proper kidney nephron number and ureteric branching (PMID:19696014, PMID:21533152).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1989 High

    Established that betaglycan exists as both membrane-bound and soluble GAG-bearing proteoglycan forms, defining the structural basis for its dual cell-surface and soluble functions.

    Evidence Biochemical characterization, liposome association and affinity labeling

    PMID:2592419

    Open questions at the time
    • Did not define the ligand-presentation function
    • GAG contribution to function not yet tested
  2. 1991 High

    cDNA cloning revealed the domain architecture—extracellular GAG-bearing ectodomain with transmembrane/cytoplasmic homology to endoglin—and showed GAG chains are dispensable for TGF-β binding to the core protein, separating ligand binding from glycosylation.

    Evidence cDNA cloning, sequencing and domain analysis

    PMID:1657406

    Open questions at the time
    • Functional role of cytoplasmic domain unresolved
    • Mechanism of presentation to signaling receptors not addressed
  3. 1993 High

    Demonstrated the core co-receptor mechanism: betaglycan presents TGF-β to the type II receptor in a high-affinity ternary complex and eliminates isoform-specific differences in signaling potency.

    Evidence Receptor binding/crosslinking and cell-based functional assays with overexpression

    PMID:8391934

    Open questions at the time
    • Structural basis of the ternary complex not defined
    • How TβRI is recruited unknown
  4. 1994 High

    Mapped TGF-β binding to the N-terminal endoglin-related region, localized GAG attachment sites (Ser535/Ser546), and showed membrane anchorage is required for presentation while soluble betaglycan acts as a TGF-β antagonist—defining the enhancer-versus-antagonist duality.

    Evidence Site-directed and deletion mutagenesis with binding assays; plasmin cleavage assays

    PMID:8068006 PMID:8106553

    Open questions at the time
    • Second ligand-binding domain not yet defined
    • Physiological proteases controlling shedding unknown
  5. 1992 High

    Showed dual-domain binding capacity—bFGF binds heparan sulfate chains independently of TGF-β binding to the core—establishing betaglycan as a multi-ligand proteoglycan.

    Evidence Affinity binding, metabolic labeling and GAG analysis in osteoblasts

    PMID:1556106

    Open questions at the time
    • Signaling consequence of bFGF binding not established
  6. 2000 High

    Identified betaglycan as a high-affinity inhibin co-receptor that partners with ActRII to confer inhibin sensitivity, extending its role beyond TGF-β to activin antagonism.

    Evidence Crosslinking, co-IP and functional cell assays with overexpression

    PMID:10746731

    Open questions at the time
    • Inhibin-binding domain not localized
    • In vivo physiological requirement untested
  7. 2001 High

    Resolved a two-domain ligand architecture (endoglin-related for TGF-β presentation, uromodulin/ZP-related for inhibin A) and showed that in cells lacking endogenous betaglycan its expression inhibits TGF-β signaling by preventing type I/type II receptor association in a GAG-dependent manner.

    Evidence Deletion mutagenesis, Smad2 phosphorylation, receptor co-IP and GAG mutant analysis

    PMID:11278442 PMID:11668175

    Open questions at the time
    • Why context determines enhancement vs inhibition not fully resolved
    • Role of GAG chain size mechanistically incomplete
  8. 2003 High

    Identified MT1-MMP/MT3-MMP as the proteases that shed the betaglycan ectodomain, defining the regulated step that generates the soluble TGF-β antagonist.

    Evidence MT-MMP overexpression, metalloprotease inhibition and binding assays

    PMID:14672946

    Open questions at the time
    • Physiological triggers of shedding in vivo unclear
    • Fate of the membrane stub not addressed here
  9. 2006 Medium

    Functionally separated betaglycan's co-receptor roles by mapping overlapping inhibin/TGF-β sites in the ZP domain (V614Y abolishes both) and identifying ligand-independent signaling requiring the cytoplasmic domain via p38 MAPK.

    Evidence Mutagenesis with functional reporters; adenoviral overexpression with p38 inhibitor

    PMID:16413747 PMID:16621788

    Open questions at the time
    • Cytoplasmic-domain signaling partners undefined
    • Relationship between p38 axis and canonical Smad signaling unclear
  10. 2008 High

    Defined the inhibin α-subunit residues forming the betaglycan-binding epitope, linking a precise molecular interface to FSH regulation.

    Evidence Inhibin A mutagenesis, binding assays and pituitary FSH bioassay

    PMID:18397882

    Open questions at the time
    • Reciprocal betaglycan residues not all defined here
  11. 2009 High

    Showed that high-affinity soluble betaglycan requires both N- and C-terminal domains tethered together and that endogenous betaglycan is functionally required for high-potency inhibin antagonism in gonadotropes.

    Evidence SPR with recombinant domains and plasmin digestion; siRNA and immunoneutralization in pituitary cells; Tgfbr3-null mouse testis analysis

    PMID:19372236 PMID:19696014 PMID:19842711

    Open questions at the time
    • Structural picture of two-domain ligand engagement still indirect
    • Tissue-specific downstream effectors incompletely mapped
  12. 2010 Medium

    Identified the post-shedding steps—γ-secretase processing of the membrane stub and inhibin-A-induced clathrin-independent internalization—that convert betaglycan into a TGF-β antagonist and reduce surface ligand sites.

    Evidence γ-secretase/shedding inhibitors with signaling reporters; cell-surface internalization assays

    PMID:20160125 PMID:21167215

    Open questions at the time
    • Downstream fate/function of the intracellular fragment unknown
    • Internalization machinery not molecularly defined
  13. 2011 High

    Provided the high-resolution crystal structure of the ZP-C domain (Ig-like fold, integral EHP region) and genetic dosage analysis linking betaglycan levels to kidney nephron number and branching gene programs.

    Evidence X-ray crystallography at 2.0 Å; stereological and qRT-PCR analysis of heterozygous/null mouse kidneys

    PMID:21402931 PMID:21533152

    Open questions at the time
    • Structure of the full ligand-bound complex not yet available
    • Mechanism connecting dosage to branching genes correlative
  14. 2016 High

    Defined the biophysical hand-off model—betaglycan binds TGF-β 1:1, modestly potentiates TβRII binding, and must be displaced for TβRI to engage—and uncovered a GAG-dependent, TGF-β-independent role in Wnt3a signaling.

    Evidence SPR/ITC/SEC stoichiometry; Wnt luciferase reporters with GAG/sulfation mutants

    PMID:27784788 PMID:27951653

    Open questions at the time
    • Structural geometry of displacement not directly observed at this stage
    • Wnt-modulating GAG mechanism not resolved in vivo
  15. 2018 High

    Defined the TGF-β2 surface engaged by the betaglycan ZP-C domain and established betaglycan as an obligate inhibin A (but not inhibin B) co-receptor in gonadotropes in vivo.

    Evidence NMR/SPR interface mapping with TGF-β2 mutants; conditional gonadotrope Tgfbr3 knockout with FSH assay

    PMID:30364975 PMID:30598510

    Open questions at the time
    • Molecular basis of inhibin A vs inhibin B discrimination unresolved
  16. 2019 Medium

    Established context-specific tumor and tissue roles: betaglycan loss promotes renal carcinoma migration/metastasis via FAK-PI3K and prostate-cancer-induced osteogenesis via Wnt5a, and let-7-driven TGFBR3 induction promotes cardiomyocyte apoptosis after infarction.

    Evidence Orthotopic/xenograft mouse models, pathway inhibitors, Wnt5a-neutralization rescue, AAV9 microRNA modulation

    PMID:29391598 PMID:31401194 PMID:31409900

    Open questions at the time
    • Direct molecular link between betaglycan and FAK-PI3K not defined
    • Disease relevance to human pathology correlative
  17. 2025 High

    Provided the structural basis for the betaglycan-to-signaling-receptor hand-off and for ligand selectivity, showing interfaces distinct from endoglin.

    Evidence Cryo-EM/structural determination of TGF-β/betaglycan/TGFBR1/TGFBR2 complex

    PMID:40011426

    Open questions at the time
    • Dynamics and kinetics of displacement in living membranes not captured
    • GAG-chain contribution to the complex not structurally resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GAG chain composition, ectodomain shedding, and cell context are integrated to switch betaglycan between TGF-β enhancer and antagonist in specific tissues remains unresolved.
  • No unified model linking GAG editing to context-dependent signaling output
  • In vivo regulators of the enhancer/antagonist switch not identified
  • Mendelian disease association not established in this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005576 extracellular region 4 GO:0005886 plasma membrane 4
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 2 R-HSA-1474165 Reproduction 2
Partners
ACVR2AARRB2ENGMMP14NFKBIATGFBR1TGFBR2
Complex memberships
TGF-β/betaglycan/TβRII/TβRI ternary signaling complexbetaglycan/β-arrestin 2/IκBα complexinhibin A/betaglycan/ActRII co-receptor complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Betaglycan (TGFBR3) presents TGF-β directly to the type II signaling receptor kinase subunit, forming a high-affinity ternary complex. Membrane betaglycan increases TGF-β binding to the signaling receptor and eliminates biological differences between TGF-β isoforms. Receptor binding assays, crosslinking, cell-based functional assays with overexpression Cell High 8391934
1991 Betaglycan is a membrane-anchored proteoglycan with an extracellular domain bearing GAG attachment sites; its transmembrane and cytoplasmic domains share homology with endoglin. The ectodomain can be shed as a soluble proteoglycan. GAG chains are dispensable for TGF-β binding to the core protein. cDNA cloning, sequencing, domain analysis, biochemical characterization Cell High 1657406
1994 TGF-β binds to the NH2-terminal endoglin-related region of betaglycan. GAG attachment sites are Ser535 and Ser546; their mutation prevents GAG attachment but does not affect TGF-β binding or presentation. Membrane anchorage is required for TGF-β presentation to receptor II. Soluble betaglycan acts as a potent inhibitor (antagonist) of TGF-β binding to membrane receptors, particularly TGF-β2. Site-directed mutagenesis, deletion mutant analysis, binding assays The Journal of cell biology High 8106553
2000 Betaglycan functions as an inhibin co-receptor with ActRII. Betaglycan binds inhibin with high affinity, enhances inhibin binding in cells co-expressing ActRII and betaglycan, and forms crosslinked ternary complexes with recombinant and endogenous betaglycan and ActRII. Betaglycan confers inhibin sensitivity to otherwise poorly responsive cell lines, enabling inhibin antagonism of activin signaling. Crosslinking assays, co-immunoprecipitation, cell-based functional assays, overexpression Nature High 10746731
1989 Betaglycan exists in both membrane-bound and soluble forms. The membrane-bound form is hydrophobic and associates with liposomes; soluble forms lack a membrane anchor. Both forms carry chondroitin sulfate and/or heparan sulfate GAG chains on a 100–120 kDa core protein. Biochemical characterization, liposome association assay, affinity labeling The Journal of cell biology High 2592419
1992 Betaglycan binds basic FGF (bFGF) via its heparan sulfate chains (separate domain from TGF-β binding via the core protein). In osteoblasts, bFGF selectively reduces the heparan sulfate GAG content of betaglycan without affecting chondroitin sulfate or core protein size. Affinity binding assays, metabolic labeling, GAG analysis The Journal of biological chemistry High 1556106
2001 Betaglycan ectodomain contains two independent ligand-binding domains: the endoglin-related (membrane-distal) region and the uromodulin-related (membrane-proximal) region. Only the endoglin-related region mediates TGF-β presentation to TβRII. Inhibin A binding resides specifically in the uromodulin-related region. Both regions independently mediate Smad2 phosphorylation. Deletion mutagenesis, binding assays, Smad2 phosphorylation assays The Journal of biological chemistry High 11278442
2001 In LLC-PK1 renal epithelial cells (which lack endogenous betaglycan), betaglycan expression inhibits TGF-β signaling (Smad2/3 phosphorylation, reporter activity, collagen production) by preventing association between type I and type II TGF-β receptors. This inhibitory function depends on the molecular weight of the GAG chains; a GAG-deficient betaglycan mutant does not inhibit signaling or type I/type II receptor association in these cells. Reporter assay, thymidine incorporation, collagen production, Smad phosphorylation, co-immunoprecipitation of receptor complexes, GAG mutant analysis The Journal of biological chemistry High 11668175
2003 Betaglycan shedding is mediated by MT1-MMP (membrane type-1 matrix metalloprotease), which generates a 90 kDa soluble fragment (sBG-90) in a TIMP-2-sensitive manner. MT3-MMP can also generate this fragment. Pervanadate (a tyrosine phosphatase inhibitor) induces shedding. The shed sBG-90 retains higher affinity for TGF-β2 than TGF-β1. MT-MMP overexpression, metalloprotease inhibitor treatment, Western blot, binding competition assays The Journal of biological chemistry High 14672946
1994 Plasmin selectively cleaves betaglycan on the cell surface, releasing a 60 kDa TGF-β complex into the medium and reducing TGF-β binding to cellular betaglycan. Type I and type II TGF-β receptors are not plasmin substrates. Conditioned medium from plasmin-treated cells contains increased active TGF-β. Affinity labeling, SDS-PAGE, bioassay for TGF-β activity The Biochemical journal Medium 8068006
2009 Soluble betaglycan requires both its N-terminal (45 kDa) and C-terminal (55 kDa) domains tethered together for high-affinity TGF-β binding (low nM Kd). Isolated domains bind TGF-β with 1–2 orders of magnitude lower affinity and have severely diminished ability to neutralize TGF-β activity. Plasmin cleaves the linker between domains, separating them and inactivating TGF-β neutralizing activity. Plasmin digestion, N-terminal sequencing, surface plasmon resonance, recombinant domain expression, TGF-β neutralization assays Biochemistry High 19842711
2006 Distinct and partially overlapping binding sites for inhibin and TGF-β reside within amino acids 591–700 of betaglycan's ZP domain. Mutation of Val614 to Tyr abolishes both inhibin and TGF-β binding to this domain. Full-length betaglycan V614Y retains TGF-β binding via the N-terminal domain but cannot bind inhibin A or mediate inhibin antagonism of activin signaling, functionally separating these co-receptor actions. Mutagenesis, binding assays, functional activin/inhibin reporter assays The Journal of biological chemistry High 16621788
2011 Crystal structure (2.0 Å) of betaglycan ZP-C domain reveals an immunoglobulin-like fold. The EHP region is integral to the ZP-C domain. The AB loop and convex surface pocket are implicated in TGF-β ligand binding. Betaglycan lacks the maturation cleavage site present in polymerizing ZP proteins, explaining its non-polymerizing behavior. X-ray crystallography at 2.0 Å resolution Proceedings of the National Academy of Sciences of the United States of America High 21402931
2016 Betaglycan binds TGF-β homodimers with 1:1 stoichiometry and modestly potentiates TβRII binding. Betaglycan must be displaced to allow TβRI to bind. These findings suggest betaglycan concentrates TGF-β2 on the cell surface and promotes TβRII binding via membrane localization and allostery, with TβRI recruitment driving displacement of betaglycan to complete signaling complex formation. Surface plasmon resonance, isothermal titration calorimetry, size-exclusion chromatography Biochemistry High 27951653
2025 Cryo-EM/structural analysis of TGF-β bound to betaglycan and signaling receptors (TGFBR1 and TGFBR2) reveals the structural basis for ligand selectivity and provides a structural explanation for the hand-off mechanism in which betaglycan is displaced as signaling receptors engage TGF-β. Binding interfaces differ from those used by the related co-receptor endoglin, demonstrating evolutionary adaptation for ligand selectivity. Structural determination (cryo-EM/crystallography) of ternary complex Nature communications High 40011426
2018 NMR titrations and SPR measurements map the betaglycan ZP-C domain binding site on TGF-β2 to the inner concave surface of its extended finger region, involving residues Ile-92, Lys-97, and Glu-99 that are specific to TGF-β isoforms and InhA α-subunit but absent from other TGF-β family members such as BMP-2. Methyl-labeled NMR titrations, surface plasmon resonance with TGF-β2 mutant variants The Journal of biological chemistry High 30598510
1998 Overexpression of betaglycan in rat myoblasts enhances TGF-β-mediated growth inhibition and PAI-1 expression; betaglycan specifically increases TGF-β binding to the type II receptor. Analysis of endoglin/betaglycan chimeric proteins shows that the extracellular domain governs functional differences between the two co-receptors. Overexpression in myoblasts, 125I-TGF-β crosslinking, PAI-1 reporter assay, chimeric protein analysis The Journal of biological chemistry Medium 9830054
2010 Inhibin-A binding to betaglycan causes clathrin-independent endocytic internalization of betaglycan, thereby reducing available TGF-β2 binding sites on the cell surface and antagonizing TGF-β2 signaling. This is distinct from the mechanism by which TGF-β ligands induce betaglycan internalization. Cell surface binding assays, internalization assays, functional signaling readouts in adrenocortical cells Molecular endocrinology (Baltimore, Md.) Medium 20160125
2006 Betaglycan overexpression via adenoviral expression induces TGF-β target gene expression (p3TP-Lux, CTGF, fibronectin) and inhibits myogenin expression in the absence of exogenous TGF-β (ligand-independent signaling). This effect requires the cytoplasmic domain of betaglycan and is independent of Smad2 phosphorylation but involves p38 MAP kinase phosphorylation. Adenoviral overexpression, reporter assays, TGF-β neutralizing antibodies, p38 inhibitor (SB239063), Western blot for phospho-p38 and phospho-Smad2 Cellular signalling Medium 16413747
2010 The transmembrane-cytoplasmic fragment remaining after betaglycan ectodomain shedding is stable in cells and serves as a substrate for γ-secretase intramembrane proteolysis. γ-Secretase inhibition stabilizes the fragment. Expression of this fragment or γ-secretase inhibition blunts TGF-β2 signaling in HepG2 cells. γ-Secretase inhibitor treatment, ectodomain shedding inhibitor (TAPI-2), Western blot, TGF-β2 signaling reporter Biochimica et biophysica acta Medium 21167215
2013 Glucocorticoids (dexamethasone and others) upregulate Tgfbr3 expression in lung fibroblasts. Tgfbr3 acts as a 'switch' that blunts Tgfbr1/Smad2/3 signaling and potentiates Acvrl1/Smad1 signaling. Dexamethasone acts synergistically with TGF-β to drive myofibroblast differentiation through Smad1-dependent processes in an in vivo mouse model. Reporter assays, Western blot for phospho-Smad1 and phospho-Smad2/3, primary cell culture experiments, in vivo mouse dexamethasone treatment, RNAi knockdown The Journal of biological chemistry Medium 24347165
2009 Tgfbr3 knockout mice exhibit defects in seminiferous cord formation and compromised fetal Leydig cell function (reduced expression of Insl3, Cyp17a1, Cyp11a1, Star, Hsd3b1) without changes in Leydig cell counts, indicating that betaglycan is required for fetal testis structure and Leydig cell endocrine function. Tgfbr3 knockout mouse analysis, immunohistochemistry, quantitative RT-PCR, whole-mount in situ hybridization, morphometric analysis Biology of reproduction High 19696014
2011 Betaglycan heterozygous mice display augmented nephron number and accelerated ureteric branching, while betaglycan null mice exhibit renal hypoplasia and reduced nephron number. Gene expression analysis links betaglycan dosage to regulation of Bmp4, Pax2, Eya1, Gdnf, Ret, Wnt4, and Wt1 expression in developing kidneys. Stereological analysis of embryonic/adult kidneys, quantitative RT-PCR, heterozygous and null mouse analysis PloS one Medium 21533152
2009 Endogenous betaglycan is required for high-potency inhibin antagonism in rat anterior pituitary gonadotropes. Betaglycan knockdown (siRNA) or immunoneutralization with anti-betaglycan IgG each decreased the potency of inhibin antagonism of activin-induced FSH secretion by more than 1000-fold, without affecting activin responsiveness. siRNA knockdown, immunoneutralization, primary pituitary gonadotrope culture, FSH secretion assay Molecular endocrinology (Baltimore, Md.) High 19372236
2018 TGFBR3 functions as an obligate inhibin A co-receptor in murine pituitary gonadotropes in vivo, but is not required for inhibin B suppression of FSH. Conditional knockout of Tgfbr3 in gonadotropes impairs inhibin A but not inhibin B suppression of FSH synthesis in cultured pituitaries. Conditional gonadotrope-specific Tgfbr3 knockout mice, pituitary cell culture, FSH assay Endocrinology High 30364975
2016 TGFBR3 regulates canonical Wnt3a signaling independently of its TGF-β co-receptor function. Heparan sulfate GAG chains on TGFBR3 sequester Wnt3a and inhibit Wnt signaling, while chondroitin sulfate GAG chains promote Wnt3a signaling. The balance of these modifications determines the net effect on Wnt pathway activation. Overexpression/knockdown, luciferase reporter assays for Wnt signaling, GAG-deficient and sulfation mutants The Journal of biological chemistry Medium 27784788
2008 The inhibin A binding epitope on betaglycan involves residues Tyr50, Val108, Thr111, Ser112, Phe118, Lys119, and Tyr120 of the inhibin α-subunit. Simultaneous mutation of Thr111, Ser112, and Tyr120 to alanine abolishes betaglycan binding and renders inhibin A unable to suppress activin-induced FSH release from pituitary cells. Mutagenesis of inhibin A, binding assays, pituitary cell FSH bioassay The Journal of biological chemistry High 18397882
2019 Loss of TGFBR3 in clear-cell renal cell carcinoma enhances cell migration through TGF-β-independent activation of FAK-PI3K signaling with increased lamellipodium formation, and also enhances TGF-β2-dependent reduction in the ALDH-positive cancer-initiating cell population. Orthotopic inoculation showed that low TGFBR3 enhances primary tumor formation and lung metastasis. Orthotopic mouse inoculation, cell migration assays, ALDH flow cytometry, signaling pathway inhibitors Oncogene Medium 29391598
2019 Betaglycan loss in MSCs augments TGF-β signaling, blocks the MSC-osteoblast differentiation program, and is required for prostate cancer-induced osteogenesis in vivo. Mechanistically, betaglycan loss induces >60-fold increase in Wnt5a expression, activating canonical Wnt signaling; Wnt5a neutralizing antibody rescues osteogenic gene expression in betaglycan-ablated MSCs. Betaglycan knockdown in MSCs, osteoblast differentiation assays, in vivo xenograft osteogenesis, gene expression analysis, Wnt5a neutralizing antibody rescue Oncogene Medium 31409900
2014 TGFBR3 forms a complex with β-arrestin 2 and IκBα. Overexpression of TGFBR3 decreases phospho-p65 (NF-κB) and increases IκBα expression in oral cancer cells; these effects are abolished by β-arrestin 2 knockdown. Co-immunoprecipitation, Western blot, siRNA knockdown Cell adhesion & migration Medium 29130787
2014 Betaglycan suppresses NFκB activity in granulosa tumor cells, reduces basal and TGF-β2-stimulated NFκB activity, and reduces cell viability in concert with NFκB inhibition. ERK1/2 activation converges the NFκB, SMAD3, and TGF-β2/betaglycan pathways. SMAD3 and NFκB form a positive feedback loop; betaglycan expression disrupts this loop. NFκB reporter assay, SMAD2/3 knockdown, pharmacological NFκB inhibition, cell viability assay, overexpression of betaglycan in GCT cell lines Molecular endocrinology (Baltimore, Md.) Medium 23322721
2012 Granzyme B cleaves soluble betaglycan as an extracellular substrate, releasing active TGF-β1 sequestered by betaglycan. Released TGF-β1 retains bioactivity as demonstrated by Smad3 phosphorylation in smooth muscle cells. In vitro protease cleavage assay, TGF-β1 cytokine release assay, Smad3 phosphorylation Western blot PloS one Medium 22479366
2014 Lactoferrin directly binds betaglycan (TGFBR3) and induces formation of TβRIII/TβRII/TβRI complex, leading to TβRI and Smad3 phosphorylation and IgA/IgG2b isotype switching in B cells. This represents a ligand-mediated mechanism for betaglycan to initiate canonical TGF-β signaling. Binding assays (lactoferrin-betaglycan direct interaction), co-immunoprecipitation of receptor complex, Western blot for Smad3 phosphorylation, B cell Ig class switching assays Mucosal immunology Medium 25492477
2002 TGF-β competes with inhibin A for binding to betaglycan on gonadotrope cells, reducing inhibin's ability to antagonize activin-induced FSH synthesis. TGF-β1 and TGF-β2 competed with 125I-inhibin for betaglycan binding in crosslinking experiments, suggesting TGF-β can counter inhibin action by occupying the shared betaglycan binding site. Radiolabeled inhibin A competition binding, immunoprecipitation of crosslinked receptor complexes, activin-responsive reporter assays in LβT2 cells Molecular endocrinology (Baltimore, Md.) Medium 12456797
2000 Endoglin associates with betaglycan on human microvascular endothelial cells in a ligand-dependent and ligand-independent manner to form higher-order complexes that also include type I and/or type II TGF-β receptors. Co-immunoprecipitation, affinity labeling with radiolabeled TGF-β European journal of biochemistry Medium 10951214
2003 Endoglin forms a heteromeric complex with betaglycan on human chondrocytes in both a ligand-independent and ligand-dependent manner, independently of the type II TGF-β receptor. Co-immunoprecipitation in absence of TGF-β and after affinity labeling with radiolabeled TGF-β Journal of bone and mineral research Medium 12568406
2007 TGF-β1 pretreatment of Leydig (TM3) and Sertoli (TM4) cells suppresses betaglycan mRNA levels by 46–73%, reducing subsequent inhibin A binding and betaglycan affinity labeling. This represents an indirect mechanism by which TGF-β blocks inhibin binding via downregulation of betaglycan. In cells lacking TβRII, only direct ligand competition is operational. RT-PCR, 125I-inhibin A affinity labeling, betaglycan mRNA quantification Endocrinology Medium 17656464
2019 TGFBR3 is identified as a target of let-7 microRNAs; induction of Tgfbr3 in cardiomyocytes causes apoptosis via p38 MAPK activation following myocardial infarction. AAV9-mediated let-7 overexpression reduced cardiomyocyte apoptosis, cardiac hypertrophy, and improved ejection fraction. AAV9-mediated microRNA overexpression/knockdown in mice, MI model, apoptosis assays, Western blot for p38 MAPK activation EBioMedicine Medium 31401194
2024 Cancer-associated fibroblast-secreted SULF1 binds TGFBR3 on gastric cancer cell membranes, interfering with TGF-β1/TGFBR3 interaction and subsequently activating downstream TGF-β signaling to promote metastasis and CDDP resistance. Co-immunoprecipitation/binding assays, functional migration and drug resistance assays, in vitro cancer-fibroblast co-culture system Cell death discovery Low 38438372

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Betaglycan presents ligand to the TGF beta signaling receptor. Cell 816 8391934
1991 Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-beta receptor system. Cell 613 1657406
2000 Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. Nature 479 10746731
1994 Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors: mapping of ligand binding and GAG attachment sites. The Journal of cell biology 350 8106553
1989 Membrane-anchored and soluble forms of betaglycan, a polymorphic proteoglycan that binds transforming growth factor-beta. The Journal of cell biology 334 2592419
2019 Macrophage-derived exosomal microRNA-501-3p promotes progression of pancreatic ductal adenocarcinoma through the TGFBR3-mediated TGF-β signaling pathway. Journal of experimental & clinical cancer research : CR 281 31307515
1998 Role of endoglin in cellular responses to transforming growth factor-beta. A comparative study with betaglycan. The Journal of biological chemistry 193 9830054
2001 Ligand binding and functional properties of betaglycan, a co-receptor of the transforming growth factor-beta superfamily. Specialized binding regions for transforming growth factor-beta and inhibin A. The Journal of biological chemistry 135 11278442
1992 Binding of two growth factor families to separate domains of the proteoglycan betaglycan. The Journal of biological chemistry 127 1556106
2002 Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft. Cancer research 124 12183427
2001 Betaglycan inhibits TGF-beta signaling by preventing type I-type II receptor complex formation. Glycosaminoglycan modifications alter betaglycan function. The Journal of biological chemistry 116 11668175
2003 The shedding of betaglycan is regulated by pervanadate and mediated by membrane type matrix metalloprotease-1. The Journal of biological chemistry 105 14672946
2011 Consistent t(1;10) with rearrangements of TGFBR3 and MGEA5 in both myxoinflammatory fibroblastic sarcoma and hemosiderotic fibrolipomatous tumor. Genes, chromosomes & cancer 100 21717526
2007 Loss of betaglycan expression in ovarian cancer: role in motility and invasion. Cancer research 99 17522389
2012 Granzyme B cleaves decorin, biglycan and soluble betaglycan, releasing active transforming growth factor-β1. PloS one 96 22479366
2011 Betaglycan: a multifunctional accessory. Molecular and cellular endocrinology 94 21550381
2002 Expression of activin receptors, follistatin and betaglycan by human endometrial stromal cells; consistent with a role for activins during decidualization. Molecular human reproduction 84 11912285
2018 Upregulated lncRNA ADAMTS9-AS2 suppresses progression of lung cancer through inhibition of miR-223-3p and promotion of TGFBR3. IUBMB life 78 29707897
2001 Recombinant soluble betaglycan is a potent and isoform-selective transforming growth factor-beta neutralizing agent. The Biochemical journal 78 11256966
2011 TGFBR3, a potential negative regulator of TGF-β signaling, protects cardiac fibroblasts from hypoxia-induced apoptosis. Journal of cellular physiology 71 21792916
2002 Properties of inhibin binding to betaglycan, InhBP/p120 and the activin type II receptors. Molecular and cellular endocrinology 70 12385827
2006 Identification of distinct inhibin and transforming growth factor beta-binding sites on betaglycan: functional separation of betaglycan co-receptor actions. The Journal of biological chemistry 69 16621788
2000 Endoglin expression on human microvascular endothelial cells association with betaglycan and formation of higher order complexes with TGF-beta signalling receptors. European journal of biochemistry 68 10951214
2014 A time- and matrix-dependent TGFBR3-JUND-KRT5 regulatory circuit in single breast epithelial cells and basal-like premalignancies. Nature cell biology 66 24658685
2014 TGFBR3 and MGEA5 rearrangements in pleomorphic hyalinizing angiectatic tumors and the spectrum of related neoplasms. The American journal of surgical pathology 61 24705316
2018 Decreased TGFBR3/betaglycan expression enhances the metastatic abilities of renal cell carcinoma cells through TGF-β-dependent and -independent mechanisms. Oncogene 60 29391598
2005 Systemic administration of a soluble betaglycan suppresses tumor growth, angiogenesis, and matrix metalloproteinase-9 expression in a human xenograft model of prostate cancer. The Prostate 60 15468171
1993 Localization of transforming growth factor beta binding site in betaglycan. Comparison with small extracellular matrix proteoglycans. The Journal of biological chemistry 60 8226781
2020 Regulation of H2S-induced necroptosis and inflammation in broiler bursa of Fabricius by the miR-15b-5p/TGFBR3 axis and the involvement of oxidative stress in this process. Journal of hazardous materials 58 33307448
2013 Glucocorticoids recruit Tgfbr3 and Smad1 to shift transforming growth factor-β signaling from the Tgfbr1/Smad2/3 axis to the Acvrl1/Smad1 axis in lung fibroblasts. The Journal of biological chemistry 58 24347165
2002 The distribution of betaglycan protein and mRNA in rat brain, pituitary, and gonads: implications for a role for betaglycan in inhibin-mediated reproductive functions. Endocrinology 58 11861534
2002 Expression and localization of inhibin alpha, inhibin/activin betaA and betaB and the activin type II and inhibin beta-glycan receptors in the developing human testis. Reproduction (Cambridge, England) 57 12052232
2009 Fetal testis dysgenesis and compromised Leydig cell function in Tgfbr3 (beta glycan) knockout mice. Biology of reproduction 56 19696014
2007 TGFBR3 loss and consequences in prostate cancer. The Prostate 56 17192875
1991 Purification of the transforming growth factor-beta (TGF-beta) binding proteoglycan betaglycan. The Journal of biological chemistry 56 1744125
2010 Changes in expression of bone morphogenetic proteins (BMPs), their receptors and inhibin co-receptor betaglycan during bovine antral follicle development: inhibin can antagonize the suppressive effect of BMPs on thecal androgen production. Reproduction (Cambridge, England) 55 20739376
2019 Structural biology of betaglycan and endoglin, membrane-bound co-receptors of the TGF-beta family. Experimental biology and medicine (Maywood, N.J.) 54 31601110
2021 Transforming Growth Factor Beta Receptor 3 (TGFBR3)-Associated Membranous Nephropathy. Kidney360 49 35369660
1992 Subtypes of betaglycan and of type I and type II transforming growth factor-beta (TGF-beta) receptors with different affinities for TGF-beta 1 and TGF-beta 2 are exhibited by human placental trophoblast cells. Journal of cellular physiology 49 1310325
2006 Soluble betaglycan reduces renal damage progression in db/db mice. American journal of physiology. Renal physiology 48 16954341
2009 Loss of betaglycan contributes to the malignant properties of human granulosa tumor cells. Molecular endocrinology (Baltimore, Md.) 47 19164448
2019 Novel role of the clustered miR-23b-3p and miR-27b-3p in enhanced expression of fibrosis-associated genes by targeting TGFBR3 in atrial fibroblasts. Journal of cellular and molecular medicine 45 30729664
2011 Structure of betaglycan zona pellucida (ZP)-C domain provides insights into ZP-mediated protein polymerization and TGF-beta binding. Proceedings of the National Academy of Sciences of the United States of America 45 21402931
2018 Betaglycan (TGFBR3) Functions as an Inhibin A, but Not Inhibin B, Coreceptor in Pituitary Gonadotrope Cells in Mice. Endocrinology 44 30364975
2003 Betaglycan localization in the female rat pituitary: implications for the regulation of follicle-stimulating hormone by inhibin. Endocrinology 43 14500575
2002 Inhibin binding protein (InhBP/p120), betaglycan, and the continuing search for the inhibin receptor. Molecular endocrinology (Baltimore, Md.) 43 11818494
2002 Antagonism of activin by inhibin and inhibin receptors: a functional role for betaglycan. Molecular and cellular endocrinology 42 11911962
2016 Binding Properties of the Transforming Growth Factor-β Coreceptor Betaglycan: Proposed Mechanism for Potentiation of Receptor Complex Assembly and Signaling. Biochemistry 40 27951653
2002 Betaglycan expression is transcriptionally up-regulated during skeletal muscle differentiation. Cloning of murine betaglycan gene promoter and its modulation by MyoD, retinoic acid, and transforming growth factor-beta. The Journal of biological chemistry 40 12399463
2020 The STAT3-miR-223-TGFBR3/HMGCS1 axis modulates the progression of cervical carcinoma. Molecular oncology 39 32491253
2009 Betaglycan has two independent domains required for high affinity TGF-beta binding: proteolytic cleavage separates the domains and inactivates the neutralizing activity of the soluble receptor. Biochemistry 39 19842711
2008 Suppression of inhibin A biological activity by alterations in the binding site for betaglycan. The Journal of biological chemistry 39 18397882
2006 Betaglycan induces TGF-beta signaling in a ligand-independent manner, through activation of the p38 pathway. Cellular signalling 39 16413747
1994 Plasmin cleaves betaglycan and releases a 60 kDa transforming growth factor-beta complex from the cell surface. The Biochemical journal 39 8068006
2019 MicroRNA let-7-TGFBR3 signalling regulates cardiomyocyte apoptosis after infarction. EBioMedicine 38 31401194
2017 miR-19a and miR-424 target TGFBR3 to promote epithelial-to-mesenchymal transition and migration of tongue squamous cell carcinoma cells. Cell adhesion & migration 38 29130787
2009 Endogenous betaglycan is essential for high-potency inhibin antagonism in gonadotropes. Molecular endocrinology (Baltimore, Md.) 38 19372236
2005 Inhibin alpha-subunit and the inhibin coreceptor betaglycan are downregulated in endometrial carcinoma. European journal of endocrinology 38 15745937
2003 Endoglin is expressed on human chondrocytes and forms a heteromeric complex with betaglycan in a ligand and type II TGFbeta receptor independent manner. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 38 12568406
2007 Differential expression of TGFBR3 (betaglycan) in mouse ovary and testis during gonadogenesis. Growth factors (Chur, Switzerland) 37 18236212
2023 Exosome-derived circ_0001785 delays atherogenesis through the ceRNA network mechanism of miR-513a-5p/TGFBR3. Journal of nanobiotechnology 36 37794449
2010 Inhibin-A antagonizes TGFbeta2 signaling by down-regulating cell surface expression of the TGFbeta coreceptor betaglycan. Molecular endocrinology (Baltimore, Md.) 36 20160125
1996 Betaglycan has multiple binding sites for transforming growth factor-beta 1. The Biochemical journal 36 8645162
2014 Lactoferrin causes IgA and IgG2b isotype switching through betaglycan binding and activation of canonical TGF-β signaling. Mucosal immunology 35 25492477
2019 Hsa_circ_0042666 inhibits proliferation and invasion via regulating miR-223/TGFBR3 axis in laryngeal squamous cell carcinoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 33 31525642
2002 Transforming growth factor-beta modulates inhibin A bioactivity in the LbetaT2 gonadotrope cell line by competing for binding to betaglycan. Molecular endocrinology (Baltimore, Md.) 32 12456797
2023 Exosomal miR-103a-3p from Crohn's Creeping Fat-Derived Adipose-Derived Stem Cells Contributes to Intestinal Fibrosis by Targeting TGFBR3 and Activating Fibroblasts. Journal of Crohn's & colitis 31 36897738
2018 MicroRNA let-7a regulates angiogenesis by targeting TGFBR3 mRNA. Journal of cellular and molecular medicine 31 30467960
2021 Inhibiting microRNA-424 in bone marrow mesenchymal stem cells-derived exosomes suppresses tumor growth in colorectal cancer by upregulating TGFBR3. Archives of biochemistry and biophysics 30 34129838
2007 Alternative splicing of TGF-betas and their high-affinity receptors T beta RI, T beta RII and T beta RIII (betaglycan) reveal new variants in human prostatic cells. BMC genomics 30 17845732
2001 Antagonism of activin by inhibin and inhibin receptors: a functional role for betaglycan-glycan. Molecular and cellular endocrinology 29 11451571
1995 Serglycin and betaglycan proteoglycans are expressed in the megakaryocytic cell line CHRF 288-11 and normal human megakaryocytes. Journal of cellular physiology 29 7559813
2020 HELLS, a chromatin remodeler is highly expressed in pancreatic cancer and downregulation of it impairs tumor growth and sensitizes to cisplatin by reexpressing the tumor suppressor TGFBR3. Cancer medicine 28 33280236
2007 Transforming growth factor-beta blocks inhibin binding to different target cell types in a context-dependent manner through dual mechanisms involving betaglycan. Endocrinology 28 17656464
2019 Betaglycan drives the mesenchymal stromal cell osteogenic program and prostate cancer-induced osteogenesis. Oncogene 27 31409900
2018 Plau and Tgfbr3 are YAP-regulated genes that promote keratinocyte proliferation. Cell death & disease 27 30382077
2011 Betaglycan is required for the establishment of nephron endowment in the mouse. PloS one 27 21533152
2003 Expression of betaglycan, an inhibin coreceptor, in normal human ovaries and ovarian sex cord-stromal tumors and its regulation in cultured human granulosa-luteal cells. The Journal of clinical endocrinology and metabolism 26 14557487
2023 Exosomes Derived from E2F1-/- Adipose-Derived Stem Cells Promote Skin Wound Healing via miR-130b-5p/TGFBR3 Axis. International journal of nanomedicine 24 37941530
2013 Betaglycan alters NFκB-TGFβ2 cross talk to reduce survival of human granulosa tumor cells. Molecular endocrinology (Baltimore, Md.) 24 23322721
2025 Structures of TGF-β with betaglycan and signaling receptors reveal mechanisms of complex assembly and signaling. Nature communications 23 40011426
2016 Altering the Proteoglycan State of Transforming Growth Factor β Type III Receptor (TβRIII)/Betaglycan Modulates Canonical Wnt/β-Catenin Signaling. The Journal of biological chemistry 23 27784788
2010 The type III TGF-β receptor betaglycan transmembrane-cytoplasmic domain fragment is stable after ectodomain cleavage and is a substrate of the intramembrane protease γ-secretase. Biochimica et biophysica acta 23 21167215
2020 The Tumor Suppressor TGFBR3 Blocks Lymph Node Metastasis in Head and Neck Cancer. Cancers 22 32471132
2006 Mutational analysis of the betaglycan gene-coding region in susceptibility for ovarian failure. Human reproduction (Oxford, England) 22 16613887
1999 A regulatory role of fibroblast growth factor in the expression of decorin, biglycan, betaglycan and syndecan in osteoblasts from patients with Crouzon's syndrome. European journal of cell biology 22 10384983
2024 Cancer associated fibroblasts-derived SULF1 promotes gastric cancer metastasis and CDDP resistance through the TGFBR3-mediated TGF-β signaling pathway. Cell death discovery 21 38438372
2022 Promoter Hypomethylation of TGFBR3 as a Risk Factor of Alzheimer's Disease: An Integrated Epigenomic-Transcriptomic Analysis. Frontiers in cell and developmental biology 21 35310542
2022 LncRNA H19 alleviates sepsis-induced acute lung injury by regulating the miR-107/TGFBR3 axis. BMC pulmonary medicine 21 36180862
2024 The Role of TGFBR3 in the Development of Lung Cancer. Protein and peptide letters 20 39092729
2019 A Tale of Two Proteins: Betaglycan, IGSF1, and the Continuing Search for the Inhibin B Receptor. Trends in endocrinology and metabolism: TEM 19 31648935
2018 The t(1;10)(p22;q24) TGFBR3/MGEA5 Translocation in Pleomorphic Hyalinizing Angiectatic Tumor, Myxoinflammatory Fibroblastic Sarcoma, and Hemosiderotic Fibrolipomatous Tumor. Archives of pathology & laboratory medicine 19 29979612
2018 TGF-β2 uses the concave surface of its extended finger region to bind betaglycan's ZP domain via three residues specific to TGF-β and inhibin-α. The Journal of biological chemistry 19 30598510
2015 Retinoic acid enhances lactoferrin-induced IgA responses by increasing betaglycan expression. Cellular & molecular immunology 19 26277894
2021 Anti-TGFβ (Transforming Growth Factor β) Therapy With Betaglycan-Derived P144 Peptide Gene Delivery Prevents the Formation of Aortic Aneurysm in a Mouse Model of Marfan Syndrome. Arteriosclerosis, thrombosis, and vascular biology 18 34162229
2021 SNHG5 protects chondrocytes in interleukin-1β-stimulated osteoarthritis via regulating miR-181a-5p/TGFBR3 axis. Journal of biochemical and molecular toxicology 18 34369033
2014 Betaglycan blocks metastatic behaviors in human granulosa cell tumors by suppressing NFκB-mediated induction of MMP2. Cancer letters 18 25128652
2010 Synthesis of the glycosaminoglycan-protein linkage tetraosyl peptide moieties of betaglycan, which serve as a hexosamine acceptor for enzymatic glycosyl transfer. Carbohydrate research 18 20813352
2013 Dual role of TGFBR3 in bladder cancer. Oncology reports 17 23835618
2009 Reducing betaglycan expression by RNA interference (RNAi) attenuates inhibin bioactivity in LbetaT2 gonadotropes. Molecular and cellular endocrinology 17 19524135

Missed literature

Know a paper Affinage missed for TGFBR3? Flag it for the maintainers and the community.

No submissions yet.