TGFBR3 (betaglycan, TGF-beta type III receptor) is a single-pass type I transmembrane proteoglycan with a large ectodomain (an N-terminal endoglin-like region and a C-terminal zona pellucida domain) that carries heparan and chondroitin sulfate chains, and a short cytoplasmic tail without kinase activity. It acts as a cell-surface coreceptor that binds TGF-beta isoforms (notably TGF-beta2), inhibin A and several BMPs and presents them to the signalling type II/type I receptor kinases, thereby enhancing TGF-beta, BMP and inhibin signalling; inhibin-betaglycan-ActRII complexes antagonize activin signalling. Through its cytoplasmic tail it recruits beta-arrestin2, which drives receptor internalization and regulates cell migration, CDC42 activation and NF-kappa-B. Ectodomain shedding releases a soluble form present in serum and extracellular matrix that can sequester ligand. It participates in epithelial-mesenchymal transformation in the developing heart. The donkey protein (836 aa) is 89.5% identical to human TGFBR3 and conserves the signal peptide, ZP domain disulfides, the glycosaminoglycan-attachment serines, the ligand-interaction region, the transmembrane segment and the entire cytoplasmic tail including the threonine phosphorylated by the type II receptor; the predicted donkey product lacks a 14-residue segment of the membrane-proximal ectodomain stalk that is present in human, horse, pig, dog and rodent orthologs.
Reason: BMP-2 stimulates TbetaRIII-mediated epithelial to mesenchymal transformation in the cardiac cushion model; a physiological context of its signalling role.
The TGF-beta type III receptor (TbetaRIII or betaglycan) is an abundant cell surface proteoglycan that has been well characterized as a TGF-beta and inhibin receptor.
Reason: GO defines GO:0005024 as ligand binding coupled to serine/threonine kinase catalysis. Betaglycan has no kinase domain; it binds TGF-beta and facilitates binding to the type I/II kinase receptors. The purpose-made child term, TGF-beta receptor activity, type III (GO:0070123), describes this function exactly, and is already carried by this gene (GO_REF:0000107 row). PAINT asserted GO:0005024 at the TGFBR3 clade node PTN002678643; the MODIFY is a refinement within that judgement, not a disagreement with it.
The TGF-beta type III receptor (TbetaRIII or betaglycan) is an abundant cell surface proteoglycan that has been well characterized as a TGF-beta and inhibin receptor.
GO:0005114 type II transforming growth factor beta receptor binding
IEA GO_REF:0000120
KEEP AS NON CORE
Summary: Type II transforming growth factor beta receptor binding.
Reason: Betaglycan complexes with TGFBR2 to present ligand (human IDA; PAINT IBD at PTN002678643), and TGFBR2 phosphorylates the betaglycan cytoplasmic domain; part of the coreceptor mechanism rather than a separate function.
Summary: Glycosaminoglycan binding (TreeGrafter; human IBA).
Reason: Betaglycan is itself extensively GAG-modified, and its heparan sulfate chains mediate binding of heparin-binding growth factors; the PANTHER node also asserts GAG binding for the family. Kept as a non-core property; ligand presentation to TGF-beta superfamily receptors is the core function.
Reason: Single-pass type I membrane protein at the cell surface (human experimental evidence; PAINT IBD for plasma membrane at node PTN008553354); the transmembrane segment is conserved in donkey.
Summary: Immune response (Ensembl Compara transfer of a human IMP).
Reason: The human source annotation is based on a genetic association of SNPs in TGFBR3 (with several other pathway genes) with bacteremia in sickle cell anemia. An association study does not show that the TGFBR3 protein carries out an immune response.
Reason: Betaglycan is a TGF-beta and inhibin receptor that initiates and enhances TGF-beta receptor signalling by presenting ligand to the signalling receptors.
The TGF-beta type III receptor (TbetaRIII or betaglycan) is an abundant cell surface proteoglycan that has been well characterized as a TGF-beta and inhibin receptor.
Reason: The ligand-binding ectodomain faces the extracellular side of the plasma membrane (human IDA, PMID:12958365, a cell-surface receptor endocytosis study). In donkey the signal peptide and the transmembrane helix are conserved and the ectodomain is predicted extracellular.
Summary: Positive regulation of gene expression (Ensembl Compara transfer of a human IMP).
Reason: The human source annotation (IMP, PMID:30467960) is an indirect readout of altered signalling in one knockdown study (reduced VEGFC and MMP9 mRNA after TGFBR3 siRNA in HUVECs); this generic gene-expression term does not describe a function of a cell-surface coreceptor. (The previous version of this review cited PMID:30729664 here, which is the source of other rows, not this one.)
Alternatively, acts as a cell surface coreceptor for BMP ligands, serving to enhance ligand binding by differentially regulating BMPR1A/ALK3 and BMPR1B/ALK6 receptor trafficking
Reason: TreeGrafter transfer from the PAINT TGFBR3-clade node PTN002678643, whose cell-migration IBD rests on chicken TGFBR3 (Q90998, cardiac cushion mesenchymal invasion). In mammalian cells TGFBR3 mostly regulates (inhibits) epithelial cell migration via beta-arrestin2 and the actin cytoskeleton. Deferring to the PAINT node placement, kept as non-core; the regulatory terms carried by this gene describe the mammalian evidence more exactly.
Reason: As a coreceptor that presents TGF-beta to the type II receptor (and, as a shed soluble form, sequesters it), betaglycan modulates TGF-beta receptor signalling; TbetaRII-phosphorylated betaglycan also recruits beta-arrestin2, which internalizes both receptors and down-regulates signalling. PAINT placed this term at the TGFBR3 clade node (PTN002678643). The phosphoacceptor threonine is conserved in donkey.
The TGF-beta type III receptor (TbetaRIII or betaglycan) is an abundant cell surface proteoglycan that has been well characterized as a TGF-beta and inhibin receptor.
Reason: Human TGFBR3 inhibits directed and random epithelial cell migration via beta-arrestin2-dependent effects on the actin cytoskeleton; the source study (overexpression in tongue carcinoma cells) also shows inhibition of migration. Non-core relative to coreceptor activity.
we observed that transfection of a TGFBR3-containing plasmid dramatically inhibited epithelial-to-mesenchymal transition (EMT) and migration in CAL-27 cells.
TbetaRIII directly and specifically binds to multiple members of the BMP subfamily, including BMP-2, BMP-4, BMP-7, and GDF-5, with similar kinetics and ligand binding domains as previously identified for TGF-beta.
TbetaRIII also enhances ligand binding to the BMP type I receptors, whereas short hairpin RNA-mediated silencing of endogenous TbetaRIII attenuates BMP-mediated Smad1 phosphorylation.
GO:0032354 response to follicle-stimulating hormone
IEA GO_REF:0000107
MARK AS OVER ANNOTATED
Summary: Response to follicle-stimulating hormone (Ensembl Compara transfer of a human IDA).
Reason: The human annotation reflects hormonal regulation of TGFBR3 expression, not a function of the protein in the hormone response. Its relevant reproductive role is as an inhibin A coreceptor that controls FSH levels, which is captured by the coreceptor and inhibin complex terms.
Summary: Response to prostaglandin E (Ensembl Compara transfer of a human IDA).
Reason: Reflects up-regulation of TGFBR3 mRNA by prostaglandin E2 in cultured granulosa-luteal cells in one study, not a function of the protein in the response.
Summary: Intracellular signal transduction (Ensembl Compara transfer of a human IMP).
Reason: Betaglycan acts at the cell surface in receptor signalling; the generic intracellular signal transduction term from a hormone-response study adds nothing specific and is not where the protein acts. The source study concerns the protein kinase A pathway acting upstream of TGFBR3 mRNA, i.e. signalling that regulates the gene, not signalling carried out by its product.
The accumulation of its mRNA in cultured granulosa-luteal cells is up-regulated by gonadotropins and prostaglandin E(2), probably via the protein kinase A pathway.
TbetaRIII directly and specifically binds to multiple members of the BMP subfamily, including BMP-2, BMP-4, BMP-7, and GDF-5, with similar kinetics and ligand binding domains as previously identified for TGF-beta.
GO:0043124 negative regulation of canonical NF-kappaB signal transduction
IEA GO_REF:0000107
KEEP AS NON CORE
Summary: Negative regulation of canonical NF-kappaB signal transduction.
Reason: Via beta-arrestin2 interaction, TGFBR3 inhibits NF-kappa-B (human IDA, overexpression in carcinoma cells); a context-dependent effect of its cytoplasmic-tail scaffolding, which is fully conserved in donkey.
By interacting with the scaffolding protein beta- arrestin2/ARRB2, regulates migration or actin cytoskeleton and promotes the activation of CDC42 as well as the inhibition of NF-kappa-B
TbetaRIII associated with ALK3 primarily through their extracellular domains, whereas its interaction with ALK6 required both the extracellular and cytoplasmic domains.
Summary: SMAD binding (Ensembl Compara transfer of a human IMP).
Reason: A binding activity cannot be established by a mutant phenotype, and there is no evidence that the short cytoplasmic tail of betaglycan binds SMAD proteins; its known cytoplasmic partner is beta-arrestin2. SMAD involvement is downstream of the signalling receptors it presents ligand to.
By interacting with the scaffolding protein beta- arrestin2/ARRB2, regulates migration or actin cytoskeleton and promotes the activation of CDC42 as well as the inhibition of NF-kappa-B
Reason: Developmental phenotypes (heart, liver) of betaglycan loss reflect its signalling role; the very broad organ-development term adds no specific information about what the protein does and is better captured by the signalling terms and cardiac EMT.
Reason: Core ligand-binding activity of betaglycan (human IDA; PAINT IBD at node PTN002678643, the TGFBR3 clade of PTHR14002 to which the donkey protein belongs as subfamily SF7). The ligand-interaction region mapped from human is 14 of 15 residues identical in donkey.
The TGF-beta type III receptor (TbetaRIII or betaglycan) is an abundant cell surface proteoglycan that has been well characterized as a TGF-beta and inhibin receptor.
TbetaRIII also enhances ligand binding to the BMP type I receptors, whereas short hairpin RNA-mediated silencing of endogenous TbetaRIII attenuates BMP-mediated Smad1 phosphorylation.
GO:0060392 negative regulation of SMAD protein signal transduction
IEA GO_REF:0000107
KEEP AS NON CORE
Summary: Negative regulation of SMAD protein signal transduction (Ensembl Compara transfer of a human IMP).
Reason: In atrial fibroblasts TGFBR3 knockdown activated Smad3, consistent with its context-dependent ligand-sequestering role (e.g. soluble betaglycan). Kept as a non-core, context-dependent effect.
TGFBR3 siRNA could increase fibrosis-related genes expression, along with the Smad1 inactivation and Smad3 activation in HAFs.
GO:0070123 transforming growth factor beta receptor activity, type III
IEA GO_REF:0000107
ACCEPT
Summary: Transforming growth factor beta receptor activity, type III.
Reason: The defining activity of betaglycan: it binds TGF-beta and facilitates ligand binding to the type I and type II receptors (human IDA). The donkey ectodomain and transmembrane segment are conserved.
The TGF-beta type III receptor (TbetaRIII or betaglycan) is an abundant cell surface proteoglycan that has been well characterized as a TGF-beta and inhibin receptor.
Donkey A0A8C4M6Z6 (836 aa) aligned globally to human Q03167 (851 aa): 89.47% identity over 836 paired residues
GO:0090050 positive regulation of cell migration involved in sprouting angiogenesis
IEA GO_REF:0000107
KEEP AS NON CORE
Summary: Positive regulation of cell migration involved in sprouting angiogenesis (Ensembl Compara transfer of a human IMP).
Reason: A single knockdown study in endothelial cells (reduced HUVEC tube formation and wound-closure migration after TGFBR3 siRNA); plausible downstream effect of altered TGF-beta/BMP signalling, kept as non-core.
Overexpression of let-7a or knockdown of TGFBR3 in cell culture inhibited the tube formation and reduced migration rate.
GO:0090100 positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway
IEA GO_REF:0000117
KEEP AS NON CORE
Summary: Positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway (ARBA).
Reason: Correct: betaglycan enhances ligand binding to BMP type I receptors and BMP-induced Smad1 phosphorylation, and potentiates TGF-beta signalling; non-core relative to its coreceptor activity.
TbetaRIII also enhances ligand binding to the BMP type I receptors, whereas short hairpin RNA-mediated silencing of endogenous TbetaRIII attenuates BMP-mediated Smad1 phosphorylation.
GO:1901202 negative regulation of extracellular matrix assembly
IEA GO_REF:0000107
MARK AS OVER ANNOTATED
Summary: Negative regulation of extracellular matrix assembly (Ensembl Compara transfer of a human IMP).
Reason: The source study measured fibrosis-related gene expression (collagen, ACTA2 mRNA) after TGFBR3 knockdown in atrial fibroblasts; it did not assess extracellular matrix assembly. The effect is an indirect consequence of altered SMAD signalling.
TGFBR3 siRNA could increase fibrosis-related genes expression, along with the Smad1 inactivation and Smad3 activation in HAFs.
Core Functions
Cell-surface proteoglycan coreceptor (betaglycan) that binds TGF-beta, inhibin and BMP ligands and presents them to the signalling type II/I receptor kinases.
The TGF-beta type III receptor (TbetaRIII or betaglycan) is an abundant cell surface proteoglycan that has been well characterized as a TGF-beta and inhibin receptor.
The TGF-beta type III receptor (TbetaRIII or betaglycan) is an abundant cell surface proteoglycan that has been well characterized as a TGF-beta and inhibin receptor.
Q: GO:0070123 (TGF-beta receptor activity, type III) is an is_a child of GO:0005024, whose definition requires serine/threonine kinase catalysis that betaglycan lacks. Should GO:0070123 instead sit under coreceptor activity / transforming growth factor beta binding?
External Prediction Reviews
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
Assessment of the single ProtNLM2 GO prediction for donkey TGFBR3 (A0A8C4M6Z6, betaglycan), 89.5% identical to human TGFBR3. Extracellular region is correct, reflecting the shed soluble ectodomain, and is absent from donkey GOA (COR). ProtNLM2 also emitted subcellular locations Extracellular matrix, Secreted and Extracellular space (not scored); these match the soluble form, but the output omits the primary cell-membrane (single-pass type I) location. No function text was emitted.
Prediction method: ProtNLM2 Β· Version: UniProt API snapshot 2026-10-14
Review rationale: Betaglycan exists both as a membrane-bound receptor and as a soluble form in serum and extracellular matrix; the soluble ectodomain is released by proteolytic shedding mediated by MT1-MMP (PMID:14672946), and the human gene review keeps extracellular region as a non-core location. The donkey protein conserves the signal peptide, ZP domain and transmembrane helix, so the same membrane-bound and shed forms are expected. The donkey GOA has plasma membrane and external side of plasma membrane but not extracellular region, so the prediction adds a correct location. It is a secondary location; the primary site of receptor function is the plasma membrane.
PMID:14672946: "A soluble form of betaglycan can be released by proteolytic cleavage (also known as shedding) of the membrane-bound form, yielding soluble betaglycan."