LRRC32 (GARP, glycoprotein A repetitions predominant) is a single-pass type I transmembrane protein whose large extracellular region is almost entirely leucine-rich repeats. It is expressed at the surface of activated FOXP3+ regulatory T cells and platelets, where it is the cell-surface docking receptor for latent TGF-beta. It forms disulfide bonds (via Cys192 and Cys331) with the latency-associated peptide of proTGFB1, outcompeting LTBP1, and tethers the latent cytokine to the plasma membrane. GARP holds TGF-beta in its latent state and presents it for activation by integrins alphaV-beta6/beta8, thereby controlling the bioavailability and activation of TGF-beta that underlies regulatory T cell immunosuppression; the murine ortholog is also required for TGF-beta3 activation during palate fusion. GARP is a genuine, constitutively surface-exposed cell-surface protein with its ligand-binding LRR ectodomain facing the extracellular space.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:19651619 GARP (LRRC32) is essential for the surface expression of lat... | MODIFY | Summary: GARP binds the TGF-beta1 latency-associated peptide (P01137). Reason: Following the protein-binding policy, the informative activity is binding of latent TGF-beta; the partner P01137 is the TGFB1 (LAP) chain. Proposed replacements: transforming growth factor beta binding Supporting Evidence: PMID:22278742 We find that Cys-192 and Cys-331 of GARP disulfide link to the TGFฮฒ1 prodomain PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. |
| GO:0005515 protein binding | IPI PMID:26126825 Lysosomal-associated Transmembrane Protein 4B (LAPTM4B) Decr... | REMOVE | Summary: Interaction reported with a regulatory partner (LAPTM4B) or in high-throughput interactome screens. Reason: Bare protein binding is uninformative under the protein-binding policy. The functionally relevant partner is latent TGF-beta, captured by TGF-beta binding; LAPTM4B is a regulator of GARP-TGFB1 production. Removal does not mean the interactions are false. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: GARP binds the TGF-beta1 latency-associated peptide (P01137). Reason: Following the protein-binding policy, the informative activity is binding of latent TGF-beta; the partner P01137 is the TGFB1 (LAP) chain. Proposed replacements: transforming growth factor beta binding Supporting Evidence: PMID:22278742 We find that Cys-192 and Cys-331 of GARP disulfide link to the TGFฮฒ1 prodomain PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. |
| GO:0005515 protein binding | IPI PMID:30361387 Structural basis of latent TGF-ฮฒ1 presentation and activatio... | MODIFY | Summary: GARP binds the TGF-beta1 latency-associated peptide (P01137). Reason: Following the protein-binding policy, the informative activity is binding of latent TGF-beta; the partner P01137 is the TGFB1 (LAP) chain. Proposed replacements: transforming growth factor beta binding Supporting Evidence: PMID:22278742 We find that Cys-192 and Cys-331 of GARP disulfide link to the TGFฮฒ1 prodomain PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: GARP binds the TGF-beta1 latency-associated peptide (P01137). Reason: Following the protein-binding policy, the informative activity is binding of latent TGF-beta; the partner P01137 is the TGFB1 (LAP) chain. Proposed replacements: transforming growth factor beta binding Supporting Evidence: PMID:22278742 We find that Cys-192 and Cys-331 of GARP disulfide link to the TGFฮฒ1 prodomain PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MODIFY | Summary: GARP binds the TGF-beta1 latency-associated peptide (P01137). Reason: Following the protein-binding policy, the informative activity is binding of latent TGF-beta; the partner P01137 is the TGFB1 (LAP) chain. Proposed replacements: transforming growth factor beta binding Supporting Evidence: PMID:22278742 We find that Cys-192 and Cys-331 of GARP disulfide link to the TGFฮฒ1 prodomain PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | REMOVE | Summary: Nucleoplasm from a high-throughput antibody localization screen. Reason: GARP is a type I single-pass plasma membrane protein with a cleaved signal peptide and an extracellular LRR domain; a nucleoplasmic location is inconsistent with its topology and function and likely reflects antibody cross-reactivity. Supporting Evidence: PMID:19750484 latent TGF-beta, i.e. both LAP and mature TGF-beta, binds to glycoprotein A repetitions predominant (GARP), a transmembrane protein containing leucine rich repeats, which is present on the surface of stimulated Treg clones but not on Th clones. |
| GO:0005886 plasma membrane | EXP PMID:19651619 GARP (LRRC32) is essential for the surface expression of lat... | ACCEPT | Summary: GARP is a single-pass type I plasma membrane protein presenting latent TGF-beta on the cell surface. Reason: GARP is expressed on the membrane of activated Tregs and platelets, where it tethers latent TGF-beta; this is its functional location. Supporting Evidence: PMID:19651619 We show that GARP or LRRC32, a leucine-rich repeat molecule of unknown function, is critical for tethering TGF-beta to the cell surface. PMID:19750484 latent TGF-beta, i.e. both LAP and mature TGF-beta, binds to glycoprotein A repetitions predominant (GARP), a transmembrane protein containing leucine rich repeats, which is present on the surface of stimulated Treg clones but not on Th clones. |
| GO:0005886 plasma membrane | EXP PMID:19750484 Membrane protein GARP is a receptor for latent TGF-beta on t... | ACCEPT | Summary: GARP is a single-pass type I plasma membrane protein presenting latent TGF-beta on the cell surface. Reason: GARP is expressed on the membrane of activated Tregs and platelets, where it tethers latent TGF-beta; this is its functional location. Supporting Evidence: PMID:19651619 We show that GARP or LRRC32, a leucine-rich repeat molecule of unknown function, is critical for tethering TGF-beta to the cell surface. PMID:19750484 latent TGF-beta, i.e. both LAP and mature TGF-beta, binds to glycoprotein A repetitions predominant (GARP), a transmembrane protein containing leucine rich repeats, which is present on the surface of stimulated Treg clones but not on Th clones. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: GARP is a single-pass type I plasma membrane protein presenting latent TGF-beta on the cell surface. Reason: GARP is expressed on the membrane of activated Tregs and platelets, where it tethers latent TGF-beta; this is its functional location. Supporting Evidence: PMID:19651619 We show that GARP or LRRC32, a leucine-rich repeat molecule of unknown function, is critical for tethering TGF-beta to the cell surface. PMID:19750484 latent TGF-beta, i.e. both LAP and mature TGF-beta, binds to glycoprotein A repetitions predominant (GARP), a transmembrane protein containing leucine rich repeats, which is present on the surface of stimulated Treg clones but not on Th clones. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: GARP is a single-pass type I plasma membrane protein presenting latent TGF-beta on the cell surface. Reason: GARP is expressed on the membrane of activated Tregs and platelets, where it tethers latent TGF-beta; this is its functional location. Supporting Evidence: PMID:19651619 We show that GARP or LRRC32, a leucine-rich repeat molecule of unknown function, is critical for tethering TGF-beta to the cell surface. PMID:19750484 latent TGF-beta, i.e. both LAP and mature TGF-beta, binds to glycoprotein A repetitions predominant (GARP), a transmembrane protein containing leucine rich repeats, which is present on the surface of stimulated Treg clones but not on Th clones. |
| GO:0005886 plasma membrane | TAS PMID:8180135 The GARP gene encodes a new member of the family of leucine-... | ACCEPT | Summary: GARP is a single-pass type I plasma membrane protein presenting latent TGF-beta on the cell surface. Reason: GARP is expressed on the membrane of activated Tregs and platelets, where it tethers latent TGF-beta; this is its functional location. Supporting Evidence: PMID:19651619 We show that GARP or LRRC32, a leucine-rich repeat molecule of unknown function, is critical for tethering TGF-beta to the cell surface. PMID:19750484 latent TGF-beta, i.e. both LAP and mature TGF-beta, binds to glycoprotein A repetitions predominant (GARP), a transmembrane protein containing leucine rich repeats, which is present on the surface of stimulated Treg clones but not on Th clones. |
| GO:0007179 transforming growth factor beta receptor signaling pathway | IDA PMID:19750484 Membrane protein GARP is a receptor for latent TGF-beta on t... | KEEP AS NON CORE | Summary: GARP presents latent TGF-beta for activation, feeding into TGF-beta receptor signaling. Reason: GARP participates in TGF-beta signaling by controlling activation of the cytokine, but it is a presentation/docking molecule rather than a component of the receptor signal transduction machinery. Supporting Evidence: PMID:22278742 Integrin ฮฑ(V)ฮฒ(6) and to a lesser extent ฮฑ(V)ฮฒ(8) are able to activate TGFฮฒ from the GARP-proTGFฮฒ1 complex. |
| GO:0009986 cell surface | IDA PMID:19651619 GARP (LRRC32) is essential for the surface expression of lat... | ACCEPT | Summary: GARP is exposed on the cell surface with its LRR ectodomain facing outward. Reason: GARP and its bound latent TGF-beta are detectable on the surface of stimulated Tregs and platelets; the ligand-binding ectodomain is extracellular. Supporting Evidence: PMID:19750484 latent TGF-beta, i.e. both LAP and mature TGF-beta, binds to glycoprotein A repetitions predominant (GARP), a transmembrane protein containing leucine rich repeats, which is present on the surface of stimulated Treg clones but not on Th clones. PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. |
| GO:0009986 cell surface | IDA PMID:19750484 Membrane protein GARP is a receptor for latent TGF-beta on t... | ACCEPT | Summary: GARP is exposed on the cell surface with its LRR ectodomain facing outward. Reason: GARP and its bound latent TGF-beta are detectable on the surface of stimulated Tregs and platelets; the ligand-binding ectodomain is extracellular. Supporting Evidence: PMID:19750484 latent TGF-beta, i.e. both LAP and mature TGF-beta, binds to glycoprotein A repetitions predominant (GARP), a transmembrane protein containing leucine rich repeats, which is present on the surface of stimulated Treg clones but not on Th clones. PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. |
| GO:0009986 cell surface | IEA GO_REF:0000044 | ACCEPT | Summary: GARP is exposed on the cell surface with its LRR ectodomain facing outward. Reason: GARP and its bound latent TGF-beta are detectable on the surface of stimulated Tregs and platelets; the ligand-binding ectodomain is extracellular. Supporting Evidence: PMID:19750484 latent TGF-beta, i.e. both LAP and mature TGF-beta, binds to glycoprotein A repetitions predominant (GARP), a transmembrane protein containing leucine rich repeats, which is present on the surface of stimulated Treg clones but not on Th clones. PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. |
| GO:0030512 negative regulation of transforming growth factor beta receptor signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: GARP keeps TGF-beta latent, limiting TGF-beta receptor signaling until activation. Reason: By sequestering proTGFB1 in a latent, non-secreted state, GARP negatively regulates TGF-beta signaling; this is the restraining side of its dual role in bioavailability control. Supporting Evidence: PMID:22278742 Association between GARP and proTGFฮฒ1 prevents the secretion of TGFฮฒ1. |
| GO:0035592 establishment of protein localization to extracellular region | IDA PMID:19750484 Membrane protein GARP is a receptor for latent TGF-beta on t... | ACCEPT | Summary: GARP establishes surface/extracellular localization of latent TGF-beta. Reason: GARP knockdown abolishes surface latent TGF-beta on Tregs, and GARP expression is sufficient to tether latent TGF-beta to the membrane; GARP directs the cytokine to the cell surface. Supporting Evidence: PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. PMID:19651619 We show that GARP or LRRC32, a leucine-rich repeat molecule of unknown function, is critical for tethering TGF-beta to the cell surface. |
| GO:0035592 establishment of protein localization to extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: GARP establishes surface/extracellular localization of latent TGF-beta. Reason: GARP knockdown abolishes surface latent TGF-beta on Tregs, and GARP expression is sufficient to tether latent TGF-beta to the membrane; GARP directs the cytokine to the cell surface. Supporting Evidence: PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. PMID:19651619 We show that GARP or LRRC32, a leucine-rich repeat molecule of unknown function, is critical for tethering TGF-beta to the cell surface. |
| GO:0035592 establishment of protein localization to extracellular region | IMP PMID:19651619 GARP (LRRC32) is essential for the surface expression of lat... | ACCEPT | Summary: GARP establishes surface/extracellular localization of latent TGF-beta. Reason: GARP knockdown abolishes surface latent TGF-beta on Tregs, and GARP expression is sufficient to tether latent TGF-beta to the membrane; GARP directs the cytokine to the cell surface. Supporting Evidence: PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. PMID:19651619 We show that GARP or LRRC32, a leucine-rich repeat molecule of unknown function, is critical for tethering TGF-beta to the cell surface. |
| GO:0038023 signaling receptor activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Signaling receptor activity propagated across the LRR family. Reason: GARP is called a "receptor" for latent TGF-beta but it does not transduce a signal across the membrane; its ectodomain binds and presents the cytokine. The binding activity is captured by TGF-beta binding and receptor ligand inhibitor activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: FB:FBgn0034476 SUPPORTS SOURCE BUT NOT TARGET Drosophila LRR node annotated as signaling receptor; GARP is a docking/presentation molecule, not a signal transducer. Supporting Evidence: PMID:19750484 latent TGF-beta, i.e. both LAP and mature TGF-beta, binds to glycoprotein A repetitions predominant (GARP), a transmembrane protein containing leucine rich repeats, which is present on the surface of stimulated Treg clones but not on Th clones. |
| GO:0050431 transforming growth factor beta binding | IBA GO_REF:0000033 | ACCEPT | Summary: GARP binds latent TGF-beta (proTGFB1) directly, via disulfide bonds to the LAP prodomain. Reason: Direct binding of GARP to latent TGF-beta1 is shown by co-immunoprecipitation, direct binding of recombinant latent TGF-beta1, and mapping of disulfide links (Cys192/Cys331) to the TGFB1 prodomain; this is the core molecular interaction. Supporting Evidence: PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. PMID:22278742 We find that Cys-192 and Cys-331 of GARP disulfide link to the TGFฮฒ1 prodomain |
| GO:0050431 transforming growth factor beta binding | IDA PMID:22278742 GARP regulates the bioavailability and activation of TGFฮฒ. | ACCEPT | Summary: GARP binds latent TGF-beta (proTGFB1) directly, via disulfide bonds to the LAP prodomain. Reason: Direct binding of GARP to latent TGF-beta1 is shown by co-immunoprecipitation, direct binding of recombinant latent TGF-beta1, and mapping of disulfide links (Cys192/Cys331) to the TGFB1 prodomain; this is the core molecular interaction. Supporting Evidence: PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. PMID:22278742 We find that Cys-192 and Cys-331 of GARP disulfide link to the TGFฮฒ1 prodomain |
| GO:0050431 transforming growth factor beta binding | IEA GO_REF:0000120 | ACCEPT | Summary: GARP binds latent TGF-beta (proTGFB1) directly, via disulfide bonds to the LAP prodomain. Reason: Direct binding of GARP to latent TGF-beta1 is shown by co-immunoprecipitation, direct binding of recombinant latent TGF-beta1, and mapping of disulfide links (Cys192/Cys331) to the TGFB1 prodomain; this is the core molecular interaction. Supporting Evidence: PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. PMID:22278742 We find that Cys-192 and Cys-331 of GARP disulfide link to the TGFฮฒ1 prodomain |
| GO:0050431 transforming growth factor beta binding | IPI PMID:19651619 GARP (LRRC32) is essential for the surface expression of lat... | ACCEPT | Summary: GARP binds latent TGF-beta (proTGFB1) directly, via disulfide bonds to the LAP prodomain. Reason: Direct binding of GARP to latent TGF-beta1 is shown by co-immunoprecipitation, direct binding of recombinant latent TGF-beta1, and mapping of disulfide links (Cys192/Cys331) to the TGFB1 prodomain; this is the core molecular interaction. Supporting Evidence: PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. PMID:22278742 We find that Cys-192 and Cys-331 of GARP disulfide link to the TGFฮฒ1 prodomain |
| GO:0050431 transforming growth factor beta binding | IPI PMID:19651619 GARP (LRRC32) is essential for the surface expression of lat... | ACCEPT | Summary: GARP binds latent TGF-beta (proTGFB1) directly, via disulfide bonds to the LAP prodomain. Reason: Direct binding of GARP to latent TGF-beta1 is shown by co-immunoprecipitation, direct binding of recombinant latent TGF-beta1, and mapping of disulfide links (Cys192/Cys331) to the TGFB1 prodomain; this is the core molecular interaction. Supporting Evidence: PMID:19651619 The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. PMID:22278742 We find that Cys-192 and Cys-331 of GARP disulfide link to the TGFฮฒ1 prodomain |
| GO:0062009 secondary palate development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse Garp is required for TGF-beta3 activation during palate fusion. Reason: The palate role is an organismal consequence of GARP-mediated TGF-beta3 activation, transferred from the mouse ortholog; downstream of its presentation function. Supporting Evidence: file:human/LRRC32/LRRC32-uniprot.txt Required for epithelial fusion during palate development by regulating activation of TGF-beta-3 (TGFB3) |
| GO:0062009 secondary palate development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse Garp is required for TGF-beta3 activation during palate fusion. Reason: The palate role is an organismal consequence of GARP-mediated TGF-beta3 activation, transferred from the mouse ortholog; downstream of its presentation function. Supporting Evidence: file:human/LRRC32/LRRC32-uniprot.txt Required for epithelial fusion during palate development by regulating activation of TGF-beta-3 (TGFB3) |
| GO:0141069 receptor ligand inhibitor activity | IDA PMID:22278742 GARP regulates the bioavailability and activation of TGFฮฒ. | ACCEPT | Summary: GARP binds latent TGF-beta and keeps it in the inactive, latent state. Reason: GARP associates with proTGFB1 and prevents secretion of active TGF-beta, holding the ligand latent until integrin-mediated activation; this fits receptor ligand inhibitor activity (binding and decreasing the activity of a receptor ligand). Supporting Evidence: PMID:22278742 Association between GARP and proTGFฮฒ1 prevents the secretion of TGFฮฒ1. PMID:22278742 Noncovalent association is sufficiently strong for GARP to outcompete latent TGFฮฒ-binding protein for binding to proTGFฮฒ1. |
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Experiment: Test integrin alphaVbeta8-dependent activation of TGF-beta from purified GARP:proTGFB1 complexes with disulfide and membrane-anchoring mutants.
Type: reconstituted activation assay
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