TGOLN2 encodes TGN46 (with splice variants TGN48 and TGN51), a heavily glycosylated single-pass type I membrane glycoprotein whose large mucin-like lumenal domain contains 14 tandem 14-residue repeats and whose short cytosolic tail carries a YQRL tyrosine-based sorting motif. It is the human ortholog of rodent TGN38 and resides mainly in the trans-Golgi network, from which it constitutively cycles to the plasma membrane and returns via endosomes; return depends on the cytosolic tyrosine motif. TGN46 leaves the TGN in CARTS, protein kinase D-dependent carriers to the cell surface, and is required for efficient sorting and secretion of the soluble CARTS cargo PAUF (ZG16B), a sorting activity encoded in its lumenal domain. It is widely used as a TGN marker. Lumenal residues are phosphorylated by the secretory kinase FAM20C.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote... | REMOVE | Summary: High-throughput interaction (SH3 peptide-array screen with NCK1) reported for TGOLN2 (UniProtKB:P16333). Reason: Bare protein binding is uninformative and the interaction comes from a large-scale screen with no follow-up linking it to TGN46 trafficking or sorting function. Removal follows the generic protein-binding policy and does not imply that the reported interaction is false; no more informative molecular function can be derived from this evidence. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction (proteome-scale yeast two-hybrid with KRTAP10-9) reported for TGOLN2 (UniProtKB:P60411). Reason: Bare protein binding is uninformative and the interaction comes from a large-scale screen with no follow-up linking it to TGN46 trafficking or sorting function. Removal follows the generic protein-binding policy and does not imply that the reported interaction is false; no more informative molecular function can be derived from this evidence. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8952289 | REMOVE | Summary: Reactome places TGOLN2 in the ER lumen as a substrate of the FAM20C luminal kinase reaction. Reason: TGN46 is a single-pass type I membrane protein (signal peptide, lumenal domain 22-381, TM helix 382-402) whose steady-state location is the TGN, from which it cycles to the cell surface (PMID:8907712, PMID:9084986). Its lumenal Ser/Thr residues are FAM20C substrates (UniProt MOD_RES), but an integral membrane protein is not a soluble component of the ER lumen; the location is an artifact of the compartment chosen for the generic Reactome FAM20C substrate reaction, and there is no evidence of ER retention. Supporting Evidence: file:human/TGOLN2/TGOLN2-uniprot.txt Cell membrane; Single-pass type I membrane PMID:8907712 TGN but is present on the cell surface and returns via endosomes |
| GO:0005794 Golgi apparatus | IDA GO_REF:0000052 | MODIFY | Summary: Human Protein Atlas immunofluorescence localizing TGOLN2 to the Golgi apparatus. Reason: TGN46 is a resident of the trans-Golgi network rather than the Golgi stack: quantitative immuno-EM in HeLa cells places most TGN46 in TGN tubules with little overlap with the stack enzyme GalT (PMID:9084986). The broad Golgi apparatus term is correct but less specific than the evidence supports, so it is refined to trans-Golgi network (GO:0005802), a part_of descendant that this gene already carries by IDA and IBA. Proposed replacements: trans-Golgi network Supporting Evidence: PMID:9084986 was in the Golgi stack, whereas 80% of TGN46 was detected in tubules |
| GO:0005794 Golgi apparatus | IDA PMID:22797923 ZNRF2 is released from membranes by growth factors and, toge... | MODIFY | Summary: Golgi localization from the ZNRF2 study, in which TGN46 serves as a Golgi/TGN marker. Reason: TGN46 is a resident of the trans-Golgi network rather than the Golgi stack: quantitative immuno-EM in HeLa cells places most TGN46 in TGN tubules with little overlap with the stack enzyme GalT (PMID:9084986). The broad Golgi apparatus term is correct but less specific than the evidence supports, so it is refined to trans-Golgi network (GO:0005802), a part_of descendant that this gene already carries by IDA and IBA. Proposed replacements: trans-Golgi network Supporting Evidence: PMID:9084986 was in the Golgi stack, whereas 80% of TGN46 was detected in tubules PMID:8907712 TGN but is present on the cell surface and returns via endosomes |
| GO:0005794 Golgi apparatus | IDA PMID:27435297 Regulation of post-Golgi LH3 trafficking is essential for co... | MODIFY | Summary: TGN46 used as the TGN marker for LH3/VIPAR colocalization in human skin fibroblasts. Reason: TGN46 is a resident of the trans-Golgi network rather than the Golgi stack: quantitative immuno-EM in HeLa cells places most TGN46 in TGN tubules with little overlap with the stack enzyme GalT (PMID:9084986). The broad Golgi apparatus term is correct but less specific than the evidence supports, so it is refined to trans-Golgi network (GO:0005802), a part_of descendant that this gene already carries by IDA and IBA. Proposed replacements: trans-Golgi network Supporting Evidence: PMID:27435297 the trans-Golgi network (TGN) protein TGN46 PMID:9084986 was in the Golgi stack, whereas 80% of TGN46 was detected in tubules |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | MODIFY | Summary: UniProt subcellular-location mapping (SL-0132 Golgi apparatus) to Golgi apparatus. Reason: TGN46 is a resident of the trans-Golgi network rather than the Golgi stack: quantitative immuno-EM in HeLa cells places most TGN46 in TGN tubules with little overlap with the stack enzyme GalT (PMID:9084986). The broad Golgi apparatus term is correct but less specific than the evidence supports, so it is refined to trans-Golgi network (GO:0005802), a part_of descendant that this gene already carries by IDA and IBA. Proposed replacements: trans-Golgi network Supporting Evidence: PMID:9084986 was in the Golgi stack, whereas 80% of TGN46 was detected in tubules |
| GO:0005802 trans-Golgi network | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT propagation of trans-Golgi network from node PTN000575073, seeded by experimental TGN annotations of mouse Tgoln1/Tgoln2, rat TGN38 and human TGOLN2 itself. Reason: TGN residence is the defining, experimentally established property of TGN46 and its rodent orthologs, which lie in the same subfamily (PTHR23211:SF0). Human TGOLN2 appears among the IBD seeds because of its own experimental annotation; the IBA adds that the location is inherited within the clade. Core location. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:9084986 was in the Golgi stack, whereas 80% of TGN46 was detected in tubules |
| GO:0005802 trans-Golgi network | IDA PMID:18166528 SLC24A5 encodes a trans-Golgi network protein with potassium... | ACCEPT | Summary: TGN46 was used as the TGN marker for colocalization with NCKX5/SLC24A5 in human melanocytes. Reason: The cached record is abstract-only and the abstract concerns SLC24A5; the curator will have read the figure in which TGN46 marks the TGN. TGN residence of TGN46 is independently well established (PMID:8907712, PMID:9084986), so the annotation is accepted, deferring to the curator. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:9084986 was in the Golgi stack, whereas 80% of TGN46 was detected in tubules |
| GO:0005802 trans-Golgi network | IDA PMID:22456507 Dynamic and transient interactions of Atg9 with autophagosom... | ACCEPT | Summary: TGN46 is used as the TGN marker in gradient fractionation and immunofluorescence of HEK293 cells in this Atg9 study. Reason: The full text uses TGN46 explicitly as the TGN marker and positive control for TGN colocalization. TGN residence is the defining, best-established property of TGN46, supported also by dedicated human studies (PMID:8907712, PMID:9084986). Supporting Evidence: PMID:22456507 TGN46 (TGN) PMID:8907712 TGN but is present on the cell surface and returns via endosomes |
| GO:0005802 trans-Golgi network | IDA PMID:23386608 Dynamics of the rhomboid-like protein RHBDD2 expression in m... | ACCEPT | Summary: Anti-TGN38 antibody is used as a trans-Golgi marker in HEK293 cells in this RHBDD2 study. Reason: In human HEK293 cells the anti-TGN38 antibody detects the human ortholog TGN46, used as a trans-Golgi marker. The marker use supports the location, which is independently established for human TGN46 (PMID:8907712). Supporting Evidence: PMID:23386608 anti-TGN38, a trans -Golgi marker protein PMID:8907712 TGN but is present on the cell surface and returns via endosomes |
| GO:0005802 trans-Golgi network | TAS PMID:9422759 Molecular cloning and expression of a novel human trans-Golg... | ACCEPT | Summary: The original cloning paper of hTGN46/48/51 shows TGN localization of the isoforms expressed in CHO cells and its dependence on tail tyrosine motifs. Reason: TAS from the primary characterization paper. The abstract states that hTGN51 localizes to the TGN, and that tyrosine motif mutants of hTGN46/hTGN48 are no longer retrieved to the TGN, i.e. TGN localization is experimentally shown and signal dependent. Supporting Evidence: PMID:9422759 mutated hTGN48 and hTGN46 are no longer retrieved PMID:8907712 TGN but is present on the cell surface and returns via endosomes |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping (SL-0039 cell membrane) to plasma membrane. Reason: Human TGN46 is present on the cell surface and returns to the TGN via endosomes (PMID:8907712), and it exits the TGN in CARTS bound for the plasma membrane (PMID:38466628). The plasma membrane is a genuine but transient station of its cycling itinerary rather than its steady-state functional compartment, so it is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:38466628 TGN38/TGN46 rapidly cycles between the TGN and the plasma membrane (PM), exiting the TGN in specific carriers called CARTS |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8866277 | KEEP AS NON CORE | Summary: Reactome clathrin-mediated endocytosis reaction (Reactome:R-HSA-8866277) in which TGOLN2 is a cargo at the plasma membrane. Reason: Human TGN46 is present on the cell surface and returns to the TGN via endosomes (PMID:8907712), and it exits the TGN in CARTS bound for the plasma membrane (PMID:38466628). The plasma membrane is a genuine but transient station of its cycling itinerary rather than its steady-state functional compartment, so it is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:38466628 TGN38/TGN46 rapidly cycles between the TGN and the plasma membrane (PM), exiting the TGN in specific carriers called CARTS |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8867754 | KEEP AS NON CORE | Summary: Reactome clathrin-mediated endocytosis reaction (Reactome:R-HSA-8867754) in which TGOLN2 is a cargo at the plasma membrane. Reason: Human TGN46 is present on the cell surface and returns to the TGN via endosomes (PMID:8907712), and it exits the TGN in CARTS bound for the plasma membrane (PMID:38466628). The plasma membrane is a genuine but transient station of its cycling itinerary rather than its steady-state functional compartment, so it is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:38466628 TGN38/TGN46 rapidly cycles between the TGN and the plasma membrane (PM), exiting the TGN in specific carriers called CARTS |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8867756 | KEEP AS NON CORE | Summary: Reactome clathrin-mediated endocytosis reaction (Reactome:R-HSA-8867756) in which TGOLN2 is a cargo at the plasma membrane. Reason: Human TGN46 is present on the cell surface and returns to the TGN via endosomes (PMID:8907712), and it exits the TGN in CARTS bound for the plasma membrane (PMID:38466628). The plasma membrane is a genuine but transient station of its cycling itinerary rather than its steady-state functional compartment, so it is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:38466628 TGN38/TGN46 rapidly cycles between the TGN and the plasma membrane (PM), exiting the TGN in specific carriers called CARTS |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868071 | KEEP AS NON CORE | Summary: Reactome clathrin-mediated endocytosis reaction (Reactome:R-HSA-8868071) in which TGOLN2 is a cargo at the plasma membrane. Reason: Human TGN46 is present on the cell surface and returns to the TGN via endosomes (PMID:8907712), and it exits the TGN in CARTS bound for the plasma membrane (PMID:38466628). The plasma membrane is a genuine but transient station of its cycling itinerary rather than its steady-state functional compartment, so it is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:38466628 TGN38/TGN46 rapidly cycles between the TGN and the plasma membrane (PM), exiting the TGN in specific carriers called CARTS |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868072 | KEEP AS NON CORE | Summary: Reactome clathrin-mediated endocytosis reaction (Reactome:R-HSA-8868072) in which TGOLN2 is a cargo at the plasma membrane. Reason: Human TGN46 is present on the cell surface and returns to the TGN via endosomes (PMID:8907712), and it exits the TGN in CARTS bound for the plasma membrane (PMID:38466628). The plasma membrane is a genuine but transient station of its cycling itinerary rather than its steady-state functional compartment, so it is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:38466628 TGN38/TGN46 rapidly cycles between the TGN and the plasma membrane (PM), exiting the TGN in specific carriers called CARTS |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868230 | KEEP AS NON CORE | Summary: Reactome clathrin-mediated endocytosis reaction (Reactome:R-HSA-8868230) in which TGOLN2 is a cargo at the plasma membrane. Reason: Human TGN46 is present on the cell surface and returns to the TGN via endosomes (PMID:8907712), and it exits the TGN in CARTS bound for the plasma membrane (PMID:38466628). The plasma membrane is a genuine but transient station of its cycling itinerary rather than its steady-state functional compartment, so it is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:38466628 TGN38/TGN46 rapidly cycles between the TGN and the plasma membrane (PM), exiting the TGN in specific carriers called CARTS |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868236 | KEEP AS NON CORE | Summary: Reactome clathrin-mediated endocytosis reaction (Reactome:R-HSA-8868236) in which TGOLN2 is a cargo at the plasma membrane. Reason: Human TGN46 is present on the cell surface and returns to the TGN via endosomes (PMID:8907712), and it exits the TGN in CARTS bound for the plasma membrane (PMID:38466628). The plasma membrane is a genuine but transient station of its cycling itinerary rather than its steady-state functional compartment, so it is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:38466628 TGN38/TGN46 rapidly cycles between the TGN and the plasma membrane (PM), exiting the TGN in specific carriers called CARTS |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868648 | KEEP AS NON CORE | Summary: Reactome clathrin-mediated endocytosis reaction (Reactome:R-HSA-8868648) in which TGOLN2 is a cargo at the plasma membrane. Reason: Human TGN46 is present on the cell surface and returns to the TGN via endosomes (PMID:8907712), and it exits the TGN in CARTS bound for the plasma membrane (PMID:38466628). The plasma membrane is a genuine but transient station of its cycling itinerary rather than its steady-state functional compartment, so it is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:38466628 TGN38/TGN46 rapidly cycles between the TGN and the plasma membrane (PM), exiting the TGN in specific carriers called CARTS |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868651 | KEEP AS NON CORE | Summary: Reactome clathrin-mediated endocytosis reaction (Reactome:R-HSA-8868651) in which TGOLN2 is a cargo at the plasma membrane. Reason: Human TGN46 is present on the cell surface and returns to the TGN via endosomes (PMID:8907712), and it exits the TGN in CARTS bound for the plasma membrane (PMID:38466628). The plasma membrane is a genuine but transient station of its cycling itinerary rather than its steady-state functional compartment, so it is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:38466628 TGN38/TGN46 rapidly cycles between the TGN and the plasma membrane (PM), exiting the TGN in specific carriers called CARTS |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868661 | KEEP AS NON CORE | Summary: Reactome clathrin-mediated endocytosis reaction (Reactome:R-HSA-8868661) in which TGOLN2 is a cargo at the plasma membrane. Reason: Human TGN46 is present on the cell surface and returns to the TGN via endosomes (PMID:8907712), and it exits the TGN in CARTS bound for the plasma membrane (PMID:38466628). The plasma membrane is a genuine but transient station of its cycling itinerary rather than its steady-state functional compartment, so it is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:38466628 TGN38/TGN46 rapidly cycles between the TGN and the plasma membrane (PM), exiting the TGN in specific carriers called CARTS |
| GO:0030133 transport vesicle | TAS PMID:9422759 Molecular cloning and expression of a novel human trans-Golg... | MODIFY | Summary: TAS from the cloning paper that TGN46/51 shuttle between the TGN and the cell surface in transport vesicles. Reason: TGN46 leaves the TGN in a specific class of TGN-derived transport carriers (CARTS) (PMID:38466628). The general term transport vesicle is correct but the evidence supports the is_a descendant trans-Golgi network transport vesicle (GO:0030140), which the gene already carries by IBA. Proposed replacements: trans-Golgi network transport vesicle Supporting Evidence: PMID:38466628 TGN38/TGN46 rapidly cycles between the TGN and the plasma membrane (PM), exiting the TGN in specific carriers called CARTS |
| GO:0030140 trans-Golgi network transport vesicle | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT propagation of trans-Golgi network transport vesicle from PTN000575073, seeded by mouse Tgoln1. Reason: Human TGN46 is directly shown to exit the TGN in CARTS, a PKD-dependent class of TGN-to-plasma-membrane carriers that were originally isolated as TGN46-containing carriers (PMID:38466628). The IBA is consistent with this human evidence. Supporting Evidence: PMID:38466628 TGN38/TGN46 rapidly cycles between the TGN and the plasma membrane (PM), exiting the TGN in specific carriers called CARTS |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868658 | KEEP AS NON CORE | Summary: Reactome clathrin-coated vesicle reaction (Reactome:R-HSA-8868658) that includes TGOLN2 among AP-2-bound endocytic cargo. Reason: TGN46 returns from the cell surface via endosomes (PMID:8907712) and carries a C-terminal YQRL tyrosine motif whose mutation abolishes retrieval to the TGN (PMID:9422759); the equivalent motif of rat TGN38 binds the AP-2 mu2 subunit (PMID:9794796). Internalization in AP-2/clathrin-coated vesicles is therefore well grounded, but the vesicle is a transient compartment for TGN46 as cargo, so the term is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:9422759 mutated hTGN48 and hTGN46 are no longer retrieved Reactome:R-HSA-8866277 AP-2 also contributes to cargo recognition and recruitment through direct binding of tyrosine- and dileucine-based sorting motifs in the cytoplasmic tails of cargo |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868659 | KEEP AS NON CORE | Summary: Reactome clathrin-coated vesicle reaction (Reactome:R-HSA-8868659) that includes TGOLN2 among AP-2-bound endocytic cargo. Reason: TGN46 returns from the cell surface via endosomes (PMID:8907712) and carries a C-terminal YQRL tyrosine motif whose mutation abolishes retrieval to the TGN (PMID:9422759); the equivalent motif of rat TGN38 binds the AP-2 mu2 subunit (PMID:9794796). Internalization in AP-2/clathrin-coated vesicles is therefore well grounded, but the vesicle is a transient compartment for TGN46 as cargo, so the term is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:9422759 mutated hTGN48 and hTGN46 are no longer retrieved Reactome:R-HSA-8866277 AP-2 also contributes to cargo recognition and recruitment through direct binding of tyrosine- and dileucine-based sorting motifs in the cytoplasmic tails of cargo |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868660 | KEEP AS NON CORE | Summary: Reactome clathrin-coated vesicle reaction (Reactome:R-HSA-8868660) that includes TGOLN2 among AP-2-bound endocytic cargo. Reason: TGN46 returns from the cell surface via endosomes (PMID:8907712) and carries a C-terminal YQRL tyrosine motif whose mutation abolishes retrieval to the TGN (PMID:9422759); the equivalent motif of rat TGN38 binds the AP-2 mu2 subunit (PMID:9794796). Internalization in AP-2/clathrin-coated vesicles is therefore well grounded, but the vesicle is a transient compartment for TGN46 as cargo, so the term is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:9422759 mutated hTGN48 and hTGN46 are no longer retrieved Reactome:R-HSA-8866277 AP-2 also contributes to cargo recognition and recruitment through direct binding of tyrosine- and dileucine-based sorting motifs in the cytoplasmic tails of cargo |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868661 | KEEP AS NON CORE | Summary: Reactome clathrin-coated vesicle reaction (Reactome:R-HSA-8868661) that includes TGOLN2 among AP-2-bound endocytic cargo. Reason: TGN46 returns from the cell surface via endosomes (PMID:8907712) and carries a C-terminal YQRL tyrosine motif whose mutation abolishes retrieval to the TGN (PMID:9422759); the equivalent motif of rat TGN38 binds the AP-2 mu2 subunit (PMID:9794796). Internalization in AP-2/clathrin-coated vesicles is therefore well grounded, but the vesicle is a transient compartment for TGN46 as cargo, so the term is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:9422759 mutated hTGN48 and hTGN46 are no longer retrieved Reactome:R-HSA-8866277 AP-2 also contributes to cargo recognition and recruitment through direct binding of tyrosine- and dileucine-based sorting motifs in the cytoplasmic tails of cargo |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8869438 | KEEP AS NON CORE | Summary: Reactome clathrin-coated vesicle reaction (Reactome:R-HSA-8869438) that includes TGOLN2 among AP-2-bound endocytic cargo. Reason: TGN46 returns from the cell surface via endosomes (PMID:8907712) and carries a C-terminal YQRL tyrosine motif whose mutation abolishes retrieval to the TGN (PMID:9422759); the equivalent motif of rat TGN38 binds the AP-2 mu2 subunit (PMID:9794796). Internalization in AP-2/clathrin-coated vesicles is therefore well grounded, but the vesicle is a transient compartment for TGN46 as cargo, so the term is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:9422759 mutated hTGN48 and hTGN46 are no longer retrieved Reactome:R-HSA-8866277 AP-2 also contributes to cargo recognition and recruitment through direct binding of tyrosine- and dileucine-based sorting motifs in the cytoplasmic tails of cargo |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8871193 | KEEP AS NON CORE | Summary: Reactome clathrin-coated vesicle reaction (Reactome:R-HSA-8871193) that includes TGOLN2 among AP-2-bound endocytic cargo. Reason: TGN46 returns from the cell surface via endosomes (PMID:8907712) and carries a C-terminal YQRL tyrosine motif whose mutation abolishes retrieval to the TGN (PMID:9422759); the equivalent motif of rat TGN38 binds the AP-2 mu2 subunit (PMID:9794796). Internalization in AP-2/clathrin-coated vesicles is therefore well grounded, but the vesicle is a transient compartment for TGN46 as cargo, so the term is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:9422759 mutated hTGN48 and hTGN46 are no longer retrieved Reactome:R-HSA-8866277 AP-2 also contributes to cargo recognition and recruitment through direct binding of tyrosine- and dileucine-based sorting motifs in the cytoplasmic tails of cargo |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8871194 | KEEP AS NON CORE | Summary: Reactome clathrin-coated vesicle reaction (Reactome:R-HSA-8871194) that includes TGOLN2 among AP-2-bound endocytic cargo. Reason: TGN46 returns from the cell surface via endosomes (PMID:8907712) and carries a C-terminal YQRL tyrosine motif whose mutation abolishes retrieval to the TGN (PMID:9422759); the equivalent motif of rat TGN38 binds the AP-2 mu2 subunit (PMID:9794796). Internalization in AP-2/clathrin-coated vesicles is therefore well grounded, but the vesicle is a transient compartment for TGN46 as cargo, so the term is kept as non-core. Supporting Evidence: PMID:8907712 TGN but is present on the cell surface and returns via endosomes PMID:9422759 mutated hTGN48 and hTGN46 are no longer retrieved Reactome:R-HSA-8866277 AP-2 also contributes to cargo recognition and recruitment through direct binding of tyrosine- and dileucine-based sorting motifs in the cytoplasmic tails of cargo |
| GO:0043001 Golgi to plasma membrane protein transport | IMP PMID:38466628 Sorting of secretory proteins at the trans-Golgi network by ... | NEW | Summary: TGN46 knockout in HeLa cells strongly reduces secretion of the CARTS cargo PAUF and its packaging into CARTS, and the TGN46 lumenal domain is necessary and sufficient to sort membrane proteins into CARTS. Reason: Human loss-of-function plus domain-mapping evidence (PMID:38466628). This passes the participation test: TGN46 is not merely transported by the pathway; its lumenal domain performs the cargo-sorting step that loads PAUF into TGN-to-PM carriers (sorting module, as for cargo receptors such as LMAN1 in ER export). The authors note that whether TGN46 also participates in carrier biogenesis is unknown, so no carrier-formation term is proposed, and no cargo receptor molecular-function term is proposed because direct TGN46-cargo binding was not demonstrated. PAINT propagated no process term from PTN000575073; this annotation rests on human data and should not be transferred to divergent family members such as fly rgn. Supporting Evidence: PMID:38466628 In TGN46-KO cells, PAUF-MycHis secretion was reduced by ~75% as compared to control cells PMID:38466628 signals encoded in the lumenal domain of TGN46 are not only necessary, but also sufficient for cargo sorting into CARTS |
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Download this section (compressed HTML)Q: Does the TGN46 lumenal domain bind PAUF (or other CARTS cargoes) directly, e.g. through its O- and N-glycans, so that 'cargo receptor activity' would be justified?
Q: Is TGN46 an active component of CARTS biogenesis or a sorting cargo that rides in the carrier?
Q: Do the TGN48 and TGN51 isoforms, with extra tyrosine motifs and distinct retrieval behaviour, differ in sorting function?
Q: Should a PAINT curator propagate any process term from PTN000575073 given that the node is placed at taxon:2759 and includes divergent members such as fly rgn that lack the TM segment and YQRL motif?
Experiment: In vitro binding (pull-down, SPR or microscale thermophoresis) of purified, glycosylated TGN46 lumenal domain with PAUF, with and without deglycosylation.
Experiment: Rescue of PAUF secretion in TGN46-KO HeLa cells with isoform-specific TGN46, TGN48 and TGN51 constructs and lumenal repeat deletions.
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