sup-17 encodes the C. elegans ortholog of ADAM10 (Drosophila Kuzbanian), a single-pass type I transmembrane zinc metalloprotease of the ADAM (disintegrin and metalloproteinase) family with a reprolysin-type catalytic domain, disintegrin domain and ADAM10-type cysteine-rich domain. SUP-17 acts cell autonomously in signal-receiving cells to facilitate LIN-12 and GLP-1 Notch signaling, dependent on the receptor extracellular domain, consistent with its role as the site-2 (S2) protease that sheds the Notch ectodomain after ligand binding and generates the substrate for gamma-secretase; this function is partially redundant with the TACE/ADAM17 ortholog ADM-4. It localizes to the (basolateral) plasma membrane and intracellular vesicles, and its surface delivery is promoted by the TspanC8-type tetraspanins TSP-12 and TSP-14. Beyond Notch, SUP-17 sheds other membrane proteins, promoting BMP-like Sma/Mab signaling (in part via UNC-40/DCC) and SDQL axon guidance (via ephrin EFN-4). Null mutants are lethal.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001708 cell fate specification | IGI PMID:16197940 Evidence for functional redundancy between C. elegans ADAM p... | KEEP AS NON CORE | Summary: Concomitant reduction of sup-17 and adm-4 gives two anchor cells, a lin-12 loss-of-function cell fate defect. Reason: SUP-17 contributes to LIN-12-mediated cell fate decisions by processing the receptor (S2 ectodomain shedding), redundantly with ADM-4/TACE. The cell fate outcome is a downstream consequence of its protease function; kept as non-core. Supporting Evidence: PMID:16197940 Furthermore, concomitant reduction of adm-4 and sup-17 activity causes the production of two anchor cells in the hermaphrodite gonad, instead of one--a phenotype associated with loss of lin-12 activity. PMID:16197940 Our results are consistent with the possibility that sup-17 and adm-4 are functionally redundant for at least a subset of LIN-12/Notch-mediated decisions in C. elegans. |
| GO:0004222 metalloendopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT node PTN005236519 (ADAM10/ADAM17 metallopeptidase family) asserts metalloendopeptidase activity, grounded in human, mouse, rat and fly ADAM10/17 experimental data. Reason: SUP-17 is the worm ADAM10/Kuzbanian ortholog with an intact Peptidase M12B (reprolysin) domain including the zinc-binding HExxHxxGxxH motif (UniProt active site and zinc-binding residues). No evidence of loss of catalytic function; the IBA is well placed. Core MF. Supporting Evidence: PMID:9428412 Here, we show that sup-17 encodes a member of the ADAM family of metalloproteases. PMID:9428412 SUP-17 is highly similar to Drosophila KUZBANIAN, which functions in Drosophila neurogenesis, and the vertebrate ADAM10 protein. PMID:16197940 In Caenorhabditis elegans, genetic evidence has implicated SUP-17, the ortholog of Drosophila Kuzbanian and mammalian ADAM10, as the protease that mediates this event. |
| GO:0004222 metalloendopeptidase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro Peptidase_M12B mapping. Reason: Correct; consistent with the IBA and domain architecture. Supporting Evidence: PMID:9428412 Here, we show that sup-17 encodes a member of the ADAM family of metalloproteases. |
| GO:0005515 protein binding | IPI PMID:28068334 Two Paralogous Tetraspanins TSP-12 and TSP-14 Function with ... | REMOVE | Summary: SUP-17 co-immunoprecipitates with the tetraspanins TSP-12 and TSP-14, and TSP-12 promotes SUP-17 cell surface localization. Reason: Generic protein binding is uninformative. The interaction itself is real (and is the worm counterpart of the TspanC8-ADAM10 partnership), but no more specific MF term is appropriate from this evidence; the functional consequence is captured by the plasma membrane localization annotations. Removal does not imply the interaction is false. Supporting Evidence: PMID:28068334 TSP-12 and TSP-14 can bind to SUP-17. PMID:28068334 We further show that the ADAM10 (a disintegrin and metalloprotease 10) ortholog SUP-17 also functions to promote BMP signaling, and that TSP-12 can bind to and promote the cell surface localization of SUP-17. |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA prediction of cytoplasm. Reason: SUP-17 is a single-pass type I membrane protein at the plasma membrane and in intracellular vesicle puncta. 'Cytoplasm' is not strictly wrong (vesicles are in the cytoplasm) but is uninformative and misleading for a transmembrane protease; the plasma membrane and cytoplasmic vesicle membrane annotations capture its location. Supporting Evidence: PMID:28068334 Also like TSP-12, SUP-17::GFP is localized both at the cell surface and in the cytoplasm in small puncta (Fig 4B, 4D, 4F and 4H). |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT PTN005236519 plasma membrane localization for ADAM10/17 family. Reason: Consistent with direct observation of SUP-17::GFP at the cell surface. Supporting Evidence: PMID:28068334 Also like TSP-12, SUP-17::GFP is localized both at the cell surface and in the cytoplasm in small puncta (Fig 4B, 4D, 4F and 4H). |
| GO:0005886 plasma membrane | IDA PMID:28068334 Two Paralogous Tetraspanins TSP-12 and TSP-14 Function with ... | ACCEPT | Summary: Functional SUP-17::GFP localizes to the cell surface, dependent on TSP-12. Reason: Direct evidence; plasma membrane is where S2 cleavage of Notch occurs. Supporting Evidence: PMID:28068334 Also like TSP-12, SUP-17::GFP is localized both at the cell surface and in the cytoplasm in small puncta (Fig 4B, 4D, 4F and 4H). PMID:28068334 We further show that the ADAM10 (a disintegrin and metalloprotease 10) ortholog SUP-17 also functions to promote BMP signaling, and that TSP-12 can bind to and promote the cell surface localization of SUP-17. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated mapping to plasma membrane. Reason: Correct. Supporting Evidence: PMID:28068334 Also like TSP-12, SUP-17::GFP is localized both at the cell surface and in the cytoplasm in small puncta (Fig 4B, 4D, 4F and 4H). |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro mapping to proteolysis. Reason: Correct but general; membrane protein ectodomain proteolysis (GO:0006509) is the informative term. Supporting Evidence: PMID:9428412 Here, we show that sup-17 encodes a member of the ADAM family of metalloproteases. |
| GO:0006509 membrane protein ectodomain proteolysis | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT PTN005236519 asserts membrane protein ectodomain proteolysis (shedding) for ADAM10/17. Reason: Worm genetic data support ectodomain shedding of LIN-12/GLP-1 (rescue by a truncated LIN-12 mimicking the shed product) and of other substrates (UNC-40, EFN-4). Core process. Supporting Evidence: PMID:16197940 Expression of a truncated form of LIN-12 that mimics the product of ectodomain shedding rescues this fertility defect, suggesting that sup-17 and adm-4 may mediate ectodomain shedding of LIN-12 and/or GLP-1. PMID:28068334 Our genetic studies suggest that the neogenin/DCC ortholog UNC-40 is one of the substrates of SUP-17. PMID:16197940 In Caenorhabditis elegans, genetic evidence has implicated SUP-17, the ortholog of Drosophila Kuzbanian and mammalian ADAM10, as the protease that mediates this event. |
| GO:0006509 membrane protein ectodomain proteolysis | ISS PMID:9428412 SUP-17, a Caenorhabditis elegans ADAM protein related to Dro... | ACCEPT | Summary: Similarity to ADAM10/Kuzbanian supports ectodomain shedding. Reason: Correct and consistent with the IBA and worm genetics. Supporting Evidence: PMID:9428412 SUP-17 is highly similar to Drosophila KUZBANIAN, which functions in Drosophila neurogenesis, and the vertebrate ADAM10 protein. PMID:9428412 Furthermore, we show by genetic analysis that the extracellular domain of LIN-12 appears to be necessary for sup-17 to facilitate lin-12 signalling and that sup-17 does not act downstream of lin-12. |
| GO:0007219 Notch signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT node PTN001374824 assigns Notch signaling pathway to the ADAM10/Kuzbanian clade (with sup-17 and adm-4 among the sources). Reason: SUP-17 facilitates LIN-12 and GLP-1 signaling cell autonomously, acting at the level of the receptor extracellular domain, consistent with S2 cleavage. The appearance of sup-17 in its own WITH/FROM reflects its experimental grounding, not circularity. Supporting Evidence: PMID:9428412 Furthermore, we show by genetic analysis that the extracellular domain of LIN-12 appears to be necessary for sup-17 to facilitate lin-12 signalling and that sup-17 does not act downstream of lin-12. PMID:9428412 Finally, we show by cell ablation experiments that sup-17 can act cell autonomously to facilitate lin-12 activity. PMID:16197940 In Caenorhabditis elegans, genetic evidence has implicated SUP-17, the ortholog of Drosophila Kuzbanian and mammalian ADAM10, as the protease that mediates this event. |
| GO:0007219 Notch signaling pathway | IGI PMID:9409830 Identification and characterization of genes that interact w... | ACCEPT | Summary: sup-17 mutations suppress lin-12 gain-of-function and enhance a glp-1 loss-of-function allele. Reason: Genetic evidence that SUP-17 acts in the LIN-12/GLP-1 pathway; its role is the S2 protease step. Supporting Evidence: PMID:9409830 Temperature-shift studies for two suppressor genes, sup-17 and lag-2, suggest that both genes act at approximately the same time as lin-12 in specifying a cell fate. |
| GO:0008237 metallopeptidase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro mapping to metallopeptidase activity. Reason: Correct; parent of the more specific metalloendopeptidase activity. Supporting Evidence: PMID:9428412 Here, we show that sup-17 encodes a member of the ADAM family of metalloproteases. |
| GO:0008237 metallopeptidase activity | ISS PMID:9428412 SUP-17, a Caenorhabditis elegans ADAM protein related to Dro... | ACCEPT | Summary: Sequence similarity to ADAM10 metalloprotease. Reason: Correct. Supporting Evidence: PMID:9428412 Here, we show that sup-17 encodes a member of the ADAM family of metalloproteases. PMID:9428412 SUP-17 is highly similar to Drosophila KUZBANIAN, which functions in Drosophila neurogenesis, and the vertebrate ADAM10 protein. |
| GO:0009792 embryo development ending in birth or egg hatching | IMP PMID:9409830 Identification and characterization of genes that interact w... | KEEP AS NON CORE | Summary: Null sup-17 mutations cause lethality. Reason: Embryonic lethality reflects SUP-17 requirement in Notch-dependent (and likely other) embryonic cell interactions; a pleiotropic consequence, kept as non-core. Supporting Evidence: PMID:9409830 The suppressor mutations in sup-17 and lag-2 were shown to be rare non-null alleles, and we present evidence that null mutations in these two genes cause lethality. |
| GO:0016323 basolateral plasma membrane | EXP PMID:28068334 Two Paralogous Tetraspanins TSP-12 and TSP-14 Function with ... | ACCEPT | Summary: Cell surface SUP-17::GFP is enriched on basolateral surfaces in early embryos. Reason: Direct observation; accepted. Supporting Evidence: PMID:28068334 In the early embryo, cell surface localized SUP-17::GFP is enriched in the basolateral, but not the apical, surfaces (Fig 4B). |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (basolateral cell membrane). Reason: Consistent with experimental data. Supporting Evidence: PMID:28068334 In the early embryo, cell surface localized SUP-17::GFP is enriched in the basolateral, but not the apical, surfaces (Fig 4B). |
| GO:0030511 positive regulation of transforming growth factor beta receptor signaling pathway | IGI PMID:28068334 Two Paralogous Tetraspanins TSP-12 and TSP-14 Function with ... | MODIFY | Summary: SUP-17 acts with TSP-12/TSP-14 and UNC-40 to promote Sma/Mab (BMP-like) signaling. Reason: The worm Sma/Mab pathway is a BMP-type pathway (DBL-1 ligand) and the authors describe SUP-17 as promoting BMP signaling; the more precise term is positive regulation of BMP signaling pathway. This is a non-core, Notch-independent function. Proposed replacements: positive regulation of BMP signaling pathway Supporting Evidence: PMID:28068334 We further show that the ADAM10 (a disintegrin and metalloprotease 10) ortholog SUP-17 also functions to promote BMP signaling, and that TSP-12 can bind to and promote the cell surface localization of SUP-17. PMID:28068334 We have evidence that the function of SUP-17, and of TSP-12/TSP-14 in BMP signaling is independent of their roles in Notch signaling. |
| GO:0030511 positive regulation of transforming growth factor beta receptor signaling pathway | IMP PMID:28068334 Two Paralogous Tetraspanins TSP-12 and TSP-14 Function with ... | MODIFY | Summary: sup-17 hypomorphs show small body size and suppress the sma-9 M lineage defect (Susm), readouts of reduced BMP signaling. Reason: As above, positive regulation of BMP signaling pathway is the more precise term. Non-core; independent of the Notch role. Proposed replacements: positive regulation of BMP signaling pathway Supporting Evidence: PMID:28068334 We further show that the ADAM10 (a disintegrin and metalloprotease 10) ortholog SUP-17 also functions to promote BMP signaling, and that TSP-12 can bind to and promote the cell surface localization of SUP-17. PMID:28068334 two strong loss-of-function alleles of sup-17, n1258 and n316, both partially suppressed the sma-9 M lineage defect |
| GO:0030659 cytoplasmic vesicle membrane | IDA PMID:28068334 Two Paralogous Tetraspanins TSP-12 and TSP-14 Function with ... | ACCEPT | Summary: SUP-17::GFP is also found in cytoplasmic puncta. Reason: Intracellular vesicle localization is consistent with trafficking of the protease to and from the surface. Supporting Evidence: PMID:28068334 Also like TSP-12, SUP-17::GFP is localized both at the cell surface and in the cytoplasm in small puncta (Fig 4B, 4D, 4F and 4H). |
| GO:0030659 cytoplasmic vesicle membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping. Reason: Consistent with experimental data. Supporting Evidence: PMID:28068334 Also like TSP-12, SUP-17::GFP is localized both at the cell surface and in the cytoplasm in small puncta (Fig 4B, 4D, 4F and 4H). |
| GO:0040025 vulval development | IGI PMID:9428412 SUP-17, a Caenorhabditis elegans ADAM protein related to Dro... | KEEP AS NON CORE | Summary: sup-17 facilitates lin-12 signaling in vulval precursor cell fate decisions. Reason: Vulval development is one downstream developmental context of SUP-17-mediated LIN-12 processing; non-core. Supporting Evidence: PMID:9428412 Furthermore, we show by genetic analysis that the extracellular domain of LIN-12 appears to be necessary for sup-17 to facilitate lin-12 signalling and that sup-17 does not act downstream of lin-12. PMID:9428412 Finally, we show by cell ablation experiments that sup-17 can act cell autonomously to facilitate lin-12 activity. |
| GO:0042661 regulation of mesodermal cell fate specification | IGI PMID:28068334 Two Paralogous Tetraspanins TSP-12 and TSP-14 Function with ... | KEEP AS NON CORE | Summary: sup-17 alleles partially suppress the sma-9 M lineage dorsoventral defect (Susm). Reason: The mesodermal fate effect reflects SUP-17 promotion of BMP signaling rather than Notch (sup-17 mutants lack lin-12-like M lineage defects). A valid but non-core developmental annotation. Supporting Evidence: PMID:28068334 two strong loss-of-function alleles of sup-17, n1258 and n316, both partially suppressed the sma-9 M lineage defect PMID:28068334 tsp-12(0), tsp-14(0), tsp-12(0); tsp-14(0) or sup-17(n1258) mutants do not exhibit any M lineage defects. |
| GO:0042661 regulation of mesodermal cell fate specification | IGI PMID:28068334 Two Paralogous Tetraspanins TSP-12 and TSP-14 Function with ... | KEEP AS NON CORE | Summary: Genetic interaction of sup-17 with sma-9 in M lineage patterning. Reason: As above; non-core, BMP-related. Supporting Evidence: PMID:28068334 two strong loss-of-function alleles of sup-17, n1258 and n316, both partially suppressed the sma-9 M lineage defect |
| GO:0043226 organelle | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA prediction of 'organelle'. Reason: Uninformative high-level location; the specific plasma membrane and vesicle membrane annotations describe SUP-17 location. Supporting Evidence: PMID:28068334 Also like TSP-12, SUP-17::GFP is localized both at the cell surface and in the cytoplasm in small puncta (Fig 4B, 4D, 4F and 4H). |
| GO:0045138 nematode male tail tip morphogenesis | IMP PMID:28068334 Two Paralogous Tetraspanins TSP-12 and TSP-14 Function with ... | KEEP AS NON CORE | Summary: sup-17(n1258) males have abnormal tails. Reason: Male tail morphogenesis is a BMP (Sma/Mab)-dependent developmental readout; non-core. Supporting Evidence: PMID:28068334 showing the smaller body size (C) and abnormal male tail (E) of sup-17(n1258) worms. |
| GO:1902667 regulation of axon guidance | IMP PMID:26903502 EFN-4 functions in LAD-2-mediated axon guidance in Caenorhab... | KEEP AS NON CORE | Summary: sup-17 mutants show SDQL axon pathfinding defects rescued by a soluble (GPI-less) EFN-4, suggesting SUP-17 sheds EFN-4. Reason: Axon guidance is supported as a context in which SUP-17 ectodomain shedding (of EFN-4) matters; non-core relative to its protease function. Supporting Evidence: PMID:26903502 We examined viable, maternally rescued sup-17 null and hypomorphic animals and identified modest but significant levels of SDQL axon pathfinding defects PMID:26903502 Indeed, SDQL-specific expression of EFN-4ΞGPI but not full-length EFN-4 rescued abnormal SDQL defects in sup-17 hypomorphic animals. |
| GO:0007220 Notch receptor processing | IGI PMID:16197940 Evidence for functional redundancy between C. elegans ADAM p... | NEW | Summary: SUP-17 (with ADM-4) is implicated as the protease for site-2 ectodomain shedding of LIN-12/GLP-1: the sup-17; adm-4 sterility is rescued by a truncated LIN-12 mimicking the shed product, and sup-17 requires the LIN-12 extracellular domain to facilitate signaling. Reason: SUP-17 is proposed to catalyse a step of Notch receptor processing (the S2 cleavage), so it passes the participation test as the enzyme, not the substrate. Comparator: mammalian ADAM10 (Adam10, NAS) and presenilins (PSEN1, IDA) carry this term. Evidence in worm is genetic and by orthology; no biochemical detection of the cleavage product in C. elegans. Supporting Evidence: PMID:16197940 Expression of a truncated form of LIN-12 that mimics the product of ectodomain shedding rescues this fertility defect, suggesting that sup-17 and adm-4 may mediate ectodomain shedding of LIN-12 and/or GLP-1. PMID:16197940 In Caenorhabditis elegans, genetic evidence has implicated SUP-17, the ortholog of Drosophila Kuzbanian and mammalian ADAM10, as the protease that mediates this event. PMID:9428412 Furthermore, we show by genetic analysis that the extracellular domain of LIN-12 appears to be necessary for sup-17 to facilitate lin-12 signalling and that sup-17 does not act downstream of lin-12. |
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Download this section (compressed HTML)Q: Is SUP-17 the direct S2 protease for LIN-12/GLP-1 in vivo (biochemical detection of the S2-cleaved NEXT fragment), and how is the work divided between SUP-17 and ADM-4 in different tissues?
Q: Do TSP-12/TSP-14 (TspanC8 homologs) determine SUP-17 substrate selectivity for Notch versus UNC-40/EFN-4, as TspanC8s do for ADAM10 in mammals?
Experiment: Express a catalytically dead (E-to-A in HExxH) SUP-17 in a sup-17 null background to test whether all Notch, BMP and axon guidance functions require protease activity.
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Download this section (compressed HTML)sup-17 encodes an ADAM protein, an integral membrane disintegrin and zinc-activated metalloproteinase, orthologous to Drosophila and mouse KUZBANIAN and the vertebrate ADAM10 proteins; SUP-17 is required maternally for embryonic development and plays a role in LIN-12/Notch-mediated cell signaling required for several cell fate decisions during vulval development; SUP-17 is also required for normal body morphology and male tail development; SUP-17 functions cell autonomously to facilitate LIN-12 signaling and requires the LIN-12 extracellular domain to do so.
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