Weary (Wry, CG31665) is a single-pass type I transmembrane protein with tandem calcium-binding EGF-like repeats that acts as a non-canonical Notch ligand. Unlike Delta and Serrate it lacks a DSL (Delta-Serrate-Lag2) domain, yet in cultured cells it mediates adhesion with Notch-expressing cells and trans-activates Notch in a gamma-secretase-dependent manner. wry deficiency causes dilated cardiomyopathy in adult flies, which is rescued by cardiac expression of Wry or of the canonical Notch ligands, and Wry can rescue cardiac but not wing defects caused by Serrate knockdown, indicating a role in Notch-dependent maintenance of adult heart function.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000902 cell morphogenesis | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Cell morphogenesis / gliogenesis / neuron development (ARBA electronic). Reason: ARBA rules transferred from canonical Notch-pathway proteins; there is no evidence that Wry acts in neural or glial development or cell morphogenesis, and wry deficiencies lack the sensory-organ and wing defects typical of Notch-pathway mutants. Supporting Evidence: PMID:20203305 Additionally, deficiencies in Wry do not possess the characteristic abnormalities in external sensory organs and wings that have been identified in mutations of Notch regulators. |
| GO:0003015 heart process | IMP PMID:20203305 Gene deletion screen for cardiomyopathy in adult Drosophila ... | KEEP AS NON CORE | Summary: wry deficiency causes dilated cardiomyopathy. Reason: Physiological context in which Wry-Notch signaling has been shown to act (adult heart function). Supporting Evidence: PMID:20203305 Expression of Wry in the heart completely rescues the abnormal cardiac function of Df(2L)Exel7007 supporting our conclusion that wry is the causative gene |
| GO:0005112 Notch binding | IBA GO_REF:0000033 | ACCEPT | Summary: Notch binding inherited from an EGF-repeat family node with Delta and Serrate donors. Reason: Consistent with the experimental Wry-Notch interaction (PMID:20203305). Supporting Evidence: PMID:20203305 Dl, Ser and Wry induced approximately 20-35% cell aggregation compared to <5% in Notch only containing cells |
| GO:0005112 Notch binding | IPI PMID:20203305 Gene deletion screen for cardiomyopathy in adult Drosophila ... | ACCEPT | Summary: Wry binds Notch and mediates aggregation with Notch-expressing cells. Reason: Core activity; cell aggregation and clustering at contacts show Wry-Notch binding. Supporting Evidence: PMID:20203305 Despite the absence of a DSL domain, Wry can mediate cellular adhesion with Notch expressing cells, and transactivate Notch signaling in Drosophila S2 cells like the two other known Notch ligands. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Calcium ion binding by EGF-like calcium-binding repeats (InterPro). Reason: Structural property of the cbEGF repeats; same decision as for Delta and Serrate. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma membrane (electronic, single-pass type I membrane protein). Reason: Consistent with cell-surface localization and contact-dependent Notch activation. The UniProt SUBCELLULAR LOCATION line is ARBA-only; the support is the sequence topology (SignalP signal peptide 1-19 and a single Phobius helical TM segment 1014-1035, i.e. a type I membrane protein), the transmembrane domain noted in the primary paper, and the Wry-dependent S2 cell aggregation assay, which requires Wry at the cell surface (an indirect, functional readout rather than imaging). Supporting Evidence: file:DROME/wry/wry-uniprot.txt TRANSMEM 1014..1035 file:DROME/wry/wry-uniprot.txt SIGNAL 1..19 PMID:20203305 The protein encoded by wry has motifs that include EGF repeats and a transmembrane domain consistent with the Notch family of proteins, but lacks a DSL domain PMID:20203305 Dl, Ser and Wry induced approximately 20-35% cell aggregation compared to <5% in Notch only containing cells |
| GO:0007154 cell communication | IEA GO_REF:0000117 | MODIFY | Summary: Cell communication / signaling (ARBA electronic). Reason: Correct but very general; the specific process is Notch signaling pathway, which Wry already carries (IMP). Proposed replacements: Notch signaling pathway Supporting Evidence: PMID:20203305 This gene, which we name weary (wry), functions as a novel Notch ligand to maintain normal heart function. |
| GO:0007219 Notch signaling pathway | IMP PMID:20203305 Gene deletion screen for cardiomyopathy in adult Drosophila ... | ACCEPT | Summary: Wry acts as a Notch ligand to induce Notch cleavage and transcription. Reason: Core pathway. Supporting Evidence: PMID:20203305 Collectively, our results suggest that Wry functions as a Notch ligand in Drosophila to induce cleavage of Notch and effectively activate transcriptional events in response to Notch signaling. |
| GO:0009986 cell surface | IDA PMID:20203305 Gene deletion screen for cardiomyopathy in adult Drosophila ... | ACCEPT | Summary: Wry is at the cell surface, clustering with Notch at contacts. Reason: Experimentally supported location for a transmembrane ligand. Supporting Evidence: PMID:20203305 these proteins are each able to promote cellular adhesion with Notch expressing cells as shown by the clustering of ligand and receptor at sites of cellular contact |
| GO:0023052 signaling | IEA GO_REF:0000117 | MODIFY | Summary: Cell communication / signaling (ARBA electronic). Reason: Correct but very general; the specific process is Notch signaling pathway, which Wry already carries (IMP). Proposed replacements: Notch signaling pathway Supporting Evidence: PMID:20203305 This gene, which we name weary (wry), functions as a novel Notch ligand to maintain normal heart function. |
| GO:0042063 gliogenesis | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Cell morphogenesis / gliogenesis / neuron development (ARBA electronic). Reason: ARBA rules transferred from canonical Notch-pathway proteins; there is no evidence that Wry acts in neural or glial development or cell morphogenesis, and wry deficiencies lack the sensory-organ and wing defects typical of Notch-pathway mutants. Supporting Evidence: PMID:20203305 Additionally, deficiencies in Wry do not possess the characteristic abnormalities in external sensory organs and wings that have been identified in mutations of Notch regulators. |
| GO:0048018 receptor ligand activity | IDA PMID:20203305 Gene deletion screen for cardiomyopathy in adult Drosophila ... | ACCEPT | Summary: Wry trans-activates Notch signaling. Reason: Core activity as a Notch ligand; activation is gamma-secretase dependent. Supporting Evidence: PMID:20203305 Importantly, Wry-mediated transactivation of Notch was blocked by the Ξ³-secretase inhibitors, compound E and DAPT |
| GO:0048666 neuron development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Cell morphogenesis / gliogenesis / neuron development (ARBA electronic). Reason: ARBA rules transferred from canonical Notch-pathway proteins; there is no evidence that Wry acts in neural or glial development or cell morphogenesis, and wry deficiencies lack the sensory-organ and wing defects typical of Notch-pathway mutants. Supporting Evidence: PMID:20203305 Additionally, deficiencies in Wry do not possess the characteristic abnormalities in external sensory organs and wings that have been identified in mutations of Notch regulators. |
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Download this section (compressed HTML)Q: Which Notch EGF repeats does Wry bind in the absence of a DSL domain, and does Wry signal in tissues other than the adult heart (it is a single-study ligand)?
Experiment: Generate a clean wry null allele and test cardiac and other Notch-dependent phenotypes, together with direct binding assays of the purified Wry ectodomain to Notch EGF-repeat fragments.
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Download this section (compressed HTML)weary (wry) encodes a ligand for the receptor encoded by N. It is involved in the Notch signaling pathway and normal heart function.
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