Cullin-2 (Cul2) is the scaffold of Cul2-RING ubiquitin ligases in Drosophila. Its N-terminal cullin-repeat region binds the Elongin B/C adaptor, which in turn binds BC-box substrate receptors such as Vhl (forming the VCB-Cul2 ligase that targets HIF-alpha/Sima) and C-degron receptors, while its C-terminal cullin homology domain binds the RING protein Roc1a that recruits the E2. Cul2 ligases act in the nucleus and cytoplasm. Genetic studies implicate Cul2 in limiting JAK/STAT signaling with Socs36E in egg-chamber border cell specification, in restricting niche Dpp/BMP signaling for germline stem cell differentiation in the ovary, in germline enclosure by somatic cyst cells in the testis, in female germline development and in larval neuromuscular junction organization. The host Cul2-EloB/C ligase is also hijacked by the Cricket paralysis virus 1A protein to degrade Argonaute-2.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nucleus. Reason: Cullins act in nuclear and cytoplasmic CRLs; IBA from PTN002631076 (donors include human CUL1-4) and UniProt subcellular location. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nucleus. Reason: Cullins act in nuclear and cytoplasmic CRLs; this agrees with the IBA from PTN002631076 (donors include human CUL1-4) on the same term. The UniProt subcellular location is ARBA-only and no cached fly paper images Cul2 in the nucleus, so the support cited is family classification: Cul2 carries the cullin family signatures, and nuclear CRL activity is a conserved feature of that family. This reaches the nucleus by family membership, not by a fly assay. Supporting Evidence: file:DROME/Cul2/Cul2-uniprot.txt PANTHER; PTHR11932; CULLIN; 1. file:DROME/Cul2/Cul2-uniprot.txt InterPro; IPR045093; Cullin. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoplasm (IBA). Reason: IBA from PTN007551075 (donors FB:FBgn0032956 Cul2, RGD Cul2, WB cul-2). Consistent with perinuclear cytoplasmic Cul2 staining in the ovary. |
| GO:0006511 ubiquitin-dependent protein catabolic process | IEA GO_REF:0000002 | MODIFY | Summary: Ubiquitin-dependent protein catabolic process (InterPro). Reason: Correct but less specific than the evidence supports: Cul2-VCB ligases target substrates such as HIF-alpha for proteasomal degradation. MODIFY to GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process. Proposed replacements: proteasome-mediated ubiquitin-dependent protein catabolic process |
| GO:0007281 germ cell development | IMP PMID:25459658 CSN maintains the germline cellular microenvironment and con... | KEEP AS NON CORE | Summary: Germ cell development (testis). Reason: Reducing cul2 in testis somatic support cells disrupts germline enclosure; developmental output. Supporting Evidence: PMID:25459658 Reducing cullin2 (cul2) from the somatic support cells disrupted germline enclosure |
| GO:0007295 growth of a germarium-derived egg chamber | IMP PMID:21869472 Cullin-5 and cullin-2 play a role in the development of neur... | KEEP AS NON CORE | Summary: Growth of egg chamber. Reason: cul-2 mutants show aberrant female germline development; developmental output. Supporting Evidence: PMID:21869472 Both cul-2 and cul-5 mutants show similar aberrations in the development of female germ line. |
| GO:0008582 regulation of synaptic assembly at neuromuscular junction | IMP PMID:21869472 Cullin-5 and cullin-2 play a role in the development of neur... | KEEP AS NON CORE | Summary: Regulation of synaptic assembly at NMJ. Reason: cul-2 loss causes synaptic bouton organization defects at the larval NMJ; non-core. Supporting Evidence: PMID:21869472 Loss of function of another cullin gene 'cul-2' results in similar defects at the larval neuromuscular junction |
| GO:0016032 viral process | IMP PMID:30308158 A Viral Protein Restricts Drosophila RNAi Immunity by Regula... | KEEP AS NON CORE | Summary: Viral process (CrPV-1A co-opting the host Cul2-EloBC ligase). Reason: GO:0016032 is the term for host gene products that take part in a viral life cycle. Cricket paralysis virus 1A uses a BC-box to recruit the host Cul2-Rbx1-EloBC ligase (including Cul2) to degrade Ago-2 and promote viral replication, so Cul2 genuinely participates in the viral process (virus co-opting host ligase function). Correct but not a core function of Cul2. Supporting Evidence: PMID:30308158 CrPV-1A also contains a BC-box motif that enables the virus to hijack a host Cul2-Rbx1-EloBC ubiquitin ligase complex, which promotes Ago-2 degradation and virus replication. |
| GO:0016567 protein ubiquitination | IBA GO_REF:0000033 | ACCEPT | Summary: Protein ubiquitination. Reason: Cul2 ligases ubiquitinate substrates such as HIF-alpha; the fly evidence shows ubiquitination without chain-type data, so this term is as precise as warranted. Core process of the scaffold. |
| GO:0016567 protein ubiquitination | IC PMID:18698375 Identifying determinants of cullin binding specificity among... | ACCEPT | Summary: Protein ubiquitination. Reason: Cul2 ligases ubiquitinate substrates such as HIF-alpha; the fly evidence shows ubiquitination without chain-type data, so this term is as precise as warranted. Core process of the scaffold. Supporting Evidence: PMID:18698375 we show that Drosophila Roc proteins bind specific Cullins: Roc1a binds Cul1-4 |
| GO:0019005 SCF ubiquitin ligase complex | IBA GO_REF:0000033 | REMOVE | Summary: SCF ubiquitin ligase complex (IBA). Reason: IBA from PANTHER node PTN000231993, whose donors are all Cul1 orthologs (FB:FBgn0015509 Cul1, human CUL1 Q13616, yeast Cdc53, S. pombe Pcu1, mouse Cul1). Cul2 assembles with Elongin B/C and BC-box receptors, not with Skp1/F-box proteins, and no fly evidence places Cul2 in an SCF complex; the SCF-specific term is over-propagated to the Cul2 paralog. |
| GO:0030163 protein catabolic process | IEA GO_REF:0000117 | MODIFY | Summary: Protein catabolic process (ARBA). Reason: Correct but less specific than the evidence supports; MODIFY to GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process. Proposed replacements: proteasome-mediated ubiquitin-dependent protein catabolic process |
| GO:0030514 negative regulation of BMP signaling pathway | IGI PMID:26206612 Reduction of Cullin-2 in somatic cells disrupts differentiat... | KEEP AS NON CORE | Summary: Negative regulation of BMP signaling (ovarian niche). Reason: Somatic Cul2 reduction upregulates Dpp signaling and expands GSC-like cells; non-cell-autonomous developmental output. Supporting Evidence: PMID:26206612 Reduction of Cul-2 in somatic cells causes upregulation of Dpp signal and produces accumulation of extra GSC-like cells inside germarium |
| GO:0030514 negative regulation of BMP signaling pathway | IGI PMID:26206612 Reduction of Cullin-2 in somatic cells disrupts differentiat... | KEEP AS NON CORE | Summary: Negative regulation of BMP signaling (ovarian niche). Reason: Somatic Cul2 reduction upregulates Dpp signaling and expands GSC-like cells; non-cell-autonomous developmental output. Supporting Evidence: PMID:26206612 Reduction of Cul-2 in somatic cells causes upregulation of Dpp signal and produces accumulation of extra GSC-like cells inside germarium |
| GO:0030514 negative regulation of BMP signaling pathway | IMP PMID:26206612 Reduction of Cullin-2 in somatic cells disrupts differentiat... | KEEP AS NON CORE | Summary: Negative regulation of BMP signaling (ovarian niche). Reason: Somatic Cul2 reduction upregulates Dpp signaling and expands GSC-like cells; non-cell-autonomous developmental output. Supporting Evidence: PMID:26206612 Reduction of Cul-2 in somatic cells causes upregulation of Dpp signal and produces accumulation of extra GSC-like cells inside germarium |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | REMOVE | Summary: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (IBA). Reason: IBA from PANTHER node PTN000231993, whose donors are all Cul1 orthologs (FB:FBgn0015509 Cul1, human CUL1 Q13616, yeast Cdc53, S. pombe Pcu1, mouse Cul1). Cul2 assembles with Elongin B/C and BC-box receptors, not with Skp1/F-box proteins, and no fly evidence places Cul2 in an SCF complex; the SCF-specific term is over-propagated to the Cul2 paralog. |
| GO:0031461 cullin-RING ubiquitin ligase complex | IEA GO_REF:0000002 | MODIFY | Summary: Cullin-RING ubiquitin ligase complex (InterPro). Reason: Correct but less specific than the evidence supports; MODIFY to GO:0031462 Cul2-RING ubiquitin ligase complex, which Cul2 already carries. Proposed replacements: Cul2-RING ubiquitin ligase complex |
| GO:0031462 Cul2-RING ubiquitin ligase complex | IBA GO_REF:0000033 | ACCEPT | Summary: Cul2-RING ubiquitin ligase complex. Reason: Cul2 is the cullin of the fly VCB-Cul2 (Vhl-EloB/C-Roc1a) ligase. |
| GO:0031462 Cul2-RING ubiquitin ligase complex | IDA PMID:18698375 Identifying determinants of cullin binding specificity among... | ACCEPT | Summary: Cul2-RING ubiquitin ligase complex. Reason: Cul2 is the cullin of the fly VCB-Cul2 (Vhl-EloB/C-Roc1a) ligase. Supporting Evidence: PMID:18698375 we show that Drosophila Roc proteins bind specific Cullins: Roc1a binds Cul1-4 |
| GO:0031462 Cul2-RING ubiquitin ligase complex | IEA GO_REF:0000117 | ACCEPT | Summary: Cul2-RING ubiquitin ligase complex. Reason: Cul2 is the cullin of the fly VCB-Cul2 (Vhl-EloB/C-Roc1a) ligase. |
| GO:0031462 Cul2-RING ubiquitin ligase complex | IPI PMID:11006129 Drosophila von Hippel-Lindau tumor suppressor complex posses... | ACCEPT | Summary: Cul2-RING ubiquitin ligase complex. Reason: Cul2 is the cullin of the fly VCB-Cul2 (Vhl-EloB/C-Roc1a) ligase. Supporting Evidence: PMID:11006129 Biochemical studies have shown that Drosophila VHL protein binds to Elongins B and C directly, and via this Elongin BC complex, associates with Cul-2 and Rbx1. |
| GO:0031462 Cul2-RING ubiquitin ligase complex | IPI PMID:30308158 A Viral Protein Restricts Drosophila RNAi Immunity by Regula... | ACCEPT | Summary: Cul2-RING ubiquitin ligase complex. Reason: Cul2 is the cullin of the fly VCB-Cul2 (Vhl-EloB/C-Roc1a) ligase. Supporting Evidence: PMID:30308158 E3 ubiquitin ligase complexes containing Cul2, EloB+EloC (herein EloBC), and Rbx1, recruit their substrates through exchangeable substrate receptors. |
| GO:0031625 ubiquitin protein ligase binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Ubiquitin protein ligase binding. Reason: Cul2 binds the RING E3 subunit Roc1a; accurate but subsumed by its scaffold activity (GO:0160072). Non-core. |
| GO:0031625 ubiquitin protein ligase binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Ubiquitin protein ligase binding. Reason: Cul2 binds the RING E3 subunit Roc1a; accurate but subsumed by its scaffold activity (GO:0160072). Non-core. |
| GO:0031981 nuclear lumen | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Nuclear lumen (ARBA). Reason: Consistent with nuclear CRL2 activity; accurate, peripheral. |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | IDA PMID:11006129 Drosophila von Hippel-Lindau tumor suppressor complex posses... | KEEP AS NON CORE | Summary: Positive regulation of proteasomal ubiquitin-dependent catabolism. Reason: The Cul2-RING (VCB-Cul2) ligase executes rather than regulates substrate degradation; the direct process for Cul2 is GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process (proposed as the replacement for the general catabolism rows). The regulation term is a common E3-ligase convention and is kept as non-core. Supporting Evidence: PMID:11006129 we provide evidence that hypoxia-inducible factor (HIF)-1alpha is the ubiquitination target of both human and Drosophila VHL complexes |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | IMP PMID:30308158 A Viral Protein Restricts Drosophila RNAi Immunity by Regula... | KEEP AS NON CORE | Summary: Positive regulation of proteasomal catabolism (Ago-2 during CrPV infection). Reason: Cul2 knockdown stabilizes Ago-2 during infection, but the ligase executes degradation (and here a viral receptor drives it); kept as non-core per the batch convention. Supporting Evidence: PMID:30308158 Compared to control cells, knockdown of either Cul2 or EloB stabilized Ago-2 protein levels by CrPV infection |
| GO:0046426 negative regulation of receptor signaling pathway via JAK-STAT | IGI PMID:26277564 Socs36E limits STAT signaling via Cullin2 and a SOCS-box ind... | KEEP AS NON CORE | Summary: Negative regulation of JAK-STAT signaling. Reason: Loss of Cul2 in follicle cells raises nuclear STAT and the number of motile cells; Cul2 acts with Socs36E. Non-core pathway output. Supporting Evidence: PMID:26277564 We demonstrated that loss of Cul2 in the follicle cells significantly increased nuclear STAT protein levels, which resulted in additional cells acquiring invasive properties. |
| GO:0048140 male germ-line cyst encapsulation | IMP PMID:25459658 CSN maintains the germline cellular microenvironment and con... | KEEP AS NON CORE | Summary: Male germ-line cyst encapsulation. Reason: Reducing cul2 in somatic support cells disrupts germline enclosure; developmental output. Supporting Evidence: PMID:25459658 Reducing cullin2 (cul2) from the somatic support cells disrupted germline enclosure |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:26206612 Reduction of Cullin-2 in somatic cells disrupts differentiat... | ACCEPT | Summary: Perinuclear region of cytoplasm. Reason: Reported from Cul2 immunostaining in ovary (abstract-only cache does not state the localization); accepted deferring to the curator. |
| GO:0140627 ubiquitin-dependent protein catabolic process via the C-end degron rule pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: C-end degron rule pathway (IBA). Reason: IBA from PTN007551075 (donor human CUL2 Q13617), where CUL2 works with KLHDC2/3/10 and APPBP2 C-degron receptors; flies have orthologs (e.g. Slim/KLHDC10) but no fly C-degron data. Plausible, peripheral. |
| GO:0160072 ubiquitin ligase complex scaffold activity | IBA GO_REF:0000033 | ACCEPT | Summary: Ubiquitin ligase complex scaffold activity. Reason: Defining cullin activity: Cul2 binds the EloB/C-receptor module and Roc1a. |
| GO:0160072 ubiquitin ligase complex scaffold activity | IPI PMID:18698375 Identifying determinants of cullin binding specificity among... | ACCEPT | Summary: Ubiquitin ligase complex scaffold activity. Reason: Defining cullin activity: Cul2 binds the EloB/C-receptor module and Roc1a. Supporting Evidence: PMID:18698375 Cullin binding specificity is strongly influenced by the Roc NH(2)-terminal domain, which forms an inter-molecular beta sheet with the Cullin |
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Download this section (compressed HTML)Q: Which substrates and receptors mediate the Cul2 requirements in the ovarian niche (Dpp) and in testis germline enclosure?
Q: Fly Cul2 received SCF-specific IBA terms from node PTN000231993, whose donors are all Cul1 orthologs; should PAINT curators check why Cul2 inherits from this node (these rows are removed here on biological grounds)?
Experiment: Knock down candidate BC-box receptors (Vhl, Socs36E, KLHDC orthologs) in ovarian escort/cap cells and score pMad and GSC-like cell number.
Hypothesis: Cul2 limits niche Dpp signaling through a Vhl-independent BC-box receptor.
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Download this section (compressed HTML)Cullin 2 (Cul2) encodes a protein that plays important roles during oogenesis. Reduction of the product of Cul2 in somatic cells produces tumorous germaria with excess germline stem cell-like cells due to the elevation of Dpp signaling in the niche.
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