Pelle (pll) is the Drosophila member of the IRAK family of serine/threonine protein kinases, with an N-terminal death domain and a C-terminal kinase domain. It is the kinase of the Toll receptor pathway. After the cytokine Spaetzle activates Toll, the adaptor MyD88 binds the Toll TIR domain and recruits the death domain adaptor Tube, which in turn recruits Pelle through a death domain heterotrimer at the plasma membrane. Clustering activates Pelle, which autophosphorylates and phosphorylates the IkappaB homologue Cactus at its signal-responsive degron; the phosphorylated Cactus is recognised by the F-box protein Slimb and degraded, releasing the NF-kappaB family transcription factors Dorsal and Dif to enter the nucleus. Maternally supplied Pelle is essential for dorsoventral axis specification of the embryo, and in larvae and adults Pelle is required for Toll-dependent induction of antifungal and anti-Gram-positive antimicrobial peptides such as Drosomycin. Pelle has also been reported to phosphorylate the STRIPAK subunit Cka, activating Hippo signalling in the fat body, and it is needed for embryonic muscle patterning.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002804 positive regulation of antifungal peptide production | IDA PMID:11743586 Drosophila MyD88 is required for the response to fungal and ... | ACCEPT | Summary: Pelle is required downstream of MyD88 and Tube for Toll-dependent induction of the antifungal peptide Drosomycin. Reason: Tauszig-Delamasure et al. showed that MyD88-driven Drs expression requires Tube and Pelle. Drosomycin induction is the principal transcriptional output of the Toll pathway in the fat body, and Pelle is the kinase that transduces that signal, so this regulatory annotation is a fair description of Pelle's role. Supporting Evidence: PMID:11743586 required the death domain proteins Tube and Pelle to activate expression of Drs, which encodes Drosomycin |
| GO:0002804 positive regulation of antifungal peptide production | IMP PMID:8808632 The dorsoventral regulatory gene cassette spΓ€tzle/Toll/cactu... | ACCEPT | Summary: pll mutants fail to induce drosomycin after infection (Lemaitre et al. 1996). Reason: The foundational paper showing that the dorsoventral cassette, including pelle, controls drosomycin expression in adults. Consistent with the Toll pathway being the main route to antifungal peptide gene induction. Supporting Evidence: PMID:8808632 the intracellular components of the dorsoventral signaling pathway (except for dorsal) and the extracellular Toll ligand, spΓ€tzle, control expression of the antifungal peptide gene drosomycin in adults |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro kinase-domain mapping to protein kinase activity. Reason: Correct but general; Pelle is an experimentally verified Ser/Thr kinase (see GO:0004674 rows). Supporting Evidence: PMID:8440018 pelle encodes a protein of 501 amino acids, the last 292 of which comprise a protein kinase catalytic domain |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:11447260 Physical and functional interactions between Drosophila TRAF... | ACCEPT | Summary: Pelle phosphorylates dTRAF2 (Traf6) in vitro. Reason: Pelle is an IRAK-family serine/threonine protein kinase whose C-terminal kinase domain is required for Toll signalling. Shen et al. showed direct in vitro phosphorylation of dTRAF2 by Pelle, supporting serine/threonine kinase activity. Supporting Evidence: PMID:11447260 is phosphorylated by Pelle in vitro |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:11881810 Tehao functions in the Toll pathway in Drosophila melanogast... | ACCEPT | Summary: IDA from the Tehao paper (Luo et al. 2001); abstract-only in cache. Reason: The abstract reports physical interaction of Tehao with Pelle and synergy in Dorsal activation but does not describe a kinase assay; the curator read the full text, and the activity itself is well established for Pelle by multiple independent in vitro assays (PMID:9806920, PMID:24086459). Accepting and deferring to the curator. Supporting Evidence: PMID:11881810 Purified recombinant Tehao interacted specifically in vitro not only with the Pelle protein kinase, but also with the Toll intracytoplasmic domain. PMID:9806920 We then demonstrate that Pelle can be autophosphorylated, and that this prevents binding to Toll as well as Tube. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:24086459 The IRAK homolog Pelle is the functional counterpart of IΞΊB ... | ACCEPT | Summary: Pelle phosphorylates Cactus at the signal-responsive degron serines and the IkappaBalpha degron in vitro (Daigneault et al. 2013). Reason: Correct. This paper further supports the more specific IkappaB kinase activity (GO:0008384, is_a protein serine/threonine kinase activity), proposed as a NEW annotation below; the general term is retained here. Supporting Evidence: PMID:24086459 We conclude that Pelle acts as a Cactus kinase and preferentially phosphorylates Cactus at the serines required for signal responsiveness. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:9806920 Phosphorylation modulates direct interactions between the To... | ACCEPT | Summary: Pelle autophosphorylates and phosphorylates the Toll intracellular domain in vitro (Shen and Manley 1998). Reason: Pelle is an IRAK-family serine/threonine protein kinase whose C-terminal kinase domain is required for Toll signalling. Direct biochemical evidence of kinase activity toward itself and Toll. Supporting Evidence: PMID:9806920 We then demonstrate that Pelle can be autophosphorylated, and that this prevents binding to Toll as well as Tube. PMID:9806920 We also show that Pelle phosphorylates Toll, within the region required for Pelle interaction |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000003 | ACCEPT | Summary: EC 2.7.11.1 mapping to protein serine/threonine kinase activity. Reason: Consistent with experimental data. Supporting Evidence: PMID:8440018 pelle encodes a protein of 501 amino acids, the last 292 of which comprise a protein kinase catalytic domain |
| GO:0004674 protein serine/threonine kinase activity | IMP PMID:26824654 Toll Receptor-Mediated Hippo Signaling Controls Innate Immun... | ACCEPT | Summary: Pelle phosphorylates the STRIPAK subunit Cka in vitro, dependent on catalytic Lys240 (Liu et al. 2016). Reason: Kinase-dead Pll-K240R fails to phosphorylate Cka, supporting Ser/Thr kinase activity. Supporting Evidence: PMID:26824654 Cka was phosphorylated in vitro by wildtype Pll, but not the kinase-dead mutant Pll-K240R, supporting our model implicating Cka as a direct substrate of Pll. |
| GO:0004674 protein serine/threonine kinase activity | TAS Reactome:R-DME-209057 | ACCEPT | Summary: Reactome: activated PLL autophosphorylates in the Toll signalling complex. Reason: Consistent with experimental evidence of autophosphorylation (PMID:9806920, PMID:24086459). Supporting Evidence: PMID:9806920 We then demonstrate that Pelle can be autophosphorylated, and that this prevents binding to Toll as well as Tube. |
| GO:0004674 protein serine/threonine kinase activity | TAS Reactome:R-DME-214859 | ACCEPT | Summary: Reactome: activated PLL autophosphorylates in the Toll-Weckle signalling complex. Reason: Consistent with experimental evidence of autophosphorylation. Supporting Evidence: PMID:9806920 We then demonstrate that Pelle can be autophosphorylated, and that this prevents binding to Toll as well as Tube. |
| GO:0005515 protein binding | IPI PMID:10330490 Oligomerisation of Tube and Pelle leads to nuclear localisat... | MODIFY | Summary: Pelle interacts with Tube (Grosshans et al. 1999; abstract-only). Reason: Protein binding is uninformative. The Tube-Pelle interaction is mediated by the N-terminal death domains of both proteins, as shown structurally and biochemically, so death domain binding is the informative MF. Proposed replacements: death domain binding Supporting Evidence: PMID:10330490 By deletion analysis we determined the domains of Tube and Pelle mediating the physical interaction and the signalling to downstream components. PMID:10589682 The interaction of the serine/threonine kinase Pelle and adaptor protein Tube through their N-terminal death domains leads to the nuclear translocation of the transcription factor Dorsal |
| GO:0005515 protein binding | IPI PMID:10330490 Oligomerisation of Tube and Pelle leads to nuclear localisat... | REMOVE | Summary: Pellino (Pli) associates with the kinase domain of Pelle. Reason: Generic protein binding is uninformative and the paper does not define a specific molecular function for the Pelle-Pellino association. Removal does not dispute the interaction. Supporting Evidence: PMID:10330490 the novel, but evolutionary conserved protein Pellino, which associates with the kinase domain of Pelle |
| GO:0005515 protein binding | IPI PMID:10512628 Formation and biochemical characterization of tube/pelle dea... | MODIFY | Summary: Tube-Pelle interaction (Schiffmann et al. 1999), duplicate row with FlyBase id for Tube. Reason: Yeast two-hybrid, SPR, ITC and ultracentrifugation show heterodimerisation of the Tube and Pelle death domains (Kd about 0.5 microM). Death domain binding is the informative term. Proposed replacements: death domain binding Supporting Evidence: PMID:10512628 we show using the yeast two-hybrid system that the wild-type tube and pelle death domains bind together |
| GO:0005515 protein binding | IPI PMID:10512628 Formation and biochemical characterization of tube/pelle dea... | MODIFY | Summary: Tube-Pelle death domain interaction (Schiffmann et al. 1999), UniProt id for Tube. Reason: As for the duplicate row: the interaction is a death domain heterodimer. Proposed replacements: death domain binding Supporting Evidence: PMID:10512628 we show using the yeast two-hybrid system that the wild-type tube and pelle death domains bind together |
| GO:0005515 protein binding | IPI PMID:10589682 Three-dimensional structure of a complex between the death d... | MODIFY | Summary: Crystal structure of the Pelle-Tube death domain heterodimer (Xiao et al. 1999). Reason: The structure defines a death domain-death domain interface that is required in vivo. Replace protein binding with death domain binding. Proposed replacements: death domain binding Supporting Evidence: PMID:10589682 The interaction of the serine/threonine kinase Pelle and adaptor protein Tube through their N-terminal death domains leads to the nuclear translocation of the transcription factor Dorsal PMID:10589682 In vivo assays of Pelle and Tube mutants confirmed that the integrity of the major heterodimer interface is critical to the activity of these molecules. |
| GO:0005515 protein binding | IPI PMID:11881810 Tehao functions in the Toll pathway in Drosophila melanogast... | MODIFY | Summary: Recombinant Tehao (Toll-5) binds Pelle in vitro. Reason: Protein binding is uninformative. Tehao is a Toll-family receptor and the interaction is with its intracellular (TIR-containing) region, consistent with Pelle's documented direct binding to the Toll intracellular domain (PMID:9806920). Toll binding (GO:0005121) is more informative; the in vivo relevance of Tehao-Pelle binding is not established. Proposed replacements: Toll binding Supporting Evidence: PMID:11881810 Purified recombinant Tehao interacted specifically in vitro not only with the Pelle protein kinase, but also with the Toll intracytoplasmic domain. |
| GO:0005515 protein binding | IPI PMID:12351681 A heterotrimeric death domain complex in Toll signaling. | MODIFY | Summary: Co-immunoprecipitation of the MyD88-Tube-Pelle death domain heterotrimer (Sun et al. 2002). Reason: Pelle is recruited into the heterotrimer via the Tube death domain. Death domain binding is the informative MF. Proposed replacements: death domain binding Supporting Evidence: PMID:12351681 we find a heterotrimeric association of the death domains of MyD88, Tube, and the protein kinase Pelle PMID:12351681 functional assays confirm that the formation of this heterotrimer is critical for signal transduction by the Toll pathway |
| GO:0005515 protein binding | IPI PMID:9367441 An activity-dependent network of interactions links the Rel ... | MODIFY | Summary: Pelle interacts with Tube in yeast two-hybrid and immunoprecipitation (Edwards et al. 1997). Reason: Pelle-Tube association is death domain-mediated (PMID:10589682); death domain binding is the informative term. Proposed replacements: death domain binding Supporting Evidence: PMID:9367441 We show that Dorsal binds specifically to Tube, Pelle and Cactus, and that the protein kinase activity of Pelle differentially regulates its interactions with Dorsal and Tube. PMID:10589682 The interaction of the serine/threonine kinase Pelle and adaptor protein Tube through their N-terminal death domains leads to the nuclear translocation of the transcription factor Dorsal |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro ATP-binding site mapping. Reason: Pelle is an active kinase with an intact ATP-binding site (UniProt BINDING 219-227, K240). Supporting Evidence: PMID:8440018 the kinase catalytic domain is required for biological activity |
| GO:0005634 nucleus | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA nuclear localization propagated from a deep kinase node (PTN000784925) including IRAK and plant/yeast kinases. Reason: Pelle acts at the plasma membrane and in the cytoplasm in the Toll receptor complex; no study places Drosophila Pelle in the nucleus, and the node that carries this term spans kinases with very different localisations. The IBA is not contradicted outright, but it adds no supported biology for Pelle. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000784925 SUPPORTS SOURCE BUT NOT TARGET Deep kinase node spanning IRAK and plant/yeast kinases; nuclear localisation of some descendants (e.g. IRAK1) is not documented for Drosophila Pelle, which acts at the plasma membrane and in the cytoplasm. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA cytoplasm. Reason: Consistent with immunolocalisation of Pelle in the embryo cytoplasm before recruitment to the membrane. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0005737 cytoplasm | IDA PMID:7635064 Interaction of the pelle kinase with the membrane-associated... | ACCEPT | Summary: Pelle is cytoplasmic/membrane-associated in syncytial blastoderm (Galindo et al. 1995). Reason: Supported by UniProt and the cited paper. Supporting Evidence: PMID:7635064 We propose a model wherein tube activates pelle by recruiting it to the plasma membrane |
| GO:0005737 cytoplasm | IDA PMID:9609827 Recruitment of Tube and Pelle to signaling sites at the surf... | ACCEPT | Summary: Pelle localisation in embryo (Towb et al. 1998). Reason: Pelle is cytoplasmic and recruited to the membrane on Toll activation. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (cytoplasm). Reason: Consistent with experimental data. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0005829 cytosol | TAS Reactome:R-DME-209057 | ACCEPT | Summary: Reactome: Pelle participates in cytosolic reactions of the Toll signalling complex. Reason: Pelle acts on the cytoplasmic face of the plasma membrane and on cytosolic Cactus/Dorsal complexes; cytosol is acceptable for these Reactome reactions. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0005829 cytosol | TAS Reactome:R-DME-209072 | ACCEPT | Summary: Reactome: Pelle participates in cytosolic reactions of the Toll signalling complex. Reason: Pelle acts on the cytoplasmic face of the plasma membrane and on cytosolic Cactus/Dorsal complexes; cytosol is acceptable for these Reactome reactions. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0005829 cytosol | TAS Reactome:R-DME-214845 | ACCEPT | Summary: Reactome: Pelle participates in cytosolic reactions of the Toll signalling complex. Reason: Pelle acts on the cytoplasmic face of the plasma membrane and on cytosolic Cactus/Dorsal complexes; cytosol is acceptable for these Reactome reactions. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0005829 cytosol | TAS Reactome:R-DME-214847 | ACCEPT | Summary: Reactome: Pelle participates in cytosolic reactions of the Toll signalling complex. Reason: Pelle acts on the cytoplasmic face of the plasma membrane and on cytosolic Cactus/Dorsal complexes; cytosol is acceptable for these Reactome reactions. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0005829 cytosol | TAS Reactome:R-DME-214857 | ACCEPT | Summary: Reactome: Pelle participates in cytosolic reactions of the Toll signalling complex. Reason: Pelle acts on the cytoplasmic face of the plasma membrane and on cytosolic Cactus/Dorsal complexes; cytosol is acceptable for these Reactome reactions. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0005829 cytosol | TAS Reactome:R-DME-214859 | ACCEPT | Summary: Reactome: Pelle participates in cytosolic reactions of the Toll signalling complex. Reason: Pelle acts on the cytoplasmic face of the plasma membrane and on cytosolic Cactus/Dorsal complexes; cytosol is acceptable for these Reactome reactions. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0005829 cytosol | TAS Reactome:R-DME-214860 | ACCEPT | Summary: Reactome: Pelle participates in cytosolic reactions of the Toll signalling complex. Reason: Pelle acts on the cytoplasmic face of the plasma membrane and on cytosolic Cactus/Dorsal complexes; cytosol is acceptable for these Reactome reactions. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0005829 cytosol | TAS Reactome:R-DME-214864 | ACCEPT | Summary: Reactome: Pelle participates in cytosolic reactions of the Toll signalling complex. Reason: Pelle acts on the cytoplasmic face of the plasma membrane and on cytosolic Cactus/Dorsal complexes; cytosol is acceptable for these Reactome reactions. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0005829 cytosol | TAS Reactome:R-DME-214878 | ACCEPT | Summary: Reactome: Pelle participates in cytosolic reactions of the Toll signalling complex. Reason: Pelle acts on the cytoplasmic face of the plasma membrane and on cytosolic Cactus/Dorsal complexes; cytosol is acceptable for these Reactome reactions. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0005829 cytosol | TAS Reactome:R-DME-214880 | ACCEPT | Summary: Reactome: Pelle participates in cytosolic reactions of the Toll signalling complex. Reason: Pelle acts on the cytoplasmic face of the plasma membrane and on cytosolic Cactus/Dorsal complexes; cytosol is acceptable for these Reactome reactions. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA plasma membrane. Reason: Pelle is recruited to the plasma membrane by Tube upon Toll activation. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0005886 plasma membrane | IDA PMID:7635064 Interaction of the pelle kinase with the membrane-associated... | ACCEPT | Summary: Pelle membrane association (Galindo et al. 1995). Reason: Supported. Supporting Evidence: PMID:7635064 We propose a model wherein tube activates pelle by recruiting it to the plasma membrane |
| GO:0005886 plasma membrane | IDA PMID:9609827 Recruitment of Tube and Pelle to signaling sites at the surf... | ACCEPT | Summary: Toll-induced recruitment of Pelle to the plasma membrane (Towb et al. 1998). Reason: Direct immunofluorescence evidence. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane PMID:9609827 targeting of either Tube or Pelle to the plasma membrane by myristylation is sufficient to activate the signal transduction pathway that leads to Dorsal nuclear translocation |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (cell membrane). Reason: Consistent with experimental data. Supporting Evidence: PMID:9609827 activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane |
| GO:0006915 apoptotic process | NAS PMID:10589682 Three-dimensional structure of a complex between the death d... | REMOVE | Summary: NAS from the Pelle-Tube death domain structure paper. Reason: The paper notes only that death domains were first described in apoptotic signalling proteins; it presents no evidence that Pelle participates in apoptosis. Pelle's death domain mediates Toll-pathway assembly, not cell death. Supporting Evidence: PMID:10589682 The amino-terminal interaction modules of Pelle and Tube show limited amino acid sequence similarity to death domains, a family of folds identified in proteins that assemble components of apoptotic signaling pathways |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro death domain mapping to signal transduction. Reason: General but correct. Supporting Evidence: PMID:7635064 tube and the protein kinase pelle transduce an intracellular signal generated by the transmembrane receptor Toll |
| GO:0007352 zygotic specification of dorsal/ventral axis | IMP PMID:6434989 Information for the dorsal--ventral pattern of the Drosophil... | MODIFY | Summary: IMP to zygotic specification of D/V axis from Anderson and Nusslein-Volhard 1984. Reason: pelle is a maternal-effect dorsal-group gene; the cited paper is about maternally stored mRNA that specifies the embryonic D/V axis. The 'zygotic' qualifier (genes expressed in the zygote) does not fit a maternally supplied product. GO:0009950 dorsal/ventral axis specification captures the role without the misleading qualifier. Proposed replacements: dorsal/ventral axis specification Supporting Evidence: PMID:6434989 Maternal-effect mutations in 10 loci in Drosophila produce totally 'dorsalized' embryos. PMID:8244004 suggesting that tube and pelle act downstream of the membrane protein Toll in the signaling pathway that defines the embryonic dorsal-ventral pattern |
| GO:0007526 larval somatic muscle development | IMP PMID:9676200 The Toll pathway is required in the epidermis for muscle dev... | KEEP AS NON CORE | Summary: spz, tube and pll mutants show embryonic muscle patterning defects (Halfon and Keshishian 1998). Reason: A genuine but secondary developmental role of Toll signalling in the epidermis; not the core function of Pelle. Supporting Evidence: PMID:9676200 We find that spΓ€tzle, tube, and pelle, but not easter, are necessary for muscle development. |
| GO:0008063 Toll signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IBA Toll signaling pathway. Reason: Pelle is the Toll pathway kinase. Supporting Evidence: PMID:7635064 tube and the protein kinase pelle transduce an intracellular signal generated by the transmembrane receptor Toll |
| GO:0008063 Toll signaling pathway | IGI PMID:11447260 Physical and functional interactions between Drosophila TRAF... | ACCEPT | Summary: Genetic interaction of pll and dTRAF2 in Dorsal activation. Reason: Consistent with Pelle as the Toll pathway kinase. Supporting Evidence: PMID:11447260 dTRAF2 and Pelle cooperate to activate Dorsal synergistically in cotransfected Schneider cells |
| GO:0008063 Toll signaling pathway | IGI PMID:8244004 Genetic characterization of tube and pelle, genes required f... | ACCEPT | Summary: Double mutant analysis places pll downstream of Toll. Reason: Core function. Supporting Evidence: PMID:8244004 suggesting that tube and pelle act downstream of the membrane protein Toll in the signaling pathway that defines the embryonic dorsal-ventral pattern |
| GO:0008063 Toll signaling pathway | IGI PMID:8846922 Functional interactions between the pelle kinase, Toll recep... | ACCEPT | Summary: Pelle cooperates with activated Toll and Tube to activate Dorsal in S2 cells. Reason: Core function. Supporting Evidence: PMID:8846922 Coexpression of pll with dl enhanced dl nuclear localization and resulted in a modest increase in transcriptional activity. |
| GO:0008063 Toll signaling pathway | IMP PMID:10973475 Toll-related receptors and the control of antimicrobial pept... | ACCEPT | Summary: Dominant-negative Pelle blocks Spaetzle-induced drosomycin. Reason: Core function. Supporting Evidence: PMID:10973475 a dominant-negative version of the kinase Pelle can block induction of drosomycin by the cytokine Spaetzle, but does not affect induction of the antibacterial peptide attacin by lipopolysaccharide |
| GO:0008063 Toll signaling pathway | IMP PMID:11606776 Drosophila MyD88 is an adapter in the Toll signaling pathway... | ACCEPT | Summary: dMyD88 acts upstream of Pelle in Toll signalling. Reason: Core function; the curator's IMP rests on dominant-negative Pelle epistasis in S2 cells. Supporting Evidence: PMID:11606776 dMyD88 is an adapter in the Toll signaling pathway that associates with both the Toll receptor and the downstream kinase Pelle |
| GO:0008063 Toll signaling pathway | IMP PMID:12351681 A heterotrimeric death domain complex in Toll signaling. | ACCEPT | Summary: Heterotrimer formation is required for Toll signal transduction. Reason: Core function. Supporting Evidence: PMID:12351681 functional assays confirm that the formation of this heterotrimer is critical for signal transduction by the Toll pathway |
| GO:0008063 Toll signaling pathway | IMP PMID:20404143 Endocytic pathway is required for Drosophila Toll innate imm... | ACCEPT | Summary: Mop acts upstream of MyD88 and Pelle in Toll signalling. Reason: Core function. Supporting Evidence: PMID:20404143 epistasis experiments show that the Mop protein functions upstream of the MyD88 adaptor and the Pelle kinase |
| GO:0008063 Toll signaling pathway | IMP PMID:24086459 The IRAK homolog Pelle is the functional counterpart of IΞΊB ... | ACCEPT | Summary: Pelle is required for Toll-directed Cactus degradation. Reason: Core function. Supporting Evidence: PMID:24086459 The protein kinase activity of Pelle is strictly required for Toll signaling and forced expression of Pelle drives Cactus degradation |
| GO:0008063 Toll signaling pathway | IMP PMID:8808632 The dorsoventral regulatory gene cassette spΓ€tzle/Toll/cactu... | ACCEPT | Summary: pll mutants block Toll pathway-dependent drosomycin induction. Reason: Core function. Supporting Evidence: PMID:8808632 the intracellular components of the dorsoventral signaling pathway (except for dorsal) and the extracellular Toll ligand, spΓ€tzle, control expression of the antifungal peptide gene drosomycin in adults |
| GO:0008063 Toll signaling pathway | IMP PMID:9025065 A gradient of cytoplasmic Cactus degradation establishes the... | ACCEPT | Summary: Signal-dependent Cactus degradation gradient (Bergmann et al. 1996). Reason: Abstract-only; the full text uses dorsal-group mutants including pll. Consistent with Pelle's established role. Supporting Evidence: PMID:9025065 In response to the signal produced and transmitted by the products of the other genes, Dorsal translocates to the nucleus preferentially on the ventral side of the embryo. |
| GO:0008063 Toll signaling pathway | TAS PMID:10589682 Three-dimensional structure of a complex between the death d... | ACCEPT | Summary: TAS from the death domain structure paper. Reason: Core function. Supporting Evidence: PMID:10589682 The interaction of the serine/threonine kinase Pelle and adaptor protein Tube through their N-terminal death domains leads to the nuclear translocation of the transcription factor Dorsal |
| GO:0009791 post-embryonic development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA machine-learning annotation to post-embryonic development. Reason: Very broad. pll mutants show some zygotic lethality, but no specific post-embryonic developmental process has been attributed to Pelle; the annotation adds nothing beyond its signalling roles. Supporting Evidence: PMID:8244004 Both tube and pelle are also important zygotically for survival |
| GO:0009953 dorsal/ventral pattern formation | IGI PMID:8244004 Genetic characterization of tube and pelle, genes required f... | ACCEPT | Summary: Genetic interaction with Toll in D/V patterning. Reason: Core developmental role. Supporting Evidence: PMID:8244004 suggesting that tube and pelle act downstream of the membrane protein Toll in the signaling pathway that defines the embryonic dorsal-ventral pattern |
| GO:0009953 dorsal/ventral pattern formation | IMP PMID:9025065 A gradient of cytoplasmic Cactus degradation establishes the... | ACCEPT | Summary: pll required for Cactus degradation gradient and Dorsal nuclear gradient. Reason: Core developmental role. Supporting Evidence: PMID:9025065 In response to the signal produced and transmitted by the products of the other genes, Dorsal translocates to the nucleus preferentially on the ventral side of the embryo. |
| GO:0019221 cytokine-mediated signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IBA cytokine-mediated signaling pathway from the IRAK clade (PTN000701353). Reason: The Toll ligand Spaetzle is a cytokine, and Pelle is the Toll pathway kinase, so this broader term is correct for Pelle even though GO:0008063 Toll signaling pathway (not an is_a descendant of GO:0019221 in current GO) is the precise description. Supporting Evidence: PMID:10973475 a dominant-negative version of the kinase Pelle can block induction of drosomycin by the cytokine Spaetzle, but does not affect induction of the antibacterial peptide attacin by lipopolysaccharide |
| GO:0019904 protein domain specific binding | IPI PMID:10589682 Three-dimensional structure of a complex between the death d... | MODIFY | Summary: Pelle binds Tube via death domains (Xiao et al. 1999). Reason: Protein domain specific binding is correct but death domain binding (GO:0070513) is the specific term supported by the crystal structure. Proposed replacements: death domain binding Supporting Evidence: PMID:10589682 The interaction of the serine/threonine kinase Pelle and adaptor protein Tube through their N-terminal death domains leads to the nuclear translocation of the transcription factor Dorsal |
| GO:0031349 positive regulation of defense response | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA annotation to positive regulation of defense response. Reason: Broad but consistent with Pelle's role in activating antimicrobial defence. Supporting Evidence: PMID:8808632 the intracellular components of the dorsoventral signaling pathway (except for dorsal) and the extracellular Toll ligand, spΓ€tzle, control expression of the antifungal peptide gene drosomycin in adults |
| GO:0031663 lipopolysaccharide-mediated signaling pathway | IBA GO_REF:0000033 | REMOVE | Summary: IBA lipopolysaccharide-mediated signaling pathway propagated from mammalian IRAK1/IRAK4 (PTN000701353). Reason: The LPS response is a TLR4-specific function in vertebrates. In Drosophila, LPS is not the ligand of Toll, and dominant-negative Pelle does not affect LPS-induced attacin expression, which runs through the IMD pathway. The ligand-specific pathway term should not transfer to the fly kinase. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000701353 SUPPORTS SOURCE BUT NOT TARGET IRAK-clade node; LPS signalling of mammalian IRAK1/IRAK4 depends on TLR4, which has no LPS-sensing counterpart in Drosophila. Dominant-negative Pelle does not affect LPS-induced attacin (PMID:10973475). Supporting Evidence: PMID:10973475 a dominant-negative version of the kinase Pelle can block induction of drosomycin by the cytokine Spaetzle, but does not affect induction of the antibacterial peptide attacin by lipopolysaccharide |
| GO:0035172 hemocyte proliferation | TAS PMID:14602069 Thicker than blood: conserved mechanisms in Drosophila and v... | UNDECIDED | Summary: TAS from a review of Drosophila hematopoiesis; abstract-only in cache. Reason: Gain-of-function Toll pathway mutations are known to cause hemocyte overproliferation, but the cached abstract does not mention pelle and a TAS from a review cannot be checked here. Left undecided pending the full text. |
| GO:0035332 positive regulation of hippo signaling | IGI PMID:26824654 Toll Receptor-Mediated Hippo Signaling Controls Innate Immun... | KEEP AS NON CORE | Summary: pll genetically interacts with Cka in Toll-induced Hippo activation (Liu et al. 2016). Reason: Pelle phosphorylates Cka and promotes its degradation, activating Hippo in the fat body. A direct but secondary output reported by one laboratory. Supporting Evidence: PMID:26824654 We further show that Gram-positive bacteria activate Hippo signaling in fat bodies through Toll-dependent, Pelle-mediated phosphorylation and degradation of Cka, an essential subunit of the STRIPAK PP2A complex, which normally associates with Hpo and antagonizes its kinase activity. |
| GO:0035556 intracellular signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: IBA intracellular signal transduction. Reason: Correct and general. Supporting Evidence: PMID:7635064 tube and the protein kinase pelle transduce an intracellular signal generated by the transmembrane receptor Toll |
| GO:0045087 innate immune response | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA innate immune response. Reason: Pelle is required for Toll-mediated innate immunity. Supporting Evidence: PMID:10973475 a dominant-negative version of the kinase Pelle can block induction of drosomycin by the cytokine Spaetzle, but does not affect induction of the antibacterial peptide attacin by lipopolysaccharide |
| GO:0045087 innate immune response | IMP PMID:12351681 A heterotrimeric death domain complex in Toll signaling. | ACCEPT | Summary: Toll pathway immunity requires the MyD88-Tube-Pelle heterotrimer. Reason: Supported. Supporting Evidence: PMID:12351681 functional assays confirm that the formation of this heterotrimer is critical for signal transduction by the Toll pathway |
| GO:0045087 innate immune response | TAS PMID:10589682 Three-dimensional structure of a complex between the death d... | ACCEPT | Summary: TAS innate immune response. Reason: Supported. Supporting Evidence: PMID:10589682 The interaction of the serine/threonine kinase Pelle and adaptor protein Tube through their N-terminal death domains leads to the nuclear translocation of the transcription factor Dorsal |
| GO:0045732 positive regulation of protein catabolic process | IMP PMID:26824654 Toll Receptor-Mediated Hippo Signaling Controls Innate Immun... | KEEP AS NON CORE | Summary: Pelle promotes Cka degradation (Liu et al. 2016). Reason: Pelle-mediated phosphorylation leads to Cka degradation; secondary to its core Toll pathway role. Supporting Evidence: PMID:26824654 We further show that Gram-positive bacteria activate Hippo signaling in fat bodies through Toll-dependent, Pelle-mediated phosphorylation and degradation of Cka, an essential subunit of the STRIPAK PP2A complex, which normally associates with Hpo and antagonizes its kinase activity. |
| GO:0048262 determination of dorsal/ventral asymmetry | IMP PMID:7635064 Interaction of the pelle kinase with the membrane-associated... | ACCEPT | Summary: Pelle-Tube interaction required for D/V signal (Galindo et al. 1995). Reason: Core developmental role. Supporting Evidence: PMID:7635064 We demonstrate that fusion of the pelle catalytic domain to the transmembrane receptor torso is sufficient to induce ventral fates |
| GO:0061760 antifungal innate immune response | IMP PMID:10973475 Toll-related receptors and the control of antimicrobial pept... | ACCEPT | Summary: DN Pelle blocks Spaetzle-induced drosomycin. Reason: Core immune role. Supporting Evidence: PMID:10973475 a dominant-negative version of the kinase Pelle can block induction of drosomycin by the cytokine Spaetzle, but does not affect induction of the antibacterial peptide attacin by lipopolysaccharide |
| GO:0106310 protein serine kinase activity | EXP PMID:8440018 pelle encodes a protein kinase required to establish dorsove... | ACCEPT | Summary: Pelle kinase activity (Shelton and Wasserman 1993; UniProt Rhea reactions cite this paper). Reason: Pelle is a Ser/Thr kinase. Supporting Evidence: PMID:8440018 pelle encodes a protein of 501 amino acids, the last 292 of which comprise a protein kinase catalytic domain PMID:8440018 the kinase catalytic domain is required for biological activity |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea mapping to protein serine kinase activity. Reason: Consistent with experimental data. Supporting Evidence: PMID:8440018 pelle encodes a protein of 501 amino acids, the last 292 of which comprise a protein kinase catalytic domain |
| GO:1902533 positive regulation of intracellular signal transduction | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA positive regulation of intracellular signal transduction. Reason: Not wrong, but Pelle is itself a component of the Toll signalling pathway rather than a separate regulator of it; GO:0008063 is the informative annotation. Supporting Evidence: PMID:7635064 tube and the protein kinase pelle transduce an intracellular signal generated by the transmembrane receptor Toll |
| GO:2000060 positive regulation of ubiquitin-dependent protein catabolic process | IMP PMID:24086459 The IRAK homolog Pelle is the functional counterpart of IΞΊB ... | ACCEPT | Summary: Pelle phosphorylates Cactus, triggering Slimb-mediated ubiquitination and proteasomal degradation. Reason: Direct: Pelle creates the phosphodegron recognised by Slimb, so it positively regulates ubiquitin-dependent degradation of Cactus. Supporting Evidence: PMID:24086459 Pelle phosphorylates Cactus, triggering recognition by the Slimb Ξ²TrCP and subsequent ubiquitination and proteasome mediated degradation. |
| GO:0008384 IkappaB kinase activity | IDA PMID:24086459 The IRAK homolog Pelle is the functional counterpart of IΞΊB ... | NEW | Summary: Pelle directly phosphorylates Cactus, the Drosophila IkappaB, at the signal-responsive degron serines, and also phosphorylates Ser32/Ser36 of the IkappaBalpha degron in vitro. Reason: Participation: Pelle is the catalyst of the step (in vitro kinase assays with recombinant Pelle; kinase activity strictly required for Toll signalling; no IKK acts in fly Toll signalling and screens found no other Cactus kinase). Comparator: the catalytic IKK subunits (human CHUK/IKBKB, fly IKKbeta) carry GO:0008384 as the enzymes that phosphorylate IkappaB; Pelle stands in that same enzymatic role for Cactus. GO:0008384 is_a GO:0004674, which Pelle already carries, so this adds specificity rather than redundancy. Supporting Evidence: PMID:24086459 We conclude that Pelle acts as a Cactus kinase and preferentially phosphorylates Cactus at the serines required for signal responsiveness. PMID:24086459 In Drosophila, Toll signaling directs Cactus degradation via a sequence motif that is highly similar to that in IΞΊBΞ±, but without involvement of IKK. PMID:24086459 The protein kinase activity of Pelle is strictly required for Toll signaling and forced expression of Pelle drives Cactus degradation |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Is Cactus the only physiological substrate needed for Toll signalling, or do Pelle phosphorylation of Tube, Toll, dTRAF2 and Cka each contribute in vivo? Which of these in vitro substrates are phosphorylated by endogenous Pelle after infection?
Q: Pelle has no counterpart of the IKK complex acting between it and Cactus. Should GO:0008384 IkappaB kinase activity be applied more widely to Pelle orthologues in insects, or is the Pelle-to-Cactus shortcut specific to Drosophila and close relatives?
Q: The IRAK clade IBA propagates LPS-mediated signalling and nuclear localisation to Pelle. Should the PAINT node carrying GO:0031663 be moved to a vertebrate-specific node so that it no longer reaches insect Pelle?
Q: Should Pelle carry a Toll-independent anti-apoptotic role? Loss of pll causes dFoxO-dependent apoptosis in the wing, and Pelle binds and phosphorylates dFoxO (PMID:26474173), which would support negative regulation of apoptosis rather than the removed apoptotic process NAS row. Is dFoxO a direct physiological substrate in vivo, and on which residues?
Experiment: Phosphoproteomics of fat bodies from wild-type and pll kinase-dead (K240R) knock-in flies after Micrococcus luteus infection, to identify Pelle-dependent phosphosites on Cactus, Tube, Cka and other candidates in vivo.
Hypothesis: Cactus degron phosphorylation depends on Pelle kinase activity in vivo, and other reported substrates may or may not be phosphorylated under physiological conditions.
Type: quantitative phosphoproteomics
Experiment: Reconstitute Toll-MyD88-Tube-Pelle assembly with purified proteins and cryo-EM, testing how death domain oligomerisation drives Pelle autophosphorylation.
Hypothesis: Pelle is activated by proximity-induced trans-autophosphorylation in a higher-order death domain assembly analogous to the vertebrate Myddosome.
Type: structural biology
Loading supporting contentβ¦
Download this section (compressed HTML)Pelle (pll) encodes a tyrosine kinase-like family serine-threonine protein kinase that functions in the Toll pathway, a signaling cascade that plays key roles in various developmental and immune processes, notably embryonic dorso-ventral patterning and regulation of antimicrobial peptide production.
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)