Kekkon 6 (Kek-6) is a single-pass transmembrane protein of the Drosophila Kekkon family, with an extracellular region of leucine-rich repeats and one immunoglobulin domain and no cytoplasmic tyrosine kinase domain, resembling the truncated, kinase-less isoforms of vertebrate Trk neurotrophin receptors. It is expressed in central interneurons and motoneurons and is located in motoneuron axons and presynaptic boutons at the larval neuromuscular junction. Kek-6 binds the Drosophila neurotrophin DNT2 (Spz5), and promiscuously DNT1, and acts presynaptically downstream of muscle-derived DNT2, through the intracellular partners CaMKII and VAP33A, to promote neuromuscular junction growth, axonal branching and active zone formation. Kek-6 binds the other DNT2 receptor, Toll-6, and the two receptors together regulate structural synaptic plasticity and homeostasis at the neuromuscular junction and synapse number, dendrite growth and survival of dopaminergic neurons in the adult brain.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005030 neurotrophin receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PAINT node PTN008615184, grounded on the experimental annotation of kek6 itself. Reason: Kek-6 binds DNT2 and DNT1 and acts genetically downstream of DNT2 in motoneurons, signalling via CaMKII; it is a kinase-less Trk-like neurotrophin receptor. The IBA's only donor is kek6 itself, which marks experimental grounding on the target, and PAINT has thereby judged the function to be inherited by the node's descendants. Supporting Evidence: PMID:28846707 DNT2 binds Kek-6, which functions via CaMKII and VAP33A downstream. PMID:28846707 demonstrating that Kek-6 functions downstream of DNT2 |
| GO:0005030 neurotrophin receptor activity | IDA PMID:28846707 Kek-6: A truncated-Trk-like receptor for Drosophila neurotro... | ACCEPT | Summary: Kek-6 binds DNT2 (co-immunoprecipitation, signaling assays) and transduces its presynaptic signal via CaMKII and VAP33A. Reason: Binding of DNT2 to Kek-6, epistasis placing Kek-6 downstream of DNT2 and upstream of CaMKII and VAP33A, and the requirement of Kek-6 for DNT2-induced NMJ growth establish a neurotrophin receptor activity, even without a kinase domain. Core function. Supporting Evidence: PMID:28846707 Kek-6 is expressed in the CNS, interacts genetically with DNTs and can bind DNT2 in signaling assays and co-immunoprecipitations. PMID:28846707 Epistasis analysis demonstrated that Kek-6 functions in motoneurons downstream of DNT2 and upstream of CaMKII and VAP33A to promote both NMJ growth, and active zone formation (Fig 12C). |
| GO:0005886 plasma membrane | ISM PMID:15020419 Conservation of an inhibitor of the epidermal growth factor ... | ACCEPT | Summary: Sequence-model inference of plasma membrane location for a Kekkon family transmembrane protein. Reason: Kek-6 has a signal peptide and a single transmembrane segment, binds the secreted ligand DNT2 extracellularly and partners intracellularly with CaMKII and VAP33A, consistent with a type I plasma membrane receptor. The cited paper concerns Kek1, but family members share the transmembrane LRR-Ig architecture. Supporting Evidence: PMID:15179511 Kek1 is the founding member of the Kek family, a group of six Drosophila transmembrane proteins that contain seven LRRs and a single Ig in their extracellular domains. file:DROME/kek6/kek6-uniprot.txt FT TRANSMEM 385..410 |
| GO:0030424 axon | IDA PMID:28846707 Kek-6: A truncated-Trk-like receptor for Drosophila neurotro... | KEEP AS NON CORE | Summary: Kek-6 reporters are distributed along motoneuron axons as well as at NMJ terminals. Reason: Directly observed, but the receptor acts at the presynaptic terminal (type I bouton), where DNT2 is received; axonal distribution is a transit/peripheral location. Supporting Evidence: PMID:28846707 (F) Kek-6>FlyBow was also distributed along the motoneuron axons, NMJ terminal (arrow) and synaptic boutons (arrows). |
| GO:0038179 neurotrophin signaling pathway | IEA GO_REF:0000108 | ACCEPT | Summary: Inferred from neurotrophin receptor activity. Reason: Kek-6 is a receptor in DNT2 signalling at the NMJ and in a dopaminergic circuit; core process. Supporting Evidence: PMID:28846707 DNT2 binds Kek-6, which functions via CaMKII and VAP33A downstream. |
| GO:0043121 neurotrophin binding | IPI PMID:28846707 Kek-6: A truncated-Trk-like receptor for Drosophila neurotro... | ACCEPT | Summary: Reciprocal co-immunoprecipitation of Kek-6 and DNT2 from co-transfected S2 cells. Reason: Direct evidence of ligand binding by the receptor, the ligand-binding half of its neurotrophin receptor activity; Kek-6 also binds DNT1. Supporting Evidence: PMID:28846707 Precipitating Kek6-HA with anti-HA, brought down DNT2-V5 detected with anti-V5 (Fig 2B). PMID:28846707 Ligand binding is promiscuous, as Kek-6 can also bind DNT1, and Kek-2 and Kek-5 can also bind DNT2. |
| GO:0048167 regulation of synaptic plasticity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PTN008615184, grounded on kek6's own experimental annotation. Reason: Consistent with the experimental data showing Kek-6 regulates structural synaptic plasticity and homeostasis at the NMJ and in an adult dopaminergic circuit. Supporting Evidence: PMID:28846707 Kek-6 and Toll-6 interact physically, and together regulate structural synaptic plasticity and homeostasis. |
| GO:0048167 regulation of synaptic plasticity | IMP PMID:28846707 Kek-6: A truncated-Trk-like receptor for Drosophila neurotro... | ACCEPT | Summary: kek6 mutants have smaller NMJs with fewer boutons and reduced branching, and fail to compensate active zones together with Toll-6 or DNT2 loss. Reason: Loss- and gain-of-function analyses show Kek-6 regulates NMJ growth, branching and active zone formation and is required for structural synaptic homeostasis; corroborated in the adult dopaminergic circuit. Core process downstream of DNT2. Supporting Evidence: PMID:28846707 Kek-6 and Toll-6 interact physically, and together regulate structural synaptic plasticity and homeostasis. PMID:39704728 DNT-2 with Toll-6 and Kek-6 induced structural plasticity in this circuit modifying brain function and behaviour. |
| GO:0061174 type I terminal bouton | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PTN008615184, grounded on kek6's own IDA. Reason: Consistent with the direct localization of Kek-6 in presynaptic type Ib boutons at the larval NMJ, where it receives retrograde DNT2. Supporting Evidence: PMID:28846707 In vivo, Kek-6 is found presynaptically in motoneurons, and DNT2 is produced by the muscle to function as a retrograde factor at the NMJ. |
| GO:0061174 type I terminal bouton | IDA PMID:28846707 Kek-6: A truncated-Trk-like receptor for Drosophila neurotro... | ACCEPT | Summary: Kek-6-GFP is in motoneuron terminals and the lumen of presynaptic boutons at the NMJ, not in muscle. Reason: Direct localization at the site where the DNT2-Kek-6 signal acts. Supporting Evidence: PMID:28846707 Kek6GFP was present in motoneuron terminals at the neuro muscular junction (NMJ) of third instar larvae and not in the muscle |
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Download this section (compressed HTML)Q: Does Kek-6 transduce a signal on its own (CaMKII activation through its cytoplasmic tail) or chiefly as a co-receptor modifying Toll-6 signalling, and would GO:0015026 coreceptor activity describe it better than neurotrophin receptor activity?
Experiment: Measure direct DNT2-Kek-6 ectodomain binding affinity (SPR/BLI) alone and with the Toll-6 ectodomain, to test whether Kek-6 and Toll-6 form a ternary DNT2 receptor complex.
Experiment: Map the Kek-6 cytoplasmic region needed for CaMKII and VAP33A binding and test a tail-deletion kek6 transgene for rescue of kek6 NMJ phenotypes.
kekkon 6 (kek6) encodes a co-receptor for spz5, its other receptor being Toll-6. kek6 functions by activating CaMKII and inducing synaptogenesis and axonal branching at the neuromuscular junction.
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