Kekkon-1 (Kek1) is a single-pass type-I transmembrane glycoprotein of Drosophila melanogaster and the founding member of the Kekkon family. Its ectodomain combines an array of leucine-rich repeats (LRRs) with a single immunoglobulin (Ig)-like domain, followed by one transmembrane helix and a long, largely disordered cytoplasmic tail. Kek1 is a dedicated negative-feedback inhibitor of the Drosophila EGF receptor (DER/EGFR); it is transcriptionally induced by EGFR activity and its extracellular LRRs bind directly to the receptor to form an inactive heterodimeric complex, blocking ligand binding, receptor autophosphorylation and downstream ERK activation. Binding and inhibition are separable activities: the first two LRRs specify high-affinity EGFR binding, while the juxta/transmembrane region is additionally required for inhibition (a bipartite mechanism), and the cytoplasmic tail directs apical plasma-membrane localization. This feedback attenuation shapes multiple EGFR-dependent developmental decisions, most notably patterning of the follicular epithelium and dorsoventral axis during oogenesis, and eye development. Kek1 was originally identified together with kek2 as an LRR+Ig cell-surface protein expressed in differentiating CNS neurons and in patterned epithelia; single kek1 deletion produces no overt phenotype, consistent with family redundancy. The EGFR-inhibitor role is conserved among dipterans but is absent from vertebrates and Caenorhabditis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005154 epidermal growth factor receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: Direct binding of Kek1 to the EGF receptor via its extracellular LRR domains is the core molecular function and is experimentally established; the phylogenetic IBA is at the correct level of specificity. Reason: EGFR binding is directly demonstrated by co-association and structure-function studies, and the IBA agrees with the experimental IPI annotations for this gene. Supporting Evidence: PMID:12900463 the extracellular Leucine-Rich Repeat (LRR) domains of Kek1 are critical for its function through direct association with DER |
| GO:0016324 apical plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Kek1 is an apically localized transmembrane protein; its cytoplasmic tail directs apical targeting, where it engages EGFR. The IBA localization matches the experimental IDA annotation. Reason: Apical plasma-membrane localization is experimentally supported and consistent across the family; the IBA is appropriate. Supporting Evidence: PMID:12900463 its cytoplasmic domain is required for apical subcellular localization |
| GO:0030547 signaling receptor inhibitor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Kek1 acts as a direct inhibitor of the EGF receptor, forming an inactive complex that blocks ligand binding and receptor autophosphorylation. This is a core molecular function well supported experimentally. Reason: Receptor-inhibitor activity is directly demonstrated (blocks growth-factor binding, autophosphorylation and ERK activation); the IBA is at the right level. Supporting Evidence: PMID:12900463 the Kek1/EGFR interaction inhibits growth factor binding, receptor autophosphorylation and Erk1/2 activation in response to EGF |
| GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Kek1 attenuates EGFR signaling in a transcriptionally-induced negative feedback loop; this is the core biological process and is strongly supported by multiple experimental studies. Reason: Negative regulation of EGFR signaling is the central, repeatedly validated role of Kek1; the IBA matches the experimental IMP/IGI/IDA annotations. Supporting Evidence: PMID:10102272 it acts in a negative feedback loop to modulate the activity of the EGFR tyrosine kinase |
| GO:0005154 epidermal growth factor receptor binding | IPI PMID:12900463 Mechanism of inhibition of the Drosophila and mammalian EGF ... | ACCEPT | Summary: Direct physical association between the Kek1 extracellular LRRs and DER was demonstrated by structure-function and co-association analysis, and extended to the mammalian ErbB family in cell-based assays. Reason: Experimental IPI directly supports EGF receptor binding, a core molecular function of Kek1. Supporting Evidence: PMID:12900463 Kek1 is capable of physically interacting with each of the known members of the mammalian ErbB receptor family PMID:12900463 the extracellular Leucine-Rich Repeat (LRR) domains of Kek1 are critical for its function through direct association with DER |
| GO:0030547 signaling receptor inhibitor activity | IDA PMID:12900463 Mechanism of inhibition of the Drosophila and mammalian EGF ... | ACCEPT | Summary: In mammalian ErbB/EGFR cell-based assays Kek1 directly inhibited growth-factor binding, receptor autophosphorylation and ERK activation, demonstrating receptor inhibitor activity. Reason: Direct experimental demonstration of receptor-inhibitor activity; a core MF. Supporting Evidence: PMID:12900463 the Kek1/EGFR interaction inhibits growth factor binding, receptor autophosphorylation and Erk1/2 activation in response to EGF |
| GO:0030547 signaling receptor inhibitor activity | IDA PMID:15166146 Bipartite inhibition of Drosophila epidermal growth factor r... | ACCEPT | Summary: Chimera and mutant analyses show Kek1 binds and inhibits the Drosophila EGFR, with LRRs sufficient for binding and the juxta/transmembrane region required for inhibition (bipartite mechanism), acting through DER domain V. Reason: Directly supports receptor-inhibitor activity; further resolves the structural basis of inhibition. Supporting Evidence: PMID:15166146 the LRRs of Kek1 in conjunction with its juxta/transmembrane region direct association and inhibition of the Drosophila EGFR through interactions with receptor domain V |
| GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway | IMP PMID:10102272 The transmembrane molecule kekkon 1 acts in a feedback loop ... | ACCEPT | Summary: Loss of kek1 increases EGFR signaling during oogenesis and overexpression mimics loss of EGFR activity, establishing kek1 as a negative-feedback regulator by mutant phenotype. Reason: Core biological process directly demonstrated by loss- and gain-of-function phenotypes. Supporting Evidence: PMID:10102272 loss of kek1 activity is associated with an increase in EGFR signaling |
| GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway | IGI PMID:10102272 The transmembrane molecule kekkon 1 acts in a feedback loop ... | ACCEPT | Summary: Genetic interaction with the EGFR/Gurken pathway places kek1 in a negative feedback loop attenuating receptor activity during oogenesis. Reason: Genetic-interaction evidence corroborates the core negative-regulation role; consistent with the IMP from the same study. Supporting Evidence: PMID:10102272 kek1 is expressed in response to the Gurken/EGFR signaling pathway, and loss of kek1 activity is associated with an increase in EGFR signaling |
| GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway | IDA PMID:12900463 Mechanism of inhibition of the Drosophila and mammalian EGF ... | ACCEPT | Summary: Kek1 downregulates DER/EGFR in a negative feedback loop, extending beyond oogenesis to other DER-mediated developmental processes; direct biochemical assays show inhibition of receptor activation. Reason: Directly supports negative regulation of EGFR signaling as a core process. Supporting Evidence: PMID:12900463 has previously been shown to act in a negative feedback loop to downregulate the Drosophila Epidermal Growth Factor Receptor (DER) during oogenesis |
| GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway | IGI PMID:15020418 Knockouts of Kekkon1 define sequence elements essential for ... | ACCEPT | Summary: kek1 knockout/loss-of-function alleles that reduce EGFR affinity or mislocalize the protein compromise inhibition during eye development, confirming negative regulation of EGFR signaling by genetic analysis. Reason: Genetic evidence for the core negative-regulation role, extended to the eye. Supporting Evidence: PMID:15020418 Kek1 inhibits EGFR activity during eye development and use this role to identify kek1 loss-of-function mutations that implicate the LRRs in directing receptor inhibition |
| GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway | IMP PMID:15166146 Bipartite inhibition of Drosophila epidermal growth factor r... | ACCEPT | Summary: Kek1-Kek2 and Kek1-EGFR chimeras and inhibition-specific alleles demonstrate by mutant phenotype that Kek1 inhibits the Drosophila EGFR, requiring both the LRRs and the juxta/transmembrane region. Reason: Mutant-phenotype evidence supporting the core negative-regulation process. Supporting Evidence: PMID:15166146 inhibition in vivo requires the Kek1 juxta/transmembrane region |
| GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway | IGI PMID:15166146 Bipartite inhibition of Drosophila epidermal growth factor r... | ACCEPT | Summary: EGFR alleles that specifically disrupt Kek1 binding/inhibition while preserving activation provide genetic-interaction evidence that Kek1 negatively regulates EGFR signaling via receptor domain V. Reason: Genetic-interaction evidence corroborating the core negative-regulation role. Supporting Evidence: PMID:15166146 we have identified a unique class of EGFR alleles that specifically disrupt Kek1 binding and inhibition, but preserve receptor activation |
| GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway | IMP PMID:11141565 Guidance of cell migration by EGF receptor signaling during ... | UNDECIDED | Summary: This paper (Duchek and Rorth) concerns EGFR/Gurken guidance of border-cell migration during oogenesis; the cached abstract does not mention kek1, so the kek1-specific supporting evidence cannot be verified from the available text. Reason: The cached record is abstract-only and foregrounds EGFR guidance of border-cell migration without naming kek1. Per curation guidance an experimental (IMP) FlyBase annotation should not be removed on the basis of an abstract that omits the gene; the full text (unavailable here) may assay kek1. Marked UNDECIDED pending full-text verification. The assigned term (negative regulation of EGFR signaling) is biologically consistent with the established function of Kek1. |
| GO:0005886 plasma membrane | IDA PMID:12900463 Mechanism of inhibition of the Drosophila and mammalian EGF ... | ACCEPT | Summary: Kek1 is a transmembrane protein localized at the plasma membrane; the more specific apical plasma-membrane annotation is captured separately. Reason: Correct localization supported by experimental data; the parent term is retained alongside the more specific apical plasma-membrane annotation. Supporting Evidence: PMID:12900463 its cytoplasmic domain is required for apical subcellular localization |
| GO:0016324 apical plasma membrane | IDA PMID:12900463 Mechanism of inhibition of the Drosophila and mammalian EGF ... | ACCEPT | Summary: Kek1 localizes apically at the plasma membrane, a targeting directed by its cytoplasmic tail and required for productive association with EGFR. Reason: Experimentally supported apical localization; the specific location where Kek1 acts. Supporting Evidence: PMID:12900463 its cytoplasmic domain is required for apical subcellular localization |
| GO:0030547 signaling receptor inhibitor activity | IDA PMID:11782411 Mechanism of activation of the Drosophila EGF Receptor by th... | UNDECIDED | Summary: This paper (Ghiglione 2002) analyzes activation of the Drosophila EGFR by the TGFalpha-like ligand Gurken (Star/Brho-mediated cleavage); the cached abstract does not mention kek1, so the receptor-inhibitor evidence cannot be verified from the available text. Reason: The cached record is abstract-only and concerns Gurken-mediated EGFR activation without naming kek1. Per curation guidance an experimental (IDA) FlyBase annotation should not be removed because the abstract omits the gene; the full text (unavailable) may assay kek1 as a control inhibitor. Marked UNDECIDED pending full-text verification. The term itself is consistent with the well-established inhibitor activity of Kek1. |
| GO:0005154 epidermal growth factor receptor binding | IPI PMID:10102272 The transmembrane molecule kekkon 1 acts in a feedback loop ... | ACCEPT | Summary: The founding study showed the Kek1 extracellular and transmembrane domains physically associate with the EGFR, directly supporting EGF receptor binding. Reason: Experimental IPI for the core binding function. Supporting Evidence: PMID:10102272 the extracellular and transmembrane domains of Kek1 can inhibit and physically associate with the EGFR |
| GO:0005154 epidermal growth factor receptor binding | IPI PMID:15166146 Bipartite inhibition of Drosophila epidermal growth factor r... | ACCEPT | Summary: Chimera analyses show the Kek1 LRRs are sufficient for EGFR binding, directly supporting EGF receptor binding. Reason: Experimental IPI for the core binding function; localizes binding to the LRRs. Supporting Evidence: PMID:15166146 while the LRRs suffice for EGFR binding |
| GO:0005886 plasma membrane | ISM PMID:15020419 Conservation of an inhibitor of the epidermal growth factor ... | ACCEPT | Summary: Kek1 is predicted from sequence to be a plasma-membrane transmembrane protein; consistent with experimentally determined apical plasma-membrane localization. Reason: Sequence-model localization consistent with experimental evidence; correct but less specific than the apical plasma-membrane annotation. Supporting Evidence: PMID:15020419 The extracellular and transmembrane portion of Kek1 is sufficient for its inhibitory activity in D. melanogaster. |
| GO:0005886 plasma membrane | ISM PMID:8812109 The Drosophila kekkon genes: novel members of both the leuci... | ACCEPT | Summary: From its predicted transmembrane topology and cell-surface signaling/adhesion homology, Kek1 was inferred to be a plasma-membrane protein. Reason: Sequence-model localization consistent with the transmembrane architecture and later experimental localization. Supporting Evidence: PMID:8812109 putative transmembrane proteins with six leucine-rich repeats and a single immunoglobulin loop |
| GO:0048477 oogenesis | IMP PMID:10102272 The transmembrane molecule kekkon 1 acts in a feedback loop ... | KEEP AS NON CORE | Summary: kek1 functions during oogenesis, where it is induced by Gurken/EGFR signaling in follicle cells and attenuates receptor activity; loss of kek1 perturbs EGFR-dependent follicular patterning. Oogenesis is the developmental arena of the EGFR-inhibitor function rather than an independent core function. Reason: Oogenesis is a broad developmental process; the specific contribution of Kek1 is the negative-feedback attenuation of EGFR signaling within it (captured by GO:0042059). The term is correct and experimentally supported, but is a developmental context rather than a core molecular role, so it is retained as non-core. Supporting Evidence: PMID:10102272 During oogenesis, kek1 is expressed in response to the Gurken/EGFR signaling pathway, and loss of kek1 activity is associated with an increase in EGFR signaling |
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Download this section (compressed HTML)Q: What is the structural basis of the Kek1-EGFR (DER domain V) interaction, and does the Ig domain contribute to binding or specificity beyond the LRRs?
Q: Does Kek1 have EGFR-independent functions in CNS neurons or at synapses, given its early neuronal expression and reported Toll-family interactions not represented in current GOA?
Experiment: Cryo-EM or crystallographic structure of the Kek1 ectodomain in complex with the DER extracellular region to define the inhibitory interface.
Experiment: Quantitative single-molecule or FRET assays to measure how the juxta/transmembrane region converts EGFR binding into inhibition (heterodimer formation versus ligand exclusion).
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