id: Q9VK54 gene_symbol: kek1 product_type: PROTEIN status: DRAFT taxon: id: NCBITaxon:7227 label: Drosophila melanogaster description: >- 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. existing_annotations: - term: id: GO:0005154 label: epidermal growth factor receptor binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: 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. action: ACCEPT 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. supported_by: - reference_id: PMID:12900463 supporting_text: the extracellular Leucine-Rich Repeat (LRR) domains of Kek1 are critical for its function through direct association with DER - term: id: GO:0016324 label: apical plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: 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. action: ACCEPT reason: Apical plasma-membrane localization is experimentally supported and consistent across the family; the IBA is appropriate. supported_by: - reference_id: PMID:12900463 supporting_text: its cytoplasmic domain is required for apical subcellular localization - term: id: GO:0030547 label: signaling receptor inhibitor activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: 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. action: ACCEPT reason: Receptor-inhibitor activity is directly demonstrated (blocks growth-factor binding, autophosphorylation and ERK activation); the IBA is at the right level. supported_by: - reference_id: PMID:12900463 supporting_text: the Kek1/EGFR interaction inhibits growth factor binding, receptor autophosphorylation and Erk1/2 activation in response to EGF - term: id: GO:0042059 label: negative regulation of epidermal growth factor receptor signaling pathway evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: 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. action: ACCEPT reason: Negative regulation of EGFR signaling is the central, repeatedly validated role of Kek1; the IBA matches the experimental IMP/IGI/IDA annotations. supported_by: - reference_id: PMID:10102272 supporting_text: it acts in a negative feedback loop to modulate the activity of the EGFR tyrosine kinase - term: id: GO:0005154 label: epidermal growth factor receptor binding evidence_type: IPI original_reference_id: PMID:12900463 qualifier: enables review: 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. action: ACCEPT reason: Experimental IPI directly supports EGF receptor binding, a core molecular function of Kek1. supported_by: - reference_id: PMID:12900463 supporting_text: Kek1 is capable of physically interacting with each of the known members of the mammalian ErbB receptor family - reference_id: PMID:12900463 supporting_text: the extracellular Leucine-Rich Repeat (LRR) domains of Kek1 are critical for its function through direct association with DER - term: id: GO:0030547 label: signaling receptor inhibitor activity evidence_type: IDA original_reference_id: PMID:12900463 qualifier: enables review: summary: In mammalian ErbB/EGFR cell-based assays Kek1 directly inhibited growth-factor binding, receptor autophosphorylation and ERK activation, demonstrating receptor inhibitor activity. action: ACCEPT reason: Direct experimental demonstration of receptor-inhibitor activity; a core MF. supported_by: - reference_id: PMID:12900463 supporting_text: the Kek1/EGFR interaction inhibits growth factor binding, receptor autophosphorylation and Erk1/2 activation in response to EGF - term: id: GO:0030547 label: signaling receptor inhibitor activity evidence_type: IDA original_reference_id: PMID:15166146 qualifier: enables review: 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. action: ACCEPT reason: Directly supports receptor-inhibitor activity; further resolves the structural basis of inhibition. supported_by: - reference_id: PMID:15166146 supporting_text: 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 - term: id: GO:0042059 label: negative regulation of epidermal growth factor receptor signaling pathway evidence_type: IMP original_reference_id: PMID:10102272 qualifier: involved_in review: 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. action: ACCEPT reason: Core biological process directly demonstrated by loss- and gain-of-function phenotypes. supported_by: - reference_id: PMID:10102272 supporting_text: loss of kek1 activity is associated with an increase in EGFR signaling - term: id: GO:0042059 label: negative regulation of epidermal growth factor receptor signaling pathway evidence_type: IGI original_reference_id: PMID:10102272 qualifier: involved_in review: summary: Genetic interaction with the EGFR/Gurken pathway places kek1 in a negative feedback loop attenuating receptor activity during oogenesis. action: ACCEPT reason: Genetic-interaction evidence corroborates the core negative-regulation role; consistent with the IMP from the same study. supported_by: - reference_id: PMID:10102272 supporting_text: kek1 is expressed in response to the Gurken/EGFR signaling pathway, and loss of kek1 activity is associated with an increase in EGFR signaling - term: id: GO:0042059 label: negative regulation of epidermal growth factor receptor signaling pathway evidence_type: IDA original_reference_id: PMID:12900463 qualifier: involved_in review: 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. action: ACCEPT reason: Directly supports negative regulation of EGFR signaling as a core process. supported_by: - reference_id: PMID:12900463 supporting_text: has previously been shown to act in a negative feedback loop to downregulate the Drosophila Epidermal Growth Factor Receptor (DER) during oogenesis - term: id: GO:0042059 label: negative regulation of epidermal growth factor receptor signaling pathway evidence_type: IGI original_reference_id: PMID:15020418 qualifier: involved_in review: 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. action: ACCEPT reason: Genetic evidence for the core negative-regulation role, extended to the eye. supported_by: - reference_id: PMID:15020418 supporting_text: 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 - term: id: GO:0042059 label: negative regulation of epidermal growth factor receptor signaling pathway evidence_type: IMP original_reference_id: PMID:15166146 qualifier: involved_in review: 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. action: ACCEPT reason: Mutant-phenotype evidence supporting the core negative-regulation process. supported_by: - reference_id: PMID:15166146 supporting_text: inhibition in vivo requires the Kek1 juxta/transmembrane region - term: id: GO:0042059 label: negative regulation of epidermal growth factor receptor signaling pathway evidence_type: IGI original_reference_id: PMID:15166146 qualifier: involved_in review: 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. action: ACCEPT reason: Genetic-interaction evidence corroborating the core negative-regulation role. supported_by: - reference_id: PMID:15166146 supporting_text: we have identified a unique class of EGFR alleles that specifically disrupt Kek1 binding and inhibition, but preserve receptor activation - term: id: GO:0042059 label: negative regulation of epidermal growth factor receptor signaling pathway evidence_type: IMP original_reference_id: PMID:11141565 qualifier: involved_in review: 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. action: UNDECIDED 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. - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:12900463 qualifier: located_in review: summary: Kek1 is a transmembrane protein localized at the plasma membrane; the more specific apical plasma-membrane annotation is captured separately. action: ACCEPT reason: Correct localization supported by experimental data; the parent term is retained alongside the more specific apical plasma-membrane annotation. supported_by: - reference_id: PMID:12900463 supporting_text: its cytoplasmic domain is required for apical subcellular localization - term: id: GO:0016324 label: apical plasma membrane evidence_type: IDA original_reference_id: PMID:12900463 qualifier: located_in review: summary: Kek1 localizes apically at the plasma membrane, a targeting directed by its cytoplasmic tail and required for productive association with EGFR. action: ACCEPT reason: Experimentally supported apical localization; the specific location where Kek1 acts. supported_by: - reference_id: PMID:12900463 supporting_text: its cytoplasmic domain is required for apical subcellular localization - term: id: GO:0030547 label: signaling receptor inhibitor activity evidence_type: IDA original_reference_id: PMID:11782411 qualifier: enables review: 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. action: UNDECIDED 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. - term: id: GO:0005154 label: epidermal growth factor receptor binding evidence_type: IPI original_reference_id: PMID:10102272 qualifier: enables review: summary: The founding study showed the Kek1 extracellular and transmembrane domains physically associate with the EGFR, directly supporting EGF receptor binding. action: ACCEPT reason: Experimental IPI for the core binding function. supported_by: - reference_id: PMID:10102272 supporting_text: the extracellular and transmembrane domains of Kek1 can inhibit and physically associate with the EGFR - term: id: GO:0005154 label: epidermal growth factor receptor binding evidence_type: IPI original_reference_id: PMID:15166146 qualifier: enables review: summary: Chimera analyses show the Kek1 LRRs are sufficient for EGFR binding, directly supporting EGF receptor binding. action: ACCEPT reason: Experimental IPI for the core binding function; localizes binding to the LRRs. supported_by: - reference_id: PMID:15166146 supporting_text: while the LRRs suffice for EGFR binding - term: id: GO:0005886 label: plasma membrane evidence_type: ISM original_reference_id: PMID:15020419 qualifier: located_in review: summary: Kek1 is predicted from sequence to be a plasma-membrane transmembrane protein; consistent with experimentally determined apical plasma-membrane localization. action: ACCEPT reason: Sequence-model localization consistent with experimental evidence; correct but less specific than the apical plasma-membrane annotation. supported_by: - reference_id: PMID:15020419 supporting_text: The extracellular and transmembrane portion of Kek1 is sufficient for its inhibitory activity in D. melanogaster. - term: id: GO:0005886 label: plasma membrane evidence_type: ISM original_reference_id: PMID:8812109 qualifier: located_in review: summary: From its predicted transmembrane topology and cell-surface signaling/adhesion homology, Kek1 was inferred to be a plasma-membrane protein. action: ACCEPT reason: Sequence-model localization consistent with the transmembrane architecture and later experimental localization. supported_by: - reference_id: PMID:8812109 supporting_text: putative transmembrane proteins with six leucine-rich repeats and a single immunoglobulin loop - term: id: GO:0048477 label: oogenesis evidence_type: IMP original_reference_id: PMID:10102272 qualifier: involved_in review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: PMID:10102272 supporting_text: 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 core_functions: - description: Kek1 binds directly to the Drosophila EGF receptor (DER/EGFR) through its extracellular leucine-rich repeats (chiefly LRR1 and LRR2), forming a heterodimeric complex with the receptor. molecular_function: id: GO:0005154 label: epidermal growth factor receptor binding supported_by: - reference_id: PMID:12900463 supporting_text: the extracellular Leucine-Rich Repeat (LRR) domains of Kek1 are critical for its function through direct association with DER - reference_id: PMID:15166146 supporting_text: while the LRRs suffice for EGFR binding - description: By binding EGFR and forming an inactive complex, Kek1 acts as a direct inhibitor of the receptor, blocking growth-factor binding, receptor autophosphorylation and downstream ERK activation, thereby providing transcriptionally-induced negative feedback on EGFR signaling. Binding (LRRs) and inhibition (juxta/transmembrane region) are separable, and the protein acts apically at the plasma membrane. molecular_function: id: GO:0030547 label: signaling receptor inhibitor activity directly_involved_in: - id: GO:0042059 label: negative regulation of epidermal growth factor receptor signaling pathway locations: - id: GO:0016324 label: apical plasma membrane supported_by: - reference_id: PMID:12900463 supporting_text: the Kek1/EGFR interaction inhibits growth factor binding, receptor autophosphorylation and Erk1/2 activation in response to EGF - reference_id: PMID:10102272 supporting_text: it acts in a negative feedback loop to modulate the activity of the EGFR tyrosine kinase references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: PMID:10102272 title: The transmembrane molecule kekkon 1 acts in a feedback loop to negatively regulate the activity of the Drosophila EGF receptor during oogenesis. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Founding study identifying Kek1 as an EGFR inhibitor acting in a negative feedback loop during oogenesis, with physical association of the extracellular/TM domains with EGFR. Directly supports the core MF and BP annotations. PubMed-verified. - id: PMID:11141565 title: Guidance of cell migration by EGF receptor signaling during Drosophila oogenesis. findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: Cached record is abstract-only and concerns EGFR/Gurken guidance of border-cell migration; the abstract does not mention kek1, so the kek1-specific GO:0042059 IMP annotation cannot be verified from the available text (marked UNDECIDED). - id: PMID:11782411 title: Mechanism of activation of the Drosophila EGF Receptor by the TGFalpha ligand Gurken during oogenesis. findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: Cached record is abstract-only and concerns Gurken/Star/Brho-mediated EGFR activation; the abstract does not mention kek1, so the GO:0030547 IDA annotation cannot be verified from the available text (marked UNDECIDED). - id: PMID:12900463 title: Mechanism of inhibition of the Drosophila and mammalian EGF receptors by the transmembrane protein Kekkon 1. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Key mechanistic study; LRRs mediate direct DER association, the cytoplasmic tail directs apical localization, Kek1 forms a heterodimer with DER, and in mammalian assays it inhibits ligand binding, autophosphorylation and ERK activation across ErbB receptors. Supports MF (binding, inhibitor), BP and localization annotations. - id: PMID:15020418 title: Knockouts of Kekkon1 define sequence elements essential for Drosophila epidermal growth factor receptor inhibition. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Loss-of-function alleles map EGFR binding to LRR1/LRR2 (class I, affinity) and localization to class II alleles, and demonstrate that Kek1 inhibits EGFR in eye development. Supports the negative-regulation and binding annotations. - id: PMID:15020419 title: Conservation of an inhibitor of the epidermal growth factor receptor, Kekkon1, in dipterans. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Establishes kek1 as a transcriptional EGFR target attenuating the receptor, expressed in dorsal follicle cells during D/V patterning, conserved among dipterans but absent from vertebrates and Caenorhabditis. Supports localization and BP context. - id: PMID:15166146 title: Bipartite inhibition of Drosophila epidermal growth factor receptor by the extracellular and transmembrane domains of Kekkon1. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Demonstrates the bipartite mechanism (LRRs sufficient for binding, juxta/transmembrane region required for inhibition) acting via DER domain V; inhibition is unique to Kek1 among family members. Supports MF binding/inhibitor and BP annotations. - id: PMID:8812109 title: 'The Drosophila kekkon genes: novel members of both the leucine-rich repeat and immunoglobulin superfamilies expressed in the CNS.' findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Original identification of kek1/kek2 as transmembrane LRR+Ig cell-surface proteins expressed in differentiating CNS neurons and in follicle cells (D/V gradient); kek1 deletion has no overt phenotype (family redundancy). Supports architecture and predicted plasma-membrane localization. proposed_new_terms: [] suggested_questions: - question: >- 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? - question: >- 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? suggested_experiments: - description: >- Cryo-EM or crystallographic structure of the Kek1 ectodomain in complex with the DER extracellular region to define the inhibitory interface. - description: >- Quantitative single-molecule or FRET assays to measure how the juxta/transmembrane region converts EGFR binding into inhibition (heterodimer formation versus ligand exclusion).