kek1 (kekkon-1, Q9VK54, FBgn0015399) — curation notes

Drosophila melanogaster. Single-pass type-I transmembrane protein of the LRR + Ig
(immunoglobulin) superfamily. Founding member of the Kekkon family. Best-established
function: a dedicated, transcriptionally-induced negative-feedback inhibitor of the
Drosophila EGF receptor (DER/EGFR).

Provenance of the cached literature

All 8 cached publications are abstract-only (full_text_available: false; the Genetics
papers include a "Full Text" block that is only the re-printed abstract). Supporting
quotes below are verbatim from those abstracts.

Architecture (MF/domain)

• Originally cloned with kek2 as a novel class of transmembrane LRR+Ig proteins:
  PMID:8812109
  and PMID:8812109
• UniProt Q9VK54 (880 aa): signal peptide 1–20, extracellular LRR array + Ig-like domain
  (329–430), single TM helix 444–467, and a long largely disordered cytoplasmic tail.
  InterPro/Pfam: LRR (PF13855 LRR_8 x2, SMART LRR_TYP x5, LRRCT), I-set Ig (PF07679).
• The LRRs form the EGFR-binding surface; the founding-family framing is repeated in
  PMID:15166146

Molecular function: EGFR binding + signaling receptor inhibitor activity

• Kek1 was identified as a direct EGFR inhibitor:
  PMID:10102272
• It physically associates with the receptor via its extracellular/TM domains:
  PMID:10102272
• The extracellular LRRs mediate direct binding; Kek1 forms a heterodimer with DER:
  PMID:12900463
  and PMID:12900463
• Mechanism of inhibition (mammalian cell assays): blocks ligand binding and receptor
  activation, extends to all ErbB family members:
  PMID:12900463
• Binding vs. inhibition are separable: LRRs suffice for binding, but the
  juxta/transmembrane region is required for inhibition (bipartite mechanism):
  PMID:15166146
  and the receptor determinant maps to DER domain V:
  PMID:15166146
• Loss-of-function missense alleles pinpoint LRR1/LRR2 as the binding surface:
  PMID:15020418
  with separable binding-affinity vs. localization classes:
  PMID:15020418
• Inhibition is specific to Kek1 among the family and not ligand/tissue restricted:
  PMID:15166146

GO mapping: GO:0005154 (epidermal growth factor receptor binding) and GO:0030547
(signaling receptor inhibitor activity) are both directly supported and represent the
core molecular functions.

Biological process: negative feedback on EGFR signaling

• kek1 is a transcriptional target of EGFR and acts in a feedback loop during oogenesis:
  PMID:10102272
  restated in PMID:15020419
• The same feedback role operates in other DER-mediated contexts, including the eye:
  PMID:12900463
  and PMID:15020418

GO mapping: GO:0042059 (negative regulation of EGFR signaling pathway) — core BP.

Oogenesis / dorsoventral patterning (developmental context)

• kek1 is expressed in dorsal follicle cells mirroring the EGFR-activation profile during
  D/V axis formation:
  PMID:15020419
• Early expression in follicle cells in a D/V gradient:
  PMID:8812109

Oogenesis (GO:0048477) is a legitimate developmental setting but is the arena in which the
EGFR-inhibitor function acts, not an independent core function → best kept as non-core.

Localization

• Kek1 localizes to the (apical) plasma membrane; the cytoplasmic tail directs apical
  targeting:
  PMID:12900463
• Predicted membrane/cell-surface protein from sequence:
  PMID:8812109

GO mapping: GO:0016324 (apical plasma membrane) and the parent GO:0005886 (plasma membrane).

Neuronal / CNS expression (family redundancy)

• kek1 and kek2 are expressed in differentiating CNS neurons; single kek1 deletion has no
  overt phenotype, consistent with family redundancy:
  PMID:8812109
  and PMID:8812109
• Note: broader synaptic-growth / Toll-family neuronal roles reported elsewhere for the
  Kekkon family are not represented in the current GOA set and are not annotated here.

Evolutionary note

• Kek1 EGFR-inhibitor function is conserved in dipterans but absent from vertebrates and
  C. elegans:
  PMID:15020419

Annotations that could not be verified from cached abstracts

• GO:0030547 IDA / PMID:11782411 (Ghiglione 2002): the cached abstract is about Gurken
  activation of EGFR (Star/Brho-mediated cleavage) and does not mention kek1. Full text
  unavailable → UNDECIDED (do not overrule an experimental FlyBase annotation).
• GO:0042059 IMP / PMID:11141565 (Duchek & Rørth 2001, Science): abstract is about EGFR
  guidance of border-cell migration and does not mention kek1. Full text unavailable →
  UNDECIDED.

Core functions (synthesis)

1. MF: epidermal growth factor receptor binding (GO:0005154) — LRR-mediated direct
   association with DER/EGFR.
2. MF: signaling receptor inhibitor activity (GO:0030547) — forms an inactive heterodimer
   with EGFR, blocking ligand binding and autophosphorylation.
   Directly involved in: negative regulation of EGFR signaling pathway (GO:0042059).
   Location: apical plasma membrane (GO:0016324).