The Transmembrane Molecule Kekkon 1 Acts in a Feedback Loop to Negatively Regulate the Activity of the Drosophila EGF Receptor during Oogenesis

Abstract

We have identified the Drosophila transmembrane molecule kekkon 1 (kek1) as an inhibitor of the epidermal growth factor receptor (EGFR) and demonstrate that it acts in a negative feedback loop to modulate the activity of the EGFR tyrosine kinase. 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. Consistent with our loss-of-function studies, we demonstrate that ectopic overexpression of kek1 mimics a loss of EGFR activity. We show that the extracellular and transmembrane domains of Kek1 can inhibit and physically associate with the EGFR, suggesting potential models for this inhibitory mechanism.

Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence

“…2F and data not shown). This is consistent with the role of Lrig1 in reducing EGF responsiveness by mediating ubiquitinylation and degradation of activated EGFR1 (24,27).…”

“…Global expression profiling of these cDNA libraries enabled us to identify Kekkon͞Lig1͞leucine-rich repeats and Ig-like domains 1 (Lrig1; ref. 24), a negative regulator of EGFR͞ErbB receptors, as a marker of putative SC. We present evidence that Lrig1 is a major determinant of SC quiescence.…”

“…We chose Lrig1 for further investigation because of its potential role in down-regulating EGF receptor responsiveness by increasing ubiquitinylation of the activated receptor (24,27), and because Lig1-null mice exhibit epidermal hyperproliferation (26). These features suggested that Lrig1 might play a role in maintaining epidermal SC in a quiescent state.…”

Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation

“…Shortly following the identification of Sprouty as an inducible inhibitor of FGF-signaling, another feedback regulator was shown to inhibit the activity of DER during oogenesis [40]. This gene, named kekkon-1, encodes a transmembrane protein that physically binds to and directly inhibits EGFR molecules [41].…”

Connecting signaling and cell cycle progression in growth factor-stimulated cells

“…Finally, there are proteins that prevent activation of receptor tyrosine kinases. Kek-1 is a transmembrane protein that physically interacts with the drosophila EGFR and antagonizes the e ect of EGFR (Ghiglione et al, 1999). Whether functionally similar proteins exists in mammalian systems, as well as what step of the activation mechanism they impact remain open questions.…”