Abstract
The subcellular localization of the epidermal growth factor receptor (EGFR) in polarized epithelial cells profoundly affects the activity of the intracellular signaling pathways activated after EGF ligand binding. Therefore, changes in EGFR localization and signaling are implicated in various human diseases, including different types of cancer. We have performed the first in vivo EGFR localization screen in an animal model by observing the expression of the EGFR ortholog LET-23 in the vulval epithelium of live C. elegans larvae. After systematically testing all genes known to produce an aberrant vulval phenotype, we have identified 81 genes regulating various aspects of EGFR localization and expression. In particular, we have found that ERM-1, the sole C. elegans Ezrin/Radixin/Moesin homolog, regulates EGFR localization and signaling in the vulval cells. ERM-1 interacts with the EGFR at the basolateral plasma membrane in a complex distinct from the previously identified LIN-2/LIN-7/LIN-10 receptor localization complex. We propose that ERM-1 binds to and sequesters basolateral LET-23 EGFR in an actin-rich inactive membrane compartment to restrict receptor mobility and signaling. In this manner, ERM-1 prevents the immediate activation of the entire pool of LET-23 EGFR and permits the generation of a long-lasting inductive signal. The regulation of receptor localization thus serves to fine-tune the temporal activation of intracellular signaling pathways.
Highlights
The formation of epithelial tissues involves the polarized distribution of growth factor receptors that determine cell proliferation and differentiation
We are investigating the regulation of the epidermal growth factor receptor (EGFR) homolog LET-23 in the Nematode C. elegans by observing the localization of the EGFR in the epithelial cells of live animals
This approach has allowed us to study the dynamics of receptor trafficking in cells embedded in their natural environment and receiving physiological concentrations of various extracellular signals
Summary
The formation of epithelial tissues involves the polarized distribution of growth factor receptors that determine cell proliferation and differentiation. In C. elegans, the let-23 gene encodes the sole member of the EGFR/ErbB family of receptor tyrosine kinases. Let-23 is involved in a variety of developmental processes including the induction of the hermaphrodite vulva [4]. In early second stage (L2) larvae, LET-23 is expressed at equal levels in the six equivalent vulval precursor cells (VPCs) (P3.p through P8.p) (Figure 1A) [5,6]. Beginning in the L2 stage, the gonadal anchor cell (AC) secretes the EGF ortholog LIN-3, which binds to LET-23 on the basolateral plasma membrane of the VPCs to activate the LET60 RAS/MPK-1 MAPK signaling pathway [4] (Figure 1B). In order to reach high levels of receptor activity, LET-23 must be retained on the basolateral membrane of the VPCs by a ternary protein complex consisting of the PDZ-domain proteins LIN-2
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
