Cell fate-specific regulation of EGF receptor trafficking during Caenorhabditis elegans vulval development

Abstract

By controlling the subcellular localization of growth factor receptors, cells can modulate the activity of intracellular signal transduction pathways. During Caenorhabditis elegans vulval development, a ternary complex consisting of the LIN-7, LIN-2 and LIN-10 PDZ domain proteins localizes the epidermal growth factor receptor (EGFR) to the basolateral compartment of the vulval precursor cells (VPCs) to allow efficient receptor activation by the inductive EGF signal from the anchor cell. We have identified EGFR substrate protein-8 (EPS-8) as a novel component of the EGFR localization complex that links receptor trafficking to cell fate specification. EPS-8 expression is upregulated in the primary VPCs, where it creates a positive feedback loop in the EGFR/RAS/MAPK pathway. The membrane-associated guanylate kinase LIN-2 recruits EPS-8 into the receptor localization complex to retain the EGFR on the basolateral plasma membrane, and thus allow maximal receptor activation in the primary cell lineage. Low levels of EPS-8 in the neighboring secondary VPCs result in the rapid degradation of the EGFR, allowing these cells to adopt the secondary cell fate. Extracellular signals thus regulate EGFR trafficking in a cell typespecific manner to control pattern formation during organogenesis.

SEL-2, theC. elegansneurobeachin/LRBA homolog, is a negative regulator oflin-12/Notchactivity and affects endosomal traffic in polarized epithelial cells

“…When LIN-12 is activated in P5.p and P7.p by the lateral signal, LET-23/EGFR is downregulated (Stetak et al, 2006;Whitfield et al, 1999). By contrast, in a sel-2(-) mutant, LET-23/EGFR appears to accumulate aberrantly in P5.p and P7.p (Fig.…”

“…LET-23 is activated maximally in P6.p, leading to LIN-12 internalization via endocytosis and degradation via multivesicular endosomes (Shaye and Greenwald, 2002;Shaye and Greenwald, 2005), as well as to the production of ligands that activate LIN-12 in the neighboring cells, P5.p and P7.p (Chen and Greenwald, 2004). When LIN-12 is activated in P5.p and P7.p, LET-23 is downregulated (Whitfield et al, 1999;Stetak et al, 2006). target genes include factors that may negatively regulate LET-23/EGFR activity by promoting its endocytosis and degradation (Yoo et al, 2004;Yoo and Greenwald, 2005).…”

Trafficking of the EGFR ligand Spitz regulates its signaling activity in polarized tissues

“…In this context, signaling is prevented when the epithelial sheet is intact, and only upon wounding can the ligand access the receptor, thereby initiating the signaling that induces cell proliferation for wound repair (Vermeer et al, 2003). In contrast, localization of the C. elegans EGFR homolog LET-23 to the basolateral surface of vulval precursor cells is necessary to allow its interaction with LIN-3 ligand secreted from the anchor cell (Stetak et al, 2006) (Kaech et al, 1998). Our study suggests that localization of the ligand as well as the receptor regulates EGFR signaling in vivo.…”

CASK Deletion in Intestinal Epithelia Causes Mislocalization of LIN7C and the DLG1/Scrib Polarity Complex without Affecting Cell Polarity

“…(There are three closely related LIN7 isoforms in mammals, designated LIN7A,B,C/Velis-1,2,3/MALS-1,2,3; the one most widely expressed outside the nervous system is LIN7C [Butz et al, 1998;Irie et al, 1999;Jo et al, 1999].) The shared domain that mediates the CASK-LIN7 interaction is highly conserved (Doerks et al, 2000), and these two proteins can be coimmunoprecipitated from the Madin-Darby canine kidney (MDCK) epithelial cell line Stetak et al, 2006). Evidence from multiple studies suggests that LIN7 functions in the basolateral targeting of membrane proteins in mammalian epithelial cells (Perego et al, 1999;Straight et al, 2001;Alewine et al, 2007).…”