Vein is a novel component in the Drosophila epidermal growth factor receptor pathway with similarity to the neuregulins.

Abstract

The activation signal from tyrosine kinase receptors, such as the epidermal growth factor receptor (EGFR), is relayed via a highly conserved intracellular pathway involving Ras, Raf, and MAPK. In Drosophila, the EGFR and components of the intracellular pathway are broadly expressed, yet receptor activation evokes tissue-specific cell responses. Extracellular events that lead to receptor activation are one mechanism by which signaling is modulated. Here we show molecular and genetic evidence that Drosophila vein (vn) encodes a candidate EGFR ligand and that vn expression is spatially restricted. Consequently, vn may promote tissue-specific receptor activation. Unlike two other ligands, Gurken (Grk) and Spitz (Spi), which are transforming growth factor oMike proteins, Vn has both an immunoglobulin-like and an EGF-like domain. This combination of domains mirrors those in the vertebrate neuregulins that bind EGFR relatives. [Key Words: vein; Drosophila; EGF receptor; EGF; neuregulin]Received April 24, 1996; revised version accepted August 7, 1996.The Drosophila epidermal growth factor receptor (DER) is a receptor tyrosine kinase of the epidermal growth factor receptor (EGFR) subfamily that currently also includes four vertebrate proteins {EGFR/erbB1, neu/erbB2, erbB3, and erbB4) and Caenorhabditis elegans These receptors have important roles in development: EGFR mutant mice have epithelial defects that cause a number of phenotypes and early death (Miettinen et al. 1995;Sibilia and Wagner 1995;Threadgill et al. 1995); neu and erbB4 mutant embryos die in utero with heart and neural defects (Gassmann et al. 1995;Lee et al. 1995); let-23 is involved in determining vulval cell fate (Aroian et al. 1990; Hill and Sternberg 19921; and DER has multiple roles in Drosophila development involving cell survival, proliferation, and differentiation in embryos, imaginal discs, and the ovary (Shilo and

The Drosophila neuregulin homolog Vein mediates inductive interactions between myotubes and their epidermal attachment cells

“…Several partially overlapping cDNAs were isolated and sequenced. All of the cDNAs species analyzed were identical in their sequence to vein, a gene described recently by Schnepp et al (1996), which is involved in wing disc development. The hallmarks of the Vein protein demonstrated by Schnepp et al, and confirmed by our analysis, include a signal peptide at the amino-terminal domain followed by PEST sequences, an immunoglobulin-like domain, and a carboxy-terminal EGF-like domain (see Fig.…”

“…Much of the regulation of the Egfr signaling cascade is thought to be controlled by the localized release of its various ligands, as Egfr is widely expressed in all germ layers throughout embryonic development (Perrimon and Perkins 1997;Schweitzer and Shilo 1997). Three putative Egfr ligands have been described; these include two membrane-bound proteins, Spitz (Rutledge et al 1992), Gurken (Neuman-Silberberg and Schü pbach 1993), and Vein (Schnepp et al 1996), a neuregulin-like secreted protein. The similarity of Vein to vertebrate neuregulins (shown to bind various types of erbB receptors) suggests that Vein may function as a ligand of Egfr.…”

How the Dorsal gradient works: Insights from postgenome technologies

“…1). vein encodes a secreted EGF signaling molecule (18,19), whereas rho encodes a membrane protease that releases the Spitz EGF ligand from ventral regions of the neurogenic ectoderm (20,21). These EGF signals activate MAP kinase in both ventral and lateral regions of the neurogenic ectoderm (22).…”

DER signaling restricts the boundaries of the wing field during Drosophila development

“…6). The expression of vein (vn), a gene coding for a DER ligand, is restricted to a posterior and dorsal domain in second instar wing discs (7,8) (see Fig. 1H).…”