ebi regulates epidermal growth factor receptor signaling pathways in Drosophila

Abstract

ebi regulates the epidermal growth factor receptor (EGFR) signaling pathway at multiple steps in Drosophila development. Mutations in ebi and Egfr lead to similar phenotypes and show genetic interactions. However, ebi does not show genetic interactions with other RTKs (e.g., torso) or with components of the canonical Ras/MAP kinase pathway. ebi encodes an evolutionarily conserved protein with a unique amino terminus, distantly related to F-box sequences, and six tandemly arranged carboxy-terminal WD40 repeats. Epidermal growth factor receptors (EGFRs) have a central role in vertebrate and invertebrate development (for review, see van der Geer et al. 1994;Wassarman et al. 1995;Freeman 1998). Biochemical studies largely in mammalian systems and genetic studies in Caenorhabditis elegans and Drosophila have led to a detailed description of the signal transduction pathways elicited by activation of the EGFR (for review, see Kayne and Sternberg 1995; Schwietzer and Shilo 1997). These include the Ras/MAP kinase (MAPK), Ca 2+ , and phosphatidyl inositol-dependent signaling pathways (for review, see Kazlauskas 1994). In Drosophila, the Ras/MAP kinase cascade is the prominent signaling pathway triggered by the EGFR. Two other fly receptor tyrosine kinases (RTKs) that control patterning and cell fate specification, Torso (for review, see Duffy and Perrimon 1994) and Sevenless (Sev) (for review, see Zipursky and Rubin 1994), do so largely, if not exclusively, through activation of this pathway.The development of the R7 photoreceptor neuron in the fly eye has proved to be a system amenable to detailed genetic dissection of RTK signaling pathways (Wassarman et al. 1995). Whereas the Sev RTK is required for the development of R7 only, EGFR is essential for the development of most, if not all, cells, including R7 (for review, see Freeman 1996a). This dual RTK requirement is intriguing. Constitutively active overexpressed forms of both Sev and EGFR are sufficient to induce R7 development. Furthermore, overexpression of Spitz, a ligand for EGFR, can partially rescue R7 development in a sev null mutant background. These findings have led Freeman (1996b) to propose that signals from Sev and EGFR are qualitatively equivalent. This is consistent with previous findings that overexpression of activated forms of proteins in the Ras/MAP kinase pathway induce receptor-independent R7 development (Fortini et al. 1992;Dickson et al. 1992a;Brunner et al. 1994). These observations support the view that activation of the Ras/MAPK pathway is sufficient to induce R7 development during normal development.The activities of three transcription factors are modulated by the MAPK signaling pathway in the R7 precursor cell. Two ETS-domain-containing transcription factors, Yan and Pointed, are direct targets of MAPK phosphorylation: Pointed is activated by phosphorylation and promotes R7 induction (O'Neil et al. 1994), whereas Yan is inhibited by phosphorylation and acts as a transcriptional repressor (Rebay and Rubin 1995). Inactivation of a second rep...

Basolateral Junctions Utilize Warts Signaling to Control Epithelial-Mesenchymal Transition and Proliferation Crucial For Migration and Invasion of Drosophila Ovarian Epithelial Cells

“…In addition, overexpression of all enhancers except ebi suppressed dlg and Fas2 tumorigenesis ( Figures 3C and 4D), further confirming that the identified genes function in a BLJ network. BLJ pathway components in the nucleus and their putative relationship to Notch: ebi encodes an F-box protein with WD repeats that promotes protein degradation of specific targets (Dong et al 1999;Boulton et al 2000). The failure of ebi overexpression to suppress Fas2 or dlg, and the relatively mild ebi phenotypes (midoogenesis small-nucleus and epithelial-organization defects, but no defects in germinal vesicle localization), suggest that ebi may function in only one of the three branches of BLJ signaling ( Figure 1A) or in a parallel pathway to the BLJ.…”

“…Thus ebi could enhance Fas2 and dlg tumorigenesis by functioning within the proliferationrepressing branch of the BLJ, or the importance of ebi for differentiation suggests that it could function in the EMT branch of the BLJ ( Figure 1A) or both. On the other hand, ebi promotes protein degradation in response to Notch (N) and Drosophila EGF receptor (EgfR) signals (Dong et al 1999;Boulton et al 2000;Tsuda et al 2002), suggesting that it may act in a parallel pathway. Both Ebi and its mammalian homolog, TBL1, function in a corepressor complex through association with nuclear hormone transcriptional corepressor SMRTER/SMRT (Guenther et al 2000;Tsuda et al 2002).…”

Signal integration during development: Insights from the Drosophila eye

“…As described above, activation of Notch prevents R7 from assuming the R1/R6 fate. One important function of RTKs in the presumptive R7 is to activate an E3 Ligase complex composed of Seven in absentia (Sina), Phyllopod (Phyl), and Ebi (Li et al, 1997;Tang et al, 1997;Dong et al, 1999;Boulton et al, 2000;Li et al, 2002). This E3 complex ubiquitinates Tramtrack88 (Ttk88), a transcriptional repressor, targeting it for proteolysis.…”

Ligand-dependent Degradation of Smad3 by a Ubiquitin Ligase Complex of ROC1 and Associated Proteins

“…We examined whether other E3 ligases induce the ubiquitination of Smad3. Fbw1a and hEbi1 are F-box proteins containing WD40 repeats, whereas Fbl1 (also termed Skp2) and Fbl5 have leucine-rich repeats (Cenciarelli et al, 1999;Dong et al, 1999;Winston et al, 1999a). Of these F-box proteins, only Fbw1a efficiently induced the ubiquitination of Smad3C ( Figure 4D).…”