Fasciclin 2, theDrosophilaorthologue of neural cell-adhesion molecule, inhibits EGF receptor signalling

Abstract

Adhesion proteins not only control the degree to which cells adhere to each other but are increasingly recognised as regulators of intercellular signalling. Using genetic screening in Drosophila, we have identified Fasciclin 2 (Fas2), the Drosophila orthologue of neural cell adhesion molecule (NCAM), as a physiologically significant and specific inhibitor of epidermal growth factor receptor (EGFR) signalling in development. We find that loss of fas2 genetically interacts with multiple genetic conditions that perturb EGFR signalling. Fas2 is expressed in dynamic patterns during imaginal disc development, and in the eye we have shown that this depends on EGFR activity, implying participation in a negative-feedback loop. Loss of fas2 causes characteristic EGFR hyperactivity phenotypes in the eye, notum and wing, and also leads to downregulation of Yan, a transcriptional repressor targeted for degradation by EGFR activity. No significant genetic interactions were detected with the Notch, Wingless, Hedgehog or Dpp pathways, nor did Fas2 inhibit the FGF receptor or Torso, indicating specificity in the inhibitory role of Fas2 in EGFR signalling. Our results introduce a new regulatory interaction between an adhesion protein and a Drosophila signalling pathway and highlight the extent to which the EGFR pathway must be regulated at multiple levels.

Evolutionary changes in TGFα distribution underlie morphological diversity in eggshells from Drosophila species

“…Several mechanisms have been shown to regulate EGFR signaling, including negative regulators, extracellular matrix proteins and coreceptors (Boisclair Lachance et al, 2009;Mao and Freeman, 2009;Wang et al, 2008;Zartman et al, 2009). It will be important to determine whether trans-acting elements can provide further local regulation of EGFR signaling to increase the robustness of DR formation through anchoring GRK along its entire path without affecting the dorsal-ventral axis of the fly.…”

A semi-correlative technique for the subcellular localization of proteins in Drosophila synapses

“…It is believed that in adult NMJs it is accumulated in the synaptic periactive zone where it functions as a homophilic cell adhesion molecule (Ashley et al, 2005;Marie et al, 2004;Schuster et al, 1996;Kristiansen and Hortsch, 2008;Mao and Freeman, 2009). Immunofluorescence revealed that the Fas II immunoreactivity is not precisely co-localized with another component of the Star marks a silver enhanced gold particle signaling for CSP.…”

“…Fasciclin II represents the structural and functional ortholog of the vertebrate NCAM (Kristiansen and Hortsch, 2008;Mao and Freeman, 2009). It is believed that in adult NMJs it is accumulated in the synaptic periactive zone where it functions as a homophilic cell adhesion molecule (Ashley et al, 2005;Marie et al, 2004;Schuster et al, 1996;Kristiansen and Hortsch, 2008;Mao and Freeman, 2009).…”

“…In addition, we show that this approach permits a threedimensional (3D) reconstruction of labeling patterns. We tested this protocol by detecting the subcellular localization of the cell adhesion molecule, Fasciclin II (Fas II) (Ashley et al, 2005;Mao and Freeman, 2009;Schuster et al, 1996;Kristiansen and Hortsch, 2008), and compared it with the localization of three other markers of Drosophila NMJs, which are widely used in immunofluorescence experiments: antibodies against cystein string protein, CSP (Arnold et al, 2004;Zinsmaier et al, 1994), dynamin associated protein, Dap160 (Koh et al, 2004;Marie et al, 2004), and NC82 antibody, which signals for Bruchpilot protein (Wagh et al, 2006).…”

The vav oncogene antagonises EGFR signalling and regulates adherens junction dynamics during Drosophila eye development

“…S2), consistent with the misoriented ommatidia observed in vav pupal retinas. Rotation defects and extra cells (including R7s) are also found in mutants for negative regulators of EGFR signalling, such as Sprouty and FasII (Casci et al, 1999;Mao and Freeman, 2009), as well as upon expression of dominant activators of EGFR pathway (Brunner et al, 1994;Strutt and Strutt, 2003). Thus, even though Vav has been so far shown to act positively downstream of the EGFR pathway, vav retina phenotypes are reminiscent of EGFR hyperactivity, suggesting that Vav has a new role as a negative regulator of EGFR signalling.…”