Abstract
Over the past few years, it has become increasingly apparent that signal transduction pathways are not merely linear cascades; they are organized into complex signaling networks that require high levels of regulation to generate precise and unique cell responses. However, the underlying regulatory mechanisms by which signaling pathways cross-communicate remain poorly understood. Here we show that the Ras-binding protein Canoe (Cno)/AF-6, a PDZ protein normally associated with cellular junctions, is a key modulator of Wingless (Wg)/Wnt, Ras-Mitogen Activated Protein Kinase (MAPK) and Notch (N) signaling pathways cross-communication. Our data show a repressive effect of Cno/AF-6 on these three signaling pathways through physical interactions with Ras, N and the cytoplasmic protein Dishevelled (Dsh), a key Wg effector. We propose a model in which Cno, through those interactions, actively coordinates, at the membrane level, Ras-MAPK, N and Wg signaling pathways during progenitor specification.
Highlights
In multicellular organisms, cells are exposed to a complex environment in which they read numerous and sometimes conflicting stimuli
We suggest that Cno, by binding RasAct, Dsh and N, represses the signals that these proteins trigger and actively coordinates, at the membrane level, Receptor Tyrosine Kinase (RTK)-Ras-Mitogen Activated Protein Kinase (MAPK), Dl-N and Wg-Dsh signaling pathways throughout progenitor specification
The specification of dorsal somatic muscle/heart progenitors depends on the combinatorial action of multiple signaling pathways [10]
Summary
Cells are exposed to a complex environment in which they read numerous and sometimes conflicting stimuli. Somatic muscle and heart progenitors are singled out from clusters of equivalent cells (‘‘promuscle groups’’) that express the transcription factor Lethal of scute (L’sc), in a process reminiscent of neural progenitor specification [5]. These progenitors divide asymmetrically to give rise to two founder cells [6,7]. We have focused on the specification of a dorsal subset of muscle and heart progenitors that express the identity protein Eve [9] These progenitors differentiate upon the concerted and combinatorial action of four highly conserved signal transduction pathways triggered by Wingless (Wg)/Wnt, Decapentaplegic (Dpp)/TGF-b, Receptor Tyrosine Kinase (RTK)-Ras-MAPK and Notch (N) [10]. The mechanisms by which N and Ras pathways cross-communicate are only beginning to be elucidated [19,20,21,22,23]
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