Nodal points and complexity of Notch-Ras signal integration.
Metazoans use a handful of highly conserved signaling pathways to create a signaling backbone that governs development. How these few signals have such a versatile action likely depends upon the larger-scale network they form through integration, as exemplified by cross-talk between the Notch and receptor tyrosine kinase (RTK) pathways. We examined the transcriptional output of Notch-RTK cross-talk during Drosophila development and present in vivo data supporting a role for selected mutually regulated genes in signal integration. Interestingly, Notch-RTK integration did not lead to general antagonism of either pathway, as is commonly believed. Instead, integration had a combinatorial effect on specific cross-regulated targets, which unexpectedly included numerous core components of the RTK and other major signaling pathways (TGF-beta, Hh, Jak/Stat, nuclear receptor and Wnt). We find the majority of Ras-responsive genes are also Notch-responsive, suggesting Notch may function to specify the response to Ras activation.
Hurlbut
Gregory D
GD
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Kankel
Mark W
MW
Artavanis-Tsakonas
Spyros
S
D000818:Animals; D003433:Crosses, Genetic; D004331:Drosophila melanogaster; D005786:Gene Expression Regulation; D006720:Homozygote; D053613:Janus Kinase 1 / Q000378:metabolism; D008954:Models, Biological; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D051880:Receptors, Notch; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D020794:Receptor Protein-Tyrosine Kinases; D053613:Janus Kinase 1; D018631:ras Proteins