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Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2218-23. doi: 10.1073/pnas.0812024106. Epub 2009 Jan 26.

Nodal points and complexity of Notch-Ras signal integration.

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  • 1Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.


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.

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