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Science 322 (5900): 453-456

Copyright © 2008 by the American Association for the Advancement of Science

Phosphorylation Networks Regulating JNK Activity in Diverse Genetic Backgrounds

Chris Bakal,1,2*{dagger} Rune Linding,3* Flora Llense,4* Elleard Heffern,2 Enrique Martin-Blanco,4 Tony Pawson,5 Norbert Perrimon1,2

Abstract: Cellular signaling networks have evolved to enable swift and accurate responses, even in the face of genetic or environmental perturbation. Thus, genetic screens may not identify all the genes that regulate different biological processes. Moreover, although classical screening approaches have succeeded in providing parts lists of the essential components of signaling networks, they typically do not provide much insight into the hierarchical and functional relations that exist among these components. We describe a high-throughput screen in which we used RNA interference to systematically inhibit two genes simultaneously in 17,724 combinations to identify regulators of Drosophila JUN NH2-terminal kinase (JNK). Using both genetic and phosphoproteomics data, we then implemented an integrative network algorithm to construct a JNK phosphorylation network, which provides structural and mechanistic insights into the systems architecture of JNK signaling.

1 Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02215, USA.
2 Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02215, USA.
3 Cellular & Molecular Logic Team, The Institute for Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
4 Institut de Biologia Molecular de Barcelona, CSIC (Spanish Council for Scientific Research), Parc Científic de Barcelona, 08028 Spain.
5 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.

* These authors contributed equally to this work

{dagger} To whom correspondence should be addressed. E-mail: cbakal{at}receptor.med.harvard.edu


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