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Sci. Signal., 25 October 2011
Vol. 4, Issue 196, p. rs10
[DOI: 10.1126/scisignal.2002029]


Proteomic and Functional Genomic Landscape of Receptor Tyrosine Kinase and Ras to Extracellular Signal–Regulated Kinase Signaling

Adam A. Friedman1,2,3, George Tucker4, Rohit Singh4, Dong Yan1,2, Arunachalam Vinayagam1,2, Yanhui Hu1,2, Richard Binari1,2, Pengyu Hong5, Xiaoyun Sun5, Maura Porto1,2, Svetlana Pacifico6, Thilakam Murali6, Russell L. Finley Jr.6, John M. Asara7,8, Bonnie Berger4,9, and Norbert Perrimon1,2*

1 Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
2 Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
3 Harvard–MIT Division of Health Sciences and Technology, Boston, MA 02115, USA.
4 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
5 Department of Computer Science, Volen Center for Complex Systems, Brandeis University, Waltham, MA 02454, USA.
6 Center for Molecular Medicine and Genetics and Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, MI 48201, USA.
7 Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
8 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
9 Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Abstract: Characterizing the extent and logic of signaling networks is essential to understanding specificity in such physiological and pathophysiological contexts as cell fate decisions and mechanisms of oncogenesis and resistance to chemotherapy. Cell-based RNA interference (RNAi) screens enable the inference of large numbers of genes that regulate signaling pathways, but these screens cannot provide network structure directly. We describe an integrated network around the canonical receptor tyrosine kinase (RTK)–Ras–extracellular signal–regulated kinase (ERK) signaling pathway, generated by combining parallel genome-wide RNAi screens with protein-protein interaction (PPI) mapping by tandem affinity purification–mass spectrometry. We found that only a small fraction of the total number of PPI or RNAi screen hits was isolated under all conditions tested and that most of these represented the known canonical pathway components, suggesting that much of the core canonical ERK pathway is known. Because most of the newly identified regulators are likely cell type– and RTK-specific, our analysis provides a resource for understanding how output through this clinically relevant pathway is regulated in different contexts. We report in vivo roles for several of the previously unknown regulators, including CG10289 and PpV, the Drosophila orthologs of two components of the serine/threonine–protein phosphatase 6 complex; the Drosophila ortholog of TepIV, a glycophosphatidylinositol-linked protein mutated in human cancers; CG6453, a noncatalytic subunit of glucosidase II; and Rtf1, a histone methyltransferase.

* To whom correspondence should be addressed. E-mail: perrimon{at}

Citation: A. A. Friedman, G. Tucker, R. Singh, D. Yan, A. Vinayagam, Y. Hu, R. Binari, P. Hong, X. Sun, M. Porto, S. Pacifico, T. Murali, R. L. Finley, Jr., J. M. Asara, B. Berger, N. Perrimon, Proteomic and Functional Genomic Landscape of Receptor Tyrosine Kinase and Ras to Extracellular Signal–Regulated Kinase Signaling. Sci. Signal. 4, rs10 (2011).

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