RT Journal Article
SR Electronic
T1 Proteomic and Functional Genomic Landscape of Receptor Tyrosine Kinase and Ras to Extracellular Signal–Regulated Kinase Signaling
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP rs10
OP rs10
DO 10.1126/scisignal.2002029
VO 4
IS 196
A1 Friedman, Adam A.
A1 Tucker, George
A1 Singh, Rohit
A1 Yan, Dong
A1 Vinayagam, Arunachalam
A1 Hu, Yanhui
A1 Binari, Richard
A1 Hong, Pengyu
A1 Sun, Xiaoyun
A1 Porto, Maura
A1 Pacifico, Svetlana
A1 Murali, Thilakam
A1 Finley, Russell L.
A1 Asara, John M.
A1 Berger, Bonnie
A1 Perrimon, Norbert
YR 2011
UL http://stke.sciencemag.org/content/4/196/rs10.abstract
AB 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.