TY - JOUR
T1 - A Drosophila SH2-SH3 adaptor protein implicated in coupling the sevenless tyrosine kinase to an activator of Ras guanine nucleotide exchange, Sos
AU - Olivier, Jean Paul
AU - Raabe, Thomas
AU - Henkemeyer, Mark
AU - Dickson, Barry
AU - Mbamalu, Geraldine
AU - Margolis, Ben
AU - Schlessinger, Joseph
AU - Hafen, Ernst
AU - Pawson, Tony
N1 - Funding Information:
The first two authors contributed equally to this work. We thank Xiang-dong Liu for the initial characterization of the Su(SevS7)R1 mutation, Michael Hoffmann for polytene chromosome spreads, Utpal Banerjee for the gift of Sos cDNA, Alex Singer for help in construction of the pET-drk expression vector, and Gerald Gish for purification of the PET-drk protein. We are grateful to Michael Simon and Gerald Rubin for providing the E(sev)2B allele and sequence information and for helpful discussions. This work was supported by grants from Bristol-Myers-Squibb, the National Cancer Institute of Canada (NCIC), and the Medical Research Council of Canada (MRC); by an International Scholar Award from the Howard Hughes Medical Institute to T. P.; by grants from the Human Frontier Science Program and Sugen Inc. (J. S.); by a grant from the Lucille P. Markey Charitable Trust (B. M.); and by a grant from the Swiss National Science Foundation to E. H.; T. R. is supported by an EMBO long-term fellowship. M. H. is supported by a postdoctoral fellowship from the MRC. T. P. is a Terry Fox Cancer Research Scientist of the NCIC.
PY - 1993/4/9
Y1 - 1993/4/9
N2 - A Drosophila gene (drk) encodes a widely expressed protein with a single SH2 domain and two flanking SH3 domains, which is homologous to the Sem-5 protein of C. elegans and mammalian GRB2. Genetic analysis suggests that drk function is essential for signaling by the sevenless receptor tyrosine kinase. Drk biological activity correlates with binding of itS SH2 domain to activated receptor tyrosine kinases and concomitant localization of drk to the plasma membrane. In vitro, drk also binds directly to the C-terminal tall of Sos, a Ras guanine nucleotide-releasing protein (GNRP), which, like Ras1 and drk, is required for sevenless signaling. These results suggest that drk binds autophosphorylated receptor tyrosine kinases with its SH2 domain and the Sos GNRP through its SH3 domains, thereby coupling receptor tyrosine kinases to Ras activation. The conservation of these signaling proteins during evolution indicates that this is a general mechanism for linking tyrosine kinases to Ras.
AB - A Drosophila gene (drk) encodes a widely expressed protein with a single SH2 domain and two flanking SH3 domains, which is homologous to the Sem-5 protein of C. elegans and mammalian GRB2. Genetic analysis suggests that drk function is essential for signaling by the sevenless receptor tyrosine kinase. Drk biological activity correlates with binding of itS SH2 domain to activated receptor tyrosine kinases and concomitant localization of drk to the plasma membrane. In vitro, drk also binds directly to the C-terminal tall of Sos, a Ras guanine nucleotide-releasing protein (GNRP), which, like Ras1 and drk, is required for sevenless signaling. These results suggest that drk binds autophosphorylated receptor tyrosine kinases with its SH2 domain and the Sos GNRP through its SH3 domains, thereby coupling receptor tyrosine kinases to Ras activation. The conservation of these signaling proteins during evolution indicates that this is a general mechanism for linking tyrosine kinases to Ras.
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U2 - 10.1016/0092-8674(93)90170-U
DO - 10.1016/0092-8674(93)90170-U
M3 - Article
C2 - 8462098
AN - SCOPUS:0027468233
SN - 0092-8674
VL - 73
SP - 179
EP - 191
JO - Cell
JF - Cell
IS - 1
ER -