Abstract
The non-receptor tyrosine kinase Abl participates in receptor tyrosine kinase (RTK)-induced actin cytoskeleton remodelling, a signalling pathway in which the function of Rac is pivotal. More importantly, the activity of Rac is indispensable for the leukaemogenic ability of the BCR-Abl oncoprotein. Thus, Rac might function downstream of Abl and be activated by it. Here, we elucidate the molecular mechanisms through which Abl signals to Rac in RTK-activated pathways. We show that Sos-1, a dual guanine nucleotide-exchange factor (GEF), is phosphorylated on tyrosine, after activation of RTKs, in an Abl-dependent manner. Sos-1 and Abl interact in vivo, and Abl-induced tyrosine phosphorylation of Sos-1 is sufficient to elicit its Rac-GEF activity in vitro. Genetic or pharmacological interference with Abl (and the related kinase Arg) resulted in a marked decrease in Rac activation induced by physiological doses of growth factors. Thus, our data identify the molecular connections of a pathway RTKs–Abl–Sos-1–Rac that is involved in signal transduction and actin remodelling.
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Acknowledgements
We thank E. Frittoli and I. Ponzanelli for technical assistance, and M. A. Pearson for critically reading the manuscript. This work was supported by grants from: Associazione Italiana Ricerca sul Cancro (AIRC) to G.S. and P.P.D.F.; Telethon Foundation, the Consiglio Nazionale delle Ricerche (Target project Biotechnology) and the European Community (V and VI Framework) to P.P.D.F.; the Swiss National Science foundation to A.C.; and the Italian Ministry of Health (Grant R.F. 02/184) to G.S.
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Sini, P., Cannas, A., Koleske, A. et al. Abl-dependent tyrosine phosphorylation of Sos-1 mediates growth-factor-induced Rac activation. Nat Cell Biol 6, 268–274 (2004). https://doi.org/10.1038/ncb1096
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DOI: https://doi.org/10.1038/ncb1096
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