Abl-dependent tyrosine phosphorylation of Sos-1 mediates growth-factor-induced Rac activation.
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.
Sini
Patrizia
P
Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti, 435, 20141 Milan, Italy.
Cannas
Angela
A
Koleske
Anthony J
AJ
Di Fiore
Pier Paolo
PP
Scita
Giorgio
G
D008841:Actin Cytoskeleton / Q000201:enzymology*; D000818:Animals; D019556:COS Cells; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D020837:SOS1 Protein / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*
D006133:Growth Substances; D020837:SOS1 Protein; D014443:Tyrosine; D020794:Receptor Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D020744:rac GTP-Binding Proteins