Phosphorylation of SOS1 on tyrosine 1196 promotes its RAC GEF activity and contributes to BCR-ABL leukemogenesis

• DOI: 10.1038/leu.2017.267
• Publication Date: 2017-08-18T10:08:48Z
• Authors: S Gerboth; E Frittoli; A Palamidessi; F C Baltanas; M Salek; J Rappsilber; C Giuliani; F Troglio; Y Rolland; G Pruneri; S Kreutmair; I Pallavicini; M Zobel; M Cinquanta; S Minucci; C Gomez; E Santos; A L Illert; G Scita
• Keywords: Rac GTP-Binding Proteins

Son of Sevenless 1 (SOS1) is a dual guanine nucleotide exchange factor (GEF) that activates the small GTPases RAC and RAS. Although molecular mechanisms RAS GEF catalysis have been unveiled, how SOS1 acquires activity what physio-pathological relevance this much less understood. Here we show tyrosine phosphorylated on Y1196 by ABL. Phosphorylation controls inter-molecular interaction, required to promote nucleotides in vitro for platelet-derived growth (PDGF) activation RAC- RAC-dependent actin remodeling cell migration. also BCR-ABL chronic myelogenous leukemic cells. Importantly, these cells, BCR-ABL-mediated RAC, proliferation transformation xenograft mouse model. Finally, genetic removal Sos1 bone marrow-derived cells (BMDCs) from Sos1fl/fl mice infected with causes significant delay onset leukemogenesis once BMDCs are injected into recipient, lethally irradiated mice. Thus, full critically contribute leukemogenic potential BCR-ABL.