Son of Sevenless 1 (SOS1) is a dual guanine nucleotide exchange factor (GEF) that activates the small GTPases RAC and RAS. Although the molecular mechanisms of RAS GEF catalysis have been unveiled, how SOS1 acquires RAC GEF activity and what is the physio-pathological relevance of this activity is much less understood. Here we show that SOS1 is tyrosine phosphorylated on Y1196 by ABL. Phosphorylation of Y1196 controls SOS1 inter-molecular interaction, is required to promote the exchange of nucleotides on RAC in vitro and for platelet-derived growth factor (PDGF) activation of RAC- and RAC-dependent actin remodeling and cell migration. SOS1 is also phosphorylated on Y1196 by BCR-ABL in chronic myelogenous leukemic cells. Importantly, in these cells, SOS1 is required for BCR-ABL-mediated activation of RAC, cell proliferation and transformation in vitro and in a xenograft mouse model. Finally, genetic removal of Sos1 in the bone marrow-derived cells (BMDCs) from Sos1fl/flmice and infected with BCR-ABL causes a significant delay in the onset of leukemogenesis once BMDCs are injected into recipient, lethally irradiated mice. Thus, SOS1 is required for full transformation and critically contribute to the leukemogenic potential of BCR-ABL.
Phosphorylation of SOS1 on tyrosine 1196 promotes its RAC GEF activity and contributes to BCR-ABL leukemogenesis / 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. - In: LEUKEMIA. - ISSN 0887-6924. - 32:3(2018 Mar 01), pp. 820-827.
|Titolo:||Phosphorylation of SOS1 on tyrosine 1196 promotes its RAC GEF activity and contributes to BCR-ABL leukemogenesis|
GERBOTH, SILKE (Primo) [Investigation]
PRUNERI, GIANCARLO [Investigation]
ZOBEL, MARTINA MARIAROSARIA [Methodology]
MINUCCI, SAVERIO [Investigation]
SCITA, GIORGIO (Ultimo) [Writing – Original Draft Preparation] (Corresponding)
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Progetto:||Meccanismi di farmacoresistenza atipici: la plasticità delle cellule tumorali invasive come meccanismo di resistenza ai trattamenti farmacologici: il ruolo della Matrice Endocitica|
Ruolo dei network endocitici e del segnale lipidico nella plasticità della migrazione ed invazionetumorale
THE ENDOCYTIC AND CYTOSKELETAL MATRIX IN THE PLASTICITY OF TUMOR CELL INVASION AND MIGRATION
|Data di pubblicazione:||1-mar-2018|
|Data ahead of print / Data di stampa:||18-ago-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/leu.2017.267|
|Appare nelle tipologie:||01 - Articolo su periodico|