Phosphorylation of SOS1 on tyrosine 1196 promotes its RAC GEF activity and contributes to BCR-ABL leukemogenesis
Platelet-Derived Growth Factor
rac1 GTP-Binding Protein
0303 health sciences
Leukemia
Fusion Proteins, bcr-abl
610
rac GTP-Binding Proteins
Proto-Oncogene Proteins p21(ras)
Disease Models, Animal
Mice
03 medical and health sciences
Cell Transformation, Neoplastic
Cell Movement
Cell Line, Tumor
Animals
Guanine Nucleotide Exchange Factors
Humans
Tyrosine
Original Article
Phosphorylation
SOS1 Protein
Cell Proliferation
DOI:
10.1038/leu.2017.267
Publication Date:
2017-08-18T10:08:48Z
AUTHORS (19)
ABSTRACT
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/fl mice 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.
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