Related Experiment Video
Updated: Feb 24, 2026
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Phosphorylation of SOS1 on tyrosine 1196 promotes its RAC GEF activity and contributes to BCR-ABL leukemogenesis
S Gerboth1, E Frittoli1, A Palamidessi1
1Department of Molecular Oncology, IFOM Foundation, Institute FIRC of Molecular Oncology, Milan, Italy.
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.
Insights
Son of Sevenless 1 (SOS1) phosphorylation by ABL and BCR-ABL on Y1196 is crucial for RAC activation. This SOS1 activity is vital for cell migration and BCR-ABL-driven chronic myelogenous leukemia progression.
Area of Science:
- Molecular Biology
- Cell Signaling
- Oncology
Background:
- Son of Sevenless 1 (SOS1) is a GEF activating RAC and RAS, but its RAC GEF activity and pathological role are unclear.
- Understanding SOS1's RAC GEF regulation and function is critical for deciphering cell signaling pathways and cancer development.
Purpose of the Study:
- To investigate the regulation of SOS1's RAC GEF activity by tyrosine phosphorylation.
- To determine the physio-pathological relevance of SOS1's RAC GEF activity in cell migration and chronic myelogenous leukemia (CML).
Main Methods:
- Investigated SOS1 tyrosine phosphorylation by ABL and BCR-ABL.
- Assessed SOS1's role in RAC nucleotide exchange in vitro.
- Utilized platelet-derived growth factor (PDGF) stimulation for cell migration assays.
- Examined SOS1's function in BCR-ABL-positive CML cells, including proliferation and transformation models.
- Employed genetic deletion of Sos1 in bone marrow-derived cells (BMDCs) in a leukemogenesis mouse model.
Main Results:
- SOS1 is tyrosine phosphorylated on Y1196 by ABL and BCR-ABL.
- Y1196 phosphorylation is essential for SOS1's RAC GEF activity in vitro.
- This phosphorylation drives PDGF-mediated RAC activation, actin remodeling, and cell migration.
- SOS1 is required for BCR-ABL-induced RAC activation, proliferation, and transformation in CML cells and a xenograft model.
- Genetic deletion of Sos1 in BMDCs significantly delays BCR-ABL-induced leukemogenesis.
Conclusions:
- Tyrosine phosphorylation of SOS1 on Y1196 by ABL/BCR-ABL is a key regulatory mechanism for its RAC GEF activity.
- SOS1's RAC GEF activity is critical for normal cell migration and pathological processes in CML.
- SOS1 is a significant contributor to the leukemogenic potential of BCR-ABL and a potential therapeutic target in CML.
Related Concept Videos
02:38The Ras Gene
Ras is a...
02:23Abnormal Proliferation
01:24Small GTPases - Ras and Rho
Three regulatory proteins control their activity:
01:22PI3K/mTOR/AKT Signaling Pathway
01:26Receptor Tyrosine Kinases
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...