The Bcr–Abl kinase regulates the actin cytoskeleton via a GADS/Slp-76/Nck1 adaptor protein pathway
Copyright policy )The Bcr–Abl kinase regulates the actin cytoskeleton via a GADS/Slp-76/Nck1 adaptor protein pathway
Bcr-Abl is the transforming principle underlying chronic myelogenous leukaemia (CML). Here, we use a functional interaction proteomics approach to map pathways by which Bcr-Abl regulates defined cellular processes. The results show that Bcr-Abl regulates the actin cytoskeleton and non-apoptotic membrane blebbing via a GADS/Slp-76/Nck1 adaptor protein pathway. The binding of GADS to Bcr-Abl requires Bcr-Abl tyrosine kinase activity and is sensitive to the Bcr-Abl inhibitor imatinib, while the GADS/Slp-76 and Slp-76/Nck interactions are tyrosine phosphorylation independent. All three adaptor proteins co-localize with cortical actin in membrane blebs. Downregulation of each adaptor protein disrupts the actin cytoskeleton and membrane blebbing in a similar fashion and similar to imatinib. These findings highlight the importance of protein interaction dependent adaptor protein pathways in oncogenic kinase signaling.
- University of Glasgow United Kingdom
- Cancer Research UK United Kingdom
- Cancer Research UK Scotland Institute United Kingdom
Oncogene Proteins, Cell Membrane, Fusion Proteins, bcr-abl, Protein-Tyrosine Kinases, Phosphoproteins, Actins, Protein Transport, Gene Knockdown Techniques, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Humans, Cell Surface Extensions, RNA, Small Interfering, K562 Cells, Phosphotyrosine, Cytoskeleton, Adaptor Proteins, Signal Transducing, Protein Binding, Signal Transduction
Oncogene Proteins, Cell Membrane, Fusion Proteins, bcr-abl, Protein-Tyrosine Kinases, Phosphoproteins, Actins, Protein Transport, Gene Knockdown Techniques, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Humans, Cell Surface Extensions, RNA, Small Interfering, K562 Cells, Phosphotyrosine, Cytoskeleton, Adaptor Proteins, Signal Transducing, Protein Binding, Signal Transduction
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