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.
Preisinger
Christian
C
Beatson Institute for Cancer Research, Glasgow, UK. c.preisinger@uu.nl
Kolch
Walter
W
D000199:Actins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology; D022081:Cell Surface Extensions / Q000378:metabolism; D003599:Cytoskeleton / Q000201:enzymology*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000473:pathology; D015513:Oncogene Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C409587:GRAP2 protein, human; C078332:Nck protein; D015513:Oncogene Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C092947:SLP-76 signal Transducing adaptor proteins; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl