The Grb2 binding site is required for the induction of chronic myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase.
The BCR/ABL oncogene results from a balanced translocation between chromosomes 9 and 22 and is found in patients with chronic myeloid leukemia (CML) and in some patients with acute B-lymphoid leukemia. The Bcr/Abl fusion protein is a constitutively active tyrosine kinase that stimulates several intracellular signaling pathways, including activation of Ras through direct binding of the SH2-containing adapter protein Grb2 to Bcr tyrosine 177. A tyrosine-to-phenylalanine mutation (Y177F) at this site blocks the co-association of Bcr/Abl and Grb2 in vivo and impairs focus formation by Bcr/Abl in fibroblasts. However, the Bcr/Abl Y177F mutant can transform hematopoietic cell lines and primary bone marrow cells in vitro, so the importance of the Bcr/Abl-Grb2 interaction to myeloid and lymphoid leukemogenesis in vivo is unclear. We have recently demonstrated the efficient induction of CML-like myeloproliferative disease by BCR/ABL in a murine bone marrow transduction/transplantation model system. The Y177F mutation greatly attenuates the myeloproliferative disease induced by BCR/ABL, with mice developing B- and T-lymphoid leukemias of longer latency. In addition, the v-abl oncogene of Abelson murine leukemia virus, whose protein product lacks interaction with Grb2, is completely defective for the induction of CML-like disease. These results suggest that direct binding of Grb2 is required for the efficient induction of CML-like myeloproliferative disease by oncogenic Abl proteins. (Blood. 2000;96:664-670)
Million
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The Center for Blood Research, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Van Etten
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D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D016026:Bone Marrow Transplantation; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology* / Q000473:pathology; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D010649:Phenylalanine; D011506:Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection; D014443:Tyrosine
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D011506:Proteins; D014443:Tyrosine; D010649:Phenylalanine; D016044:Fusion Proteins, bcr-abl