Deletion of the Src homology 3 domain and C-terminal proline-rich sequences in Bcr-Abl prevents Abl interactor 2 degradation and spontaneous cell migration and impairs leukemogenesis.
The hematopoietic cells from patients with Bcr-Abl-positive chronic myelogenous leukemia exhibit multiple abnormalities of cytoskeletal function. The molecular events leading to these abnormalities are not fully understood. Previously we showed that Bcr-Abl elicits ubiquitin-dependent degradation of Abl interactor proteins. Because recent studies have suggested a role of Abl interactor proteins in the pathway that regulates cytoskeletal function, we investigated whether mutations in Bcr-Abl that interfere with the signaling to Abl interactor proteins affect its leukemogenic activity. We report here that the Src homology 3 domain and C-terminal proline-rich sequences of Bcr-Abl are required for its binding to Abl interactor 2 as well as for the induction of Abl interactor 2 degradation. Although the deletion of these regions did not affect the ability of the mutant Bcr-Abl to transform hematopoietic cells to growth factor independence, it abrogated its ability to stimulate spontaneous cell migration on fibronectin-coated surfaces. Furthermore, the mutant Bcr-Abl, defective in binding to Abl interactor 2 and inducing its degradation, failed to induce chronic myelogenous leukemia-like disease in mouse. These results are consistent with a role of Abl interactor proteins in the regulation of cytoskeletal function as well as in the pathogenesis of Bcr-Abl-induced leukemogenesis.
Dai
Z
Z
Experimental Hematology Laboratory, Bone Marrow Transplant Program, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. zonghan.dai@uchsc.edu
Kerzic
P
P
Schroeder
W G
WG
McNiece
I K
IK
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D016026:Bone Marrow Transplantation / Q000473:pathology; D002460:Cell Line; D002633:Chemotaxis; D005353:Fibronectins / Q000502:physiology; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D016296:Mutagenesis; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011392:Proline; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D017384:Sequence Deletion; D014162:Transfection; D014407:Tumor Cells, Cultured; D014452:Ubiquitins / Q000378:metabolism*; D018909:src Homology Domains
C096831:ABI2 protein, human; C490756:Abi2 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D005353:Fibronectins; D018398:Homeodomain Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014452:Ubiquitins; D011392:Proline; D016044:Fusion Proteins, bcr-abl