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. 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. chronic myelogenous leukemia Abl interactor bone marrow bone marrow transplantation glutathione S-transferase Src homology white blood cell interleukin wild type Bcr-Abl is generated by a reciprocal t(9;22)(q34;q11) chromosome translocation that fuses varying amounts of the breakpoint cluster region (bcr) gene on chromosome 22 with sequences upstream of the second exon of c-abl on chromosome 9. Depending on the amount of bcr sequences fused, three different Bcr-Abl fusion proteins with molecular masses of 185 kDa (p185Bcr-Abl), 210 kDa (p210Bcr-Abl), and 230 kDa (p230Bcr-Abl) may be produced (1Rosenberg N. Witte O.N. Adv. Virus Res. 1988; 35: 39-81Crossref PubMed Scopus (127) Google Scholar, 2Gotoh A. Broxmeyer H.E. Curr. Opin. Hematol. 1997; 4: 3-11Crossref PubMed Scopus (64) Google Scholar, 3Raitano A.B. Whang Y.E. Sawyers C.L. Biochim. Biophys. Acta. 1997; 1333: F201-F216PubMed Google Scholar). Expression of Bcr-Abl is associated with greater than 95% of human chronic myelogenous leukemia (CML)1and ∼20% of acute lymphocytic leukemia cases (1Rosenberg N. Witte O.N. Adv. Virus Res. 1988; 35: 39-81Crossref PubMed Scopus (127) Google Scholar, 2Gotoh A. Broxmeyer H.E. Curr. Opin. Hematol. 1997; 4: 3-11Crossref PubMed Scopus (64) Google Scholar, 3Raitano A.B. Whang Y.E. Sawyers C.L. Biochim. Biophys. Acta. 1997; 1333: F201-F216PubMed Google Scholar). Mice transgenic for Bcr-Abl (4Heisterkamp N. Jenster G. ten Hoeve J. Zovich D. Pattengale P.K. Groffen J. Nature. 1990; 344: 251-253Crossref PubMed Scopus (594) Google Scholar) or reconstituted withBcr-Abl-transduced bone marrow (BM) cells (5Daley G.Q. Van Etten R.A. Baltimore D. Science. 1990; 247: 824-830Crossref PubMed Scopus (1929) Google Scholar, 6Pear W.S. Miller J.P. Xu L. Pui J.C. Soffer B. Quackenbush R.C. Pendergast A.M. Bronson R. Aster J.C. Scott M.L. Baltimore D. Blood. 1998; 92: 3780-3792Crossref PubMed Google Scholar, 7Zhang X. Ren R. Blood. 1998; 92: 3829-3840Crossref PubMed Google Scholar, 8Li S. Ilaria Jr., R.L. Million R.P. Daley G.Q. Van Etten R.A. J. Exp. Med. 1999; 189: 1399-1412Crossref PubMed Scopus (421) Google Scholar) developed leukemia that recapitulated many aspects of human CML. The inducible expression of Bcr-Abl in transgenic mice demonstrated that Bcr-Abl is required for both induction and maintenance of the leukemia (9Huettner C.S. Zhang P. Van Etten R.A. Tenen D.G. Nat. Genet. 2000; 24: 57-60Crossref PubMed Scopus (341) Google Scholar). Although these data provide strong evidence to support a direct role of Bcr-Abl in leukemogenesis, it remains unclear how the oncogenic activation of a single proto-oncogene induces malignancy in vivo with comprehensive changes in hematopoietic cell growth, differentiation, and homing. In vitro studies of Bcr-Abl-transformed cells suggest that the expression of Bcr-Abl promotes cell proliferation, enhances cell survival, and alters cell adhesion and migration (2Gotoh A. Broxmeyer H.E. Curr. Opin. Hematol. 1997; 4: 3-11Crossref PubMed Scopus (64) Google Scholar, 3Raitano A.B. Whang Y.E. Sawyers C.L. Biochim. Biophys. Acta. 1997; 1333: F201-F216PubMed Google Scholar, 10Clarkson B.D. Strife A. Wisniewski D. Lambek C. Carpino N. Leukemia. 1997; 11: 1404-1428Crossref PubMed Scopus (69) Google Scholar, 11Salgia R. Li J.L. Ewaniuk D.S. Pear W. Pisick E. Burky S.A. Ernst T. Sattler M. Chen L.B. Griffin J.D. J. Clin. Invest. 1997; 100: 46-57Crossref PubMed Scopus (149) Google Scholar, 12Salgia R. Quackenbush E. Lin J. Souchkova N. Sattler M. Ewaniuk D.S. Klucher K.M. Daley G.Q. Kraeft S.K. Sackstein R. Alyea E.P. von Andrian U.H. Chen L.B. Gutierrez-Ramos J.C. Pendergast A.M. Griffin J.D. Blood. 1999; 94: 4233-4246PubMed Google Scholar). How the changes in these fundamental cellular processes in Bcr-Abl-expressing cells lead to the clinical phenotype of CML remains largely unknown. Bcr-Abl proteins contain multiple domains important in interactions with other cellular proteins involved in the regulation of mitogenic and apoptotic pathways (2Gotoh A. Broxmeyer H.E. Curr. Opin. Hematol. 1997; 4: 3-11Crossref PubMed Scopus (64) Google Scholar, 3Raitano A.B. Whang Y.E. Sawyers C.L. Biochim. Biophys. Acta. 1997; 1333: F201-F216PubMed Google Scholar). They also contain domains and motifs capable of binding to cytoskeleton proteins as well as the proteins involved in regulation of cell adhesion and migration (13McWhirter J.R. Wang J.Y. EMBO J. 1993; 12: 1533-1546Crossref PubMed Scopus (286) Google Scholar, 14Salgia R. Uemura N. Okuda K. Li J.L. Pisick E. Sattler M. de Jong R. Druker B. Heisterkamp N. Chen L.B. Groffen J. Griffin J.D. J. Biol. Chem. 1995; 270: 29145-29150Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, 15Bhat A. Kolibaba K. Oda T. Ohno-Jones S. Heaney C. Druker B.J. J. Biol. Chem. 1997; 272: 16170-16175Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 16Sattler M. Salgia R. Leukemia. 1998; 12: 637-644Crossref PubMed Scopus (96) Google Scholar). Previously we and others identified Abl interactor (Abi) proteins that bind to both the Src homology 3 (SH3) domain and the C-terminal proline-rich regions of Abl kinase through dual SH3-PXXP interactions (17Dai Z. Pendergast A.M. Genes Dev. 1995; 9: 2569-2582Crossref PubMed Scopus (241) Google Scholar, 18Shi Y. Alin K. Goff S.P. Genes Dev. 1995; 9: 2583-2597Crossref PubMed Scopus (218) Google Scholar). Two highly related genes, abi-1 and abi-2, were cloned. The corresponding protein products share overall 69% identity with the greatest homology observed in the N-terminal homeobox-like domain, proline-rich sequences, and the C-terminal SH3 domain (17Dai Z. Pendergast A.M. Genes Dev. 1995; 9: 2569-2582Crossref PubMed Scopus (241) Google Scholar, 18Shi Y. Alin K. Goff S.P. Genes Dev. 1995; 9: 2583-2597Crossref PubMed Scopus (218) Google Scholar). In addition to the interaction with Abl kinase, Abi proteins also interact with other signaling molecules such as the Abl-related gene product Arg (19Wang B. Mysliwiec T. Krainc D. Jensen R.A. Sonoda G. Testa J.R. Golemis E.A. Kruh G.D. Oncogene. 1996; 12: 1921-1929PubMed Google Scholar), epidermal growth factor receptor substrate Eps8 (20Biesova Z. Piccoli C. Wong W.T. Oncogene. 1997; 14: 233-241Crossref PubMed Scopus (90) Google Scholar), the cytoskeleton protein spectrin (21Ziemnicka-Kotula D. Xu J. Gu H. Potempska A. Kim K.S. Jenkins E.C. Trenkner E. Kotula L. J. Biol. Chem. 1998; 273: 13681-13692Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar), and the guanine nucleotide exchange factor Sos (22Scita G. Nordstrom J. Carbone R. Tenca P. Giardina G. Gutkind S. Bjarnegard M. Betsholtz C. Di Fiore P.P. Nature. 1999; 401: 290-293Crossref PubMed Scopus (286) Google Scholar, 23Fan P.D. Goff S.P. Mol. Cell. Biol. 2000; 20: 7591-7601Crossref PubMed Scopus (53) Google Scholar). Although little is known about the function of Abi, recent studies suggested a role of Abi in the regulation of signal transduction mediated by small GTP-binding proteins. Abi-1 (also known as e3b1) forms a tricomplex with Eps8 and Sos-1 in vivo and regulates Rac-specific guanine nucleotide exchange factor activities in vitro (22Scita G. Nordstrom J. Carbone R. Tenca P. Giardina G. Gutkind S. Bjarnegard M. Betsholtz C. Di Fiore P.P. Nature. 1999; 401: 290-293Crossref PubMed Scopus (286) Google Scholar). It was therefore proposed that Abi-1 is an important player in the transduction of signals from Ras to Rac, a pathway important in the regulation of cytoskeletal function. Consistent with this proposal, microinjection of with in of in to growth factor (22Scita G. Nordstrom J. Carbone R. Tenca P. Giardina G. Gutkind S. Bjarnegard M. Betsholtz C. Di Fiore P.P. Nature. 1999; 401: 290-293Crossref PubMed Scopus (286) Google Scholar). The of Abi proteins in signaling mediated by the wild type and oncogenic forms of Abl is suggested by of Abi proteins bind to and are of the Abl (17Dai Z. Pendergast A.M. Genes Dev. 1995; 9: 2569-2582Crossref PubMed Scopus (241) Google Scholar, 18Shi Y. Alin K. Goff S.P. Genes Dev. 1995; 9: 2583-2597Crossref PubMed Scopus (218) Google Scholar). of Abi-1 the of Abl in by the kinase pathway Y. Alin K. Goff S.P. Genes Dev. 1995; 9: 2583-2597Crossref PubMed Scopus (218) Google Scholar, 23Fan P.D. Goff S.P. Mol. Cell. Biol. 2000; 20: 7591-7601Crossref PubMed Scopus (53) Google Scholar). we that Bcr-Abl elicits the ubiquitin-dependent degradation of Z. Quackenbush R.C. D. Pendergast A.M. Genes Dev. 1998; 12: PubMed Scopus Google Scholar). the expression of is in cell and bone marrow cells from patients with Bcr-Abl-positive leukemia Z. Quackenbush R.C. D. Pendergast A.M. Genes Dev. 1998; 12: PubMed Scopus Google Scholar). These data are consistent with a that the of may a role in the of Bcr-Abl-positive this we the sequences in Bcr-Abl that are required for its interaction with the of mutant forms of Bcr-Abl defective in binding to and therefore the of the of the mutations on Bcr-Abl-induced cellular and leukemogenesis. In this report we that the deletion of the SH3 domain and C-terminal proline-rich sequences in Bcr-Abl not its interaction with also degradation, spontaneous cell migration on a fibronectin-coated and leukemogenesis. cells and cells were in and as a of The bone marrow cells from and mice were in with or growth for to The and were by W. S. Pear of and R. G. of and the and of were from and A.M. R. Witte O.N. S. A. PubMed Scopus Google Scholar), by with The were to or the and and were with sequences of or of The were to (17Dai Z. Pendergast A.M. Genes Dev. 1995; 9: 2569-2582Crossref PubMed Scopus (241) Google Scholar) to sequences of The and were the and The were and to and The cell and by A. and W. S. Pear of were to as W.S. Scott M.L. Baltimore D. S. A. 1993; PubMed Scopus Google Scholar). The were the of a was and to cells as D. C. P. Y. M. S. C. D. Blood. 1995; PubMed Google Scholar). of with the were and were of cells wild type and mutant forms of Bcr-Abl were generated by transduction as (17Dai Z. Pendergast A.M. Genes Dev. 1995; 9: 2569-2582Crossref PubMed Scopus (241) Google Scholar). transduction of bone marrow cells was as D. C. P. Y. M. S. C. D. Blood. 1995; PubMed Google Scholar) with mice were with of to marrow cells were with and cell factor in for 3 The were with The cells were with and were mice through the in were as T. G. M. J. Cell. 94: Scopus Google Scholar). The with was for were in for greater than cells were a Two bone marrow mice were for disease blood were by of white blood cells was the with for of was by as well as such as and were by and were for or other of and bone marrow cells was were by the of (17Dai Z. Pendergast A.M. Genes Dev. 1995; 9: 2569-2582Crossref PubMed Scopus (241) Google Scholar), was to a fusion The was by a E. D. Scholar). were as (17Dai Z. Pendergast A.M. Genes Dev. 1995; 9: 2569-2582Crossref PubMed Scopus (241) Google Scholar) and of and as in the cells were with and Two cells were and with or fusion protein to as (17Dai Z. Pendergast A.M. Genes Dev. 1995; 9: 2569-2582Crossref PubMed Scopus (241) Google Scholar). proteins were by to with and by the The spontaneous cell migration was as N. Griffin J.D. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The of growth were with human The of the of The cells with or for wild type and mutant forms of Bcr-Abl were in for The cells were in a of of cells were the and to the for to Abi proteins through dual SH3-PXXP interactions (17Dai Z. Pendergast A.M. Genes Dev. 1995; 9: 2569-2582Crossref PubMed Scopus (241) Google Scholar, 18Shi Y. Alin K. Goff S.P. Genes Dev. 1995; 9: 2583-2597Crossref PubMed Scopus (218) Google Scholar). whether the direct interaction is required for Bcr-Abl to induce degradation, for wild type and mutant forms of with in the SH3 domain C-terminal proline-rich sequences or both SH3 and C-terminal proline-rich regions were generated The of these wild type and mutant forms of to bind to were by an in vitro binding The to it was in by In addition to proteins with were also by the in These are the forms of Bcr-Abl that degradation were also in by not The deletion of the SH3 domain did not affect binding of to The deletion of the C-terminal proline-rich sequences did not binding of to In deletion of both the SH3 domain and C-terminal proline-rich sequences the interaction and These wild type and mutant forms of the hematopoietic cell by transduction and for to induce degradation. cells that on as a and with molecular masses of and The with are a of the M. H. A. Pendergast A.M. Mol. Cell. 2000; PubMed Scopus Google Scholar). Z. Quackenbush R.C. D. Pendergast A.M. Genes Dev. 1998; 12: PubMed Scopus Google Scholar), expression of in cells degradation of In with binding ability to induce degradation in inducing degradation results were observed in hematopoietic cell not The deletion of the SH3 domain and C-terminal proline-rich sequences not affect the kinase of the mutant forms of was demonstrated by the of the protein in cells the wild type and mutant forms of be the wild type and mutant forms of were and were to stimulate protein in cells 2 The C-terminal proline-rich sequences in also contain a binding for the proteins and M. Salgia R. Leukemia. 1998; 12: 637-644Crossref PubMed Scopus (96) Google Scholar, R. Baltimore D. Genes Dev. PubMed Scopus Google Scholar). In is Bcr-Abl and is to Bcr-Abl to multiple molecules M. Salgia R. 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Oncogene. 1996; Google Scholar), cells were and were to in the of 3 The of the SH3 domain and C-terminal proline-rich sequences in did not affect its ability to stimulate cell and three and were capable of cells to 3 Because hematopoietic cells are to be of Bcr-Abl, we the of the SH3 domain and proline-rich regions in Bcr-Abl affect its ability to transform cells for hematopoietic cells by in vitro T. G. M. J. Cell. 94: Scopus Google Scholar) was to the ability of the cells with or the wild type and mutant forms of In vitro growth of cells a of growth for cells and the cells with did not in in the of growth In the cells with wild type and mutant forms of in 3 It that the and were in cells expression in cells and in with and It was that the expression of Bcr-Abl in cells spontaneous cell migration on fibronectin-coated R. Li J.L. Ewaniuk D.S. Pear W. Pisick E. Burky S.A. Ernst T. Sattler M. Chen L.B. Griffin J.D. J. Clin. 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Invest. 1997; 100: 46-57Crossref PubMed Scopus (149) Google Scholar), a in spontaneous migration on fibronectin-coated was observed in cells with that in cells The expression of and also spontaneous migration to a with In of spontaneous migration was observed in cells with The that is defective in inducing degradation and spontaneous cell migration to these affect its leukemogenic in was by bone marrow transplantation studies in cells from mice were with or for wild type and mutant forms of that transduction were with the different with were The of wild type and mutant proteins in cells were by The cells were Consistent with W.S. Miller J.P. Xu L. Pui J.C. Soffer B. Quackenbush R.C. Pendergast A.M. Bronson R. Aster J.C. Scott M.L. Baltimore D. Blood. 1998; 92: 3780-3792Crossref PubMed Google Scholar, 7Zhang X. Ren R. Blood. 1998; 92: 3829-3840Crossref PubMed Google Scholar, 8Li S. Ilaria Jr., R.L. Million R.P. Daley G.Q. Van Etten R.A. J. Exp. Med. 1999; 189: 1399-1412Crossref PubMed Scopus (421) Google Scholar, Zhang X. Ren R. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar), the mice cells with developed These mice in the mice in blood than in mice cells with The of these mice were with greater than of The disease that developed in these mice was by the expression of the mice cells with did not the Furthermore, the expression of was in the cells of the mice The mice cells with or also developed leukemia with the to in a was observed in mice In to the mice cells with In that of mice or of mice in in disease phenotype were also observed mice and mice that 3 of mice developed that were than of In the mice developed of mice mice that in the blood and than of in The of the disease that developed in mice remains to be the of and of are in Bcr-Abl-positive suggest that these mice may have of a disease other than of disease in and is as the that mice or mice disease mice disease are from with mice for and and mice for The mice not here were that and degradation it for is as the that mice or mice disease in a are from with mice for and and mice for The mice not here were that and degradation it for These studies demonstrated that a direct interaction Bcr-Abl and is required for the induction of ubiquitin-dependent degradation. The deletion of the SH3 domain and C-terminal proline-rich regions of Bcr-Abl the interaction of Bcr-Abl with and degradation. Although the deletion of the SH3 domain and proline-rich regions little on kinase and vitro of Bcr-Abl, it abrogated the ability of Bcr-Abl to stimulate spontaneous cell migration on a fibronectin-coated the deletion of these regions the ability of Bcr-Abl to induce disease in a bone marrow these results are consistent with a role of degradation in the pathogenesis of Bcr-Abl-positive CML cells and the hematopoietic cell Bcr-Abl exhibit multiple abnormalities in cytoskeletal function. How these abnormalities of cytoskeletal function to the clinical of CML is not The that the is leukemogenic in a support for a role of Bcr-Abl-induced cytoskeletal function in the pathogenesis of CML. The in leukemogenic of is not to its to stimulate cell and the mutant protein is not as wild type in growth of hematopoietic cell as well as a in spontaneous cell as by the migration may be in that mice from mice is the of was in mice and in and mice by other W.S. Miller J.P. Xu L. Pui J.C. Soffer B. Quackenbush R.C. Pendergast A.M. Bronson R. Aster J.C. Scott M.L. Baltimore D. Blood. 1998; 92: 3780-3792Crossref PubMed Google Scholar, 7Zhang X. Ren R. Blood. 1998; 92: 3829-3840Crossref PubMed Google Scholar, 8Li S. Ilaria Jr., R.L. Million R.P. Daley G.Q. Van Etten R.A. J. Exp. Med. 1999; 189: 1399-1412Crossref PubMed Scopus (421) Google Scholar, Zhang X. Ren R. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar). of is to be the results of the and of both and cells in the and is of the of CML patients C.L. N. J. Med. 1999; Scopus Google Scholar). The that mice developed with is consistent with a that the is capable of cell and to induce the and of cells in the of cytoskeletal function in hematopoietic cells from bone and blood of and mice provide in this The of spontaneous cell migration the deletion of both the SH3 domain and C-terminal proline-rich a role for these regions in the regulation of cytoskeletal function. Although data not provide direct evidence of the by these motifs cytoskeletal function, regulation of the signaling pathway from Ras to interaction with Abi proteins is Abi proteins have to interact with both the SH3 domain and C-terminal proline-rich sequences of The of to bind to Abi and to induce degradation with the of stimulate spontaneous cell migration a role for Abi proteins in spontaneous cell migration and changes in the cytoskeleton and cell The GTP-binding proteins Rac, and are known to a role in the regulation of these fundamental cellular processes L. C. Genes Dev. 1997; 11: PubMed Scopus Google Scholar, A. Science. 1998; PubMed Scopus Google Scholar). In to function as a of the and of cells Nature. 1997; PubMed Scopus Google Scholar). is in Bcr-Abl-transformed and its is required for T. P. L. P. M. M. M. B. S. A. 1998; PubMed Scopus Google Scholar). cells and a growth showed and to marrow and T. P. L. P. M. M. M. B. S. A. 1998; PubMed Scopus Google Scholar), a phenotype that is to that observed in cells and The of Abi proteins in the regulation of signal transduction from Ras to are suggested by recent that Abi-1 to Sos and regulates Rac-specific guanine nucleotide exchange factor activities (22Scita G. Nordstrom J. Carbone R. Tenca P. Giardina G. Gutkind S. Bjarnegard M. Betsholtz C. Di Fiore P.P. Nature. 1999; 401: 290-293Crossref PubMed Scopus (286) Google Scholar). The function of is not the homology Abi-1 and a function in the signal transduction mediated by small GTP-binding proteins may be It is also that may function as an of Abi-1 by with Abi-1 for with Sos and the that both Abi-1 and are of Abl kinase and are capable of binding to the SH3 domain and C-terminal proline-rich sequences that may be by Abl It is for that the of Abi-1 by Bcr-Abl may be required for activation of the signaling the and degradation of may be a in activation of the These not have to be In support of this we have expression of both Abi-1 and in Although is to Bcr-Abl-induced ubiquitin-dependent degradation, Abi-1 is and is in and K. In addition to Abi the SH3 domain and C-terminal proline-rich regions of Bcr-Abl also interact with other molecules important in the of cell proliferation, survival, and The SH3 domain of Bcr-Abl, for may interact with Ras interactor L. J. Wong S. A. K. N. Witte O.N. J. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) and Van Etten R.A. Genes Dev. 1997; 11: PubMed Scopus Google Scholar), the C-terminal proline-rich sequences interact with proteins such as and M. Salgia R. Leukemia. 1998; 12: 637-644Crossref PubMed Scopus (96) Google Scholar, R. Baltimore D. Genes Dev. PubMed Scopus Google Scholar). it is that the deletion of the SH3 domain and C-terminal proline-rich regions in Bcr-Abl also the signal mediated by these molecules and the leukemogenic of the mutant It that the of in spontaneous cell migration is of its to signal to We have that is in cells by the deletion of the binding and ability to a with in vivo through interaction C. Kolibaba K. A. Oda T. S. S. Druker B.J. Blood. 1997; PubMed Google Scholar). W. G. and K. The that is capable of spontaneous cell migration and inducing disease in mice is consistent with the results by other that the direct binding of to Bcr-Abl is not required for Bcr-Abl C. Kolibaba K. A. Oda T. S. S. Druker B.J. Blood. 1997; PubMed Google Scholar). in with the of of mice is required to the of these signaling pathways in by We W. S. R. G. and A. for and cells and R. and C. for of the
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