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Signaling Pathways Activated by Oncogenic Forms of Abl Tyrosine Kinase

1999; Elsevier BV; Volume: 274; Issue: 26 Linguagem: Inglês

10.1074/jbc.274.26.18141

ISSN

1083-351X

Autores

Xiaoming Zou, Kathryn Calame,

Tópico(s)

Acute Lymphoblastic Leukemia research

Resumo

v-Abl, encoded by the Abelson murine leukemia virus, is a non-receptor tyrosine kinase with potent oncogenic activity in mice (for review, see Refs. 1Rosenberg N. Curr. Top. Microbiol. Immunol. 1982; 101: 95-126PubMed Google Scholar and 2Goff S.P. Proc. Soc. Exp. Biol. Med. 1985; 179: 403-412Crossref PubMed Scopus (14) Google Scholar). A similar human oncoprotein, BCR-ABL, is critical in the pathogenesis of 95% of chronic myelogenous leukemia (CML) 1The abbreviations used are: CML, chronic myelogenous leukemi; PI3K, phosphatidylinositol 3-kinase; IL, interleukin; PKC, protein kinase C; STAT, signal transducers and activators of transcription; Jak, Janus kinase; JNK, c-Jun NH2-terminal kinase; ERK, extracellular signal-regulated kinase; IκB, inhibitor of kappa B.1The abbreviations used are: CML, chronic myelogenous leukemi; PI3K, phosphatidylinositol 3-kinase; IL, interleukin; PKC, protein kinase C; STAT, signal transducers and activators of transcription; Jak, Janus kinase; JNK, c-Jun NH2-terminal kinase; ERK, extracellular signal-regulated kinase; IκB, inhibitor of kappa B.and 10% of acute lymphocytic leukemia (for review, see Refs. 3Gishizky M.L. Cytokines Mol. Ther. 1996; 2: 251-261PubMed Google Scholar and 4Cortes J.E. Talpaz M. Kantarjian H. Am. J. Med. 1996; 100: 555-570Abstract Full Text PDF PubMed Scopus (128) Google Scholar). The c-Abl proto-oncoprotein was identified as the normal cellular homolog of v-Abl (for review, see Ref. 2Goff S.P. Proc. Soc. Exp. Biol. Med. 1985; 179: 403-412Crossref PubMed Scopus (14) Google Scholar). The increased tyrosine kinase activities of v-Abl and BCR-ABL, compared with the cellular c-Abl, correlate with their transforming activities. The molecular mechanisms by which these activated tyrosine kinases cause malignant transformation have remained obscure until the last few years when there have been reports that multiple signaling pathways are activated by v-Abl and/or BCR-ABL. The intent of this review is to: 1) synthesize the current understanding of v-Abl signaling, 2) identify those signaling pathways that are critical for transformation, and 3) compare v-Abl signaling to BCR-ABL signaling, which has been reviewed elsewhere recently (for review, see Refs. 5Guo X.Y. Fontana J. Kufe D. Deisseroth A. Leuk. Lymphoma. 1998; 30: 225-235Crossref PubMed Scopus (7) Google Scholar and 6Sawyers C.L. Baillieres Clin. Haematol. 1997; 10: 223-231Abstract Full Text PDF PubMed Scopus (65) Google Scholar). There are several reasons for studying v-Abl. First, it is a potent transforming oncoprotein, and understanding its immediate substrates and final targets will help us understand the processes required for malignant transformation. Second, although in vitro v-Abl can transform many cell types, in vivo it only transforms pro or preB cells, the early B-lineage cells that have partially or completely rearranged their heavy chain genes (for review, see Ref.12Rosenberg N. Semin. Cancer Biol. 1994; 5: 95-102PubMed Google Scholar). The striking pro/preB cell tropism for transformation, in the absence of any evidence of pro/preB-specific viral infection, is likely to reveal regulatory paths that are unique to the early B-lymphocyte lineage. Finally, studying v-Abl in mice provides a convenient approach to identify activities that may be common to (or shared by) v-Abl and the human oncoprotein BCR-ABL. The v-abl oncogene in Abelson murine leukemia virus encodes a fusion protein in which a portion of retroviral Gag protein replaces the SH3 domain of c-Abl (Fig. 1) (for review, see Ref. 1Rosenberg N. Curr. Top. Microbiol. Immunol. 1982; 101: 95-126PubMed Google Scholar) (7Abelson H.T. Rabstein L.S. Cancer Res. 1970; 30: 2213-2222PubMed Google Scholar, 8Goff S.P. Gilboa E. Witte O.N. Baltimore D. Cell. 1980; 22: 777-785Abstract Full Text PDF PubMed Scopus (280) Google Scholar). Removal of the SH3 domain constitutively activates the tyrosine kinase, and a myristoylation site in the Gag moiety confers localization to the inner plasma membrane; both modifications are important in the transforming activity of v-Abl (9Prywes R. Foulkes J.G. Rosenberg N. Baltimore D. Cell. 1983; 34: 569-579Abstract Full Text PDF PubMed Scopus (73) Google Scholar). Infection of neonatal mice by Abelson murine leukemia virus results in rapid, 100% fatality because of pro/preB cell tumors. In vitro, v-Abl transforms pro/preB cells as well as myeloid cells and a subset of 3T3 fibroblasts (10Renshaw M.W. Kipreos E.T. Albrecht M.R. Wang J.Y. EMBO J. 1992; 11: 3941-3951Crossref PubMed Scopus (63) Google Scholar) (for review, see Refs. 11Rosenberg N. Witte O. Adv. Virus Res. 1988; 35: 39-81Crossref PubMed Scopus (127) Google Scholar and 12Rosenberg N. Semin. Cancer Biol. 1994; 5: 95-102PubMed Google Scholar). The human oncogene, BCR-ABL, is the result of a reciprocal chromosomal translocation in which the breakpoint cluster region (BCR) gene on chromosome 22 becomes fused to thec-ABL proto-oncogene on chromosome 9. It encodes a fusion protein in which part of the SH3 domain of c-ABL is replaced by portions of the BCR protein (for review, see Refs. 3Gishizky M.L. Cytokines Mol. Ther. 1996; 2: 251-261PubMed Google Scholar and 4Cortes J.E. Talpaz M. Kantarjian H. Am. J. Med. 1996; 100: 555-570Abstract Full Text PDF PubMed Scopus (128) Google Scholar). Different forms of BCR-ABL result when different portions of BCR are included; however, all BCR-ABL proteins have tyrosine kinase activities intermediate between the weaker c-ABL and the stronger v-Abl (13Clark S.S. McLaughlin J. Crist W.M. Champlin R. Witte O.N. Science. 1987; 235: 85-88Crossref PubMed Scopus (273) Google Scholar).In vitro BCR-ABL expression confers growth factor independence but is fully transforming only for certain cells (for review, see Ref. 14Raitano A.B. Whang Y.E. Sawyers C.L. Biochim. Biophys. Acta. 1997; 1333: 201-216PubMed Google Scholar). v-Abl and BCR-ABL share a C terminus that is unique among non-receptor kinases. It contains a nuclear localization signal, a proline-rich region capable of associating with SH3-containing proteins, a sequence-independent DNA-binding domain and an actin-binding domain (for review, see Refs. 15Chung S.W. Wong P.M. Oncogene. 1995; 10: 1261-1268PubMed Google Scholar and 16Laneuville P. Semin. Immunol. 1995; 7: 255-266Crossref PubMed Scopus (75) Google Scholar). Data from a variety of experiments show that signaling through the GTP-binding protein p21ras is essential for transformation by both v-Abl and BCR-ABL. Inhibition of p21rasactivity by antisense oligonucleotides to p21ras(17Skorski T. Kanakaraj P. Ku D.H. Nieborowska-Skorska M. Canaani E. Zon G. Perussia B. Calabretta B. J. Exp. Med. 1994; 179: 1855-1865Crossref PubMed Scopus (93) Google Scholar), microinjection of a blocking monoclonal antibody to p21ras (18Smith M.R. DeGudicibus S.J. Stacey D.W. Nature. 1986; 320: 540-543Crossref PubMed Scopus (424) Google Scholar) or expression of the catalytic domain of Ras GAP (19Sawyers C.L. McLaughlin J. Witte O.N. J. Exp. Med. 1995; 181: 307-313Crossref PubMed Scopus (247) Google Scholar) all block transformation by v-Abl and BCR-ABL. Dominant negative forms of p21ras inhibit v-Abl-dependent induction of c-myc transcription (20Zou X. Rudchenko S. Wong K. Calame K. Genes Dev. 1997; 11 (654–662): 654-662Crossref PubMed Scopus (60) Google Scholar), fibroblast and bone marrow cell transformation by v-Abl and BCR-ABL (19Sawyers C.L. McLaughlin J. Witte O.N. J. Exp. Med. 1995; 181: 307-313Crossref PubMed Scopus (247) Google Scholar), and the anti-apoptotic effect of BCR-ABL (21Cortez D. Stoica G. Pierce J.H. Pendergast A.M. Oncogene. 1996; 13: 2589-2594PubMed Google Scholar). Although other Ras family proteins have been described, their role in v-Abl or BCR-ABL signaling has not been explored (for review, see Ref. 22Campbell S.L. Khosravi-Far R. Rossman K.L. Clark G.J. Der C.J. Oncogene. 1998; 17: 1395-1413Crossref PubMed Scopus (920) Google Scholar). There are multiple links from v-Abl to p21ras. Although critical tests have not been done, it seems likely that more than one connection to p21ras may be required to mediate full oncogenic activity of v-Abl. One clear link to p21ras is direct binding of Shc to the SH2 domain of v-Abl, which may allow tyrosine phosphorylation of Shc by v-Abl and subsequent activation of the Ras pathway through assembly of a signaling complex with Grb2-mSos (23Raffel G.D. Parmar K. Rosenberg N. J. Biol. Chem. 1996; 271: 4640-4645Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). Another connection is binding of p62(dok) to v-Abl. Binding to v-Abl causes phosphorylation of p62(dok), which then binds RasGAP, a negative regulator of p21ras (24Yamanashi Y. Baltimore D. Cell. 1997; 88: 205-211Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar, 25Carpino N. Wisniewski D. Strife A. Marshak D. Kobayashi R. Stillman B. Clarkson B. Cell. 1997; 88: 197-204Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar). It is not known how phosphorylation may alter p62(dok) activity or whether a ternary complex may form in which v-Abl phosphorylates RasGAP directly, possibly inactivating RasGAP (24Yamanashi Y. Baltimore D. Cell. 1997; 88: 205-211Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar). p62(dok) is also phosphorylated in cells expressing BCR-ABL (25Carpino N. Wisniewski D. Strife A. Marshak D. Kobayashi R. Stillman B. Clarkson B. Cell. 1997; 88: 197-204Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar), another Dok-like protein, which interacts with v-Abl, has recently been identified and may play a similar role. 2S. Goff, personal communication. There is also evidence for a link between the C terminus of v-Abl and p21ras because p21rascomplements C-terminal mutants of v-Abl for bone marrow cell transformation (26Parmar K. Rosenberg N. J. Virol. 1996; 70: 1009-1015Crossref PubMed Google Scholar). The C termini of v-Abl and BCR-ABL are the same (Fig. 1); thus it is likely that both proteins make similar connections to p21ras. A variety of proteins bind this region, particularly SH3-containing proteins that associate with the proline-rich region in the C terminus. Adaptor proteins Crk, Crkl, Nck, and Grb2 can bind this region (27Ren R. Ye Z.S. Baltimore D. Genes Dev. 1994; 8: 783-795Crossref PubMed Scopus (290) Google Scholar). Of these, the Crkl adaptor protein may be a functionally important interactor because it is hyperphosphorylated in CML cells containing BCR-ABL (28Nichols G.L. Raines M.A. Vera J.C. Lacomis L. Tempst P. Golde D.W. Blood. 1994; 84: 2912-2918Crossref PubMed Google Scholar). However, the role of Crkl in BCR-ABL signaling is controversial because deletion of the Crkl-binding site in the C terminus of BCR-ABL impairs fibroblast transformation (29Senechal K. Halpern J. Sawyers C. J. Biol. Chem. 1996; 271: 23255-23261Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar) but not myeloid cell growth factor independence (30Heaney C. Kolibaba K. Bhat A. Oda T. Ohno S. Fanning S. Druker B.J. Blood. 1997; 89: 297-306Crossref PubMed Google Scholar) (for review, see Ref. 31Sattler M. Salgia R. Leukemia. 1998; 12: 637-644Crossref PubMed Scopus (96) Google Scholar). Abl interactor proteins Abi-1 (32Shi Y. Alin K. Goff S.P. Genes Dev. 1995; 9: 2583-2597Crossref PubMed Scopus (217) Google Scholar) and Abi-2 (33Dai Z. Pendergast A.M. Genes Dev. 1995; 9: 2569-2582Crossref PubMed Scopus (241) Google Scholar) bind to the C-terminal proline-rich region of v-Abl and BCR-ABL. Ectopic expression of Abi-1 inhibits v-Abl transformation (32Shi Y. Alin K. Goff S.P. Genes Dev. 1995; 9: 2583-2597Crossref PubMed Scopus (217) Google Scholar). Consistent with this finding, BCR-ABL induces proteasome-dependent degradation of Abi-2, which may be important to block its inhibitory activity and allow cell transformation (34Dai Z. Quackenbush R.C. Courtney K.D. Grove M. Cortez D. Reuther G.W. Pendergast A.M. Genes Dev. 1998; 12: 1415-1424Crossref PubMed Scopus (103) Google Scholar). These adaptor proteins appear to inhibit p21ras activation and thus block v-Abl- and BCR-ABL-dependent transformation. Abi-1 associates with Eps-8 (35Biesova Z. Piccoli C. Wong W.T. Oncogene. 1997; 14: 233-241Crossref PubMed Scopus (90) Google Scholar), a substrate of the epidermal growth factor and platelet-derived growth factor receptors, that also associates with Shc (36Matoskova B. Wong W.T. Salcini A.E. Pelicci P.G. Di Fiore P.P. Mol. Cell. Biol. 1995; 15: 3805-3812Crossref PubMed Scopus (68) Google Scholar) and inhibits ERK activation in response to epidermal growth factor signaling.2 BCR-ABL also binds directly to Grb2 (37Pendergast A. Quilliam L. Cripe L. Bassing C. Dai Z. Li N. Batzer A. Rabun K. Der C. Schlessinger J. Gishizky M. Cell. 1993; 75: 175-185Abstract Full Text PDF PubMed Scopus (592) Google Scholar). Because this association involves the BCR portion of the protein, which is absent in v-Abl, this connection is unique to the human oncogene. However, BCR-ABL also connects to p21ras and Grb2 via Shc (38Goga A. McLaughlin J. Afar D.E. Saffran D.C. Witte O.N. Cell. 1995; 82: 981-988Abstract Full Text PDF PubMed Scopus (256) Google Scholar), probably by virtue of Shc binding to the SH2 domain (23Raffel G.D. Parmar K. Rosenberg N. J. Biol. Chem. 1996; 271: 4640-4645Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). Although p21ras often activates the Raf serine kinase leading to activation of ERK, for v-Abl, there are branch points from Raf that exclude ERK. ERK is activated in v-Abl-transformed cells by a poorly understood Raf-independent path (39Weissinger E.M. Eissner G. Grammer C. Fackler S. Haefner B. Yoon L.S. Lu K.S. Bazarov A. Sedivy J.M. Mischak H. Kolch W. Mol. Cell. Biol. 1997; 17: 3229-3241Crossref PubMed Scopus (59) Google Scholar) and is not activated by BCR-ABL (40Kabarowski J.H. Allen P.B. Wiedemann L.M. EMBO J. 1994; 13: 5887-5895Crossref PubMed Scopus (109) Google Scholar, 41Raitano A.B. Halpern J.R. Hambuch T.M. Sawyers C.L. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 11746-11750Crossref PubMed Scopus (377) Google Scholar). A Ras/Raf-dependent pathway is required for v-Abl-dependent induction of c-myctranscription, which appears to be ERK-independent (20Zou X. Rudchenko S. Wong K. Calame K. Genes Dev. 1997; 11 (654–662): 654-662Crossref PubMed Scopus (60) Google Scholar). Expression of dominant negative Myc blocks transformation by either v-Abl or BCR-ABL (42Sawyers C.L. Callahan W. Witte O.N. Cell. 1992; 70: 901-910Abstract Full Text PDF PubMed Scopus (354) Google Scholar), establishing the importance of this pathway. In the c-myc induction pathway Raf ultimately activates cyclin-dependent kinases, which phosphorylate Rb family proteins and thus activate E2F transcription factors (20Zou X. Rudchenko S. Wong K. Calame K. Genes Dev. 1997; 11 (654–662): 654-662Crossref PubMed Scopus (60) Google Scholar). In addition to c-myc, v-Abl also induces mRNA encoding other E2F-dependent genes, which are required for cells to enter S phase including dihydrofolate reductase, ribonucleotide reductase, cyclin A, and cyclin E. 3M. Coutts, X. Zou, and K. Calame, unpublished data. The connection from v-Abl/p21ras/Raf to cyclin-dependent kinases may be through activation of the Cdc25A phosphatase (43Galaktionov K. Jessus C. Beach D. Genes Dev. 1995; 9: 1046-1058Crossref PubMed Scopus (230) Google Scholar), but there is presently no direct evidence for this. BCR-ABL also activates E2F proteins, leading to induction of c-myc transcription (44Stewart M.J. Litz-Jackson S. Burgess G.S. Williamson E.A. Leibowitz D.S. Boswell H.S. Leukemia. 1995; 9: 1499-1507PubMed Google Scholar), presumably by a Ras-dependent pathway similar to that for v-Abl (20Zou X. Rudchenko S. Wong K. Calame K. Genes Dev. 1997; 11 (654–662): 654-662Crossref PubMed Scopus (60) Google Scholar). Recently, expression of the p19ARF gene has been shown to be increased in a way that depends on p21ras (45Pomerantz J. Schreiber-Agus N. Liegeois N.J. Silverman A. Alland L. Chin L. Potes J. Chen K. Orlow I. Lee H.W. Cordon-Cardo C. DePinho R.A. Cell. 1998; 92: 713-723Abstract Full Text Full Text PDF PubMed Scopus (1333) Google Scholar), E2F activators (46Bates S. Phillips A.C. Clark P.A. Stott F. Peters G. Ludwig R. Vousden K.H. Nature. 1998; 395: 124-125Crossref PubMed Scopus (812) Google Scholar), and c-Myc (47Zindy F. Eischen C.M. Randle D.H. Kamijo T. Cleveland J.L. Sherr C.J. Roussel M.F. Genes Dev. 1998; 12: 2424-2433Crossref PubMed Scopus (1059) Google Scholar). Up-regulation of p19ARF leads to an increase in p53 levels (for review, see Ref. 48Chin L. Pomerantz J. DePinho R.A. Trends Biochem. Sci. 1998; 23: 291-296Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar). Because v-Abl activates p21ras and E2F proteins and induces c-Myc, it may be that v-Abl also causes an increase of p53 via p19ARF. It is attractive to speculate that relative induction of p19ARF versus c-myc and S phase genes might determine whether a cell becomes transformed or undergoes apoptosis in response to v-Abl. In support of this notion, there is evidence that a p53-dependent path inhibits transformation by v-Abl in vivo 4X. Zou and K. Calame, unpublished data. and in vitro (49Thome K.C. Radfar A. Rosenberg N. J. Virol. 1997; 71: 8149-8156Crossref PubMed Google Scholar) and plays a role in BCR-ABL-dependent blast transformation in CML (50Skorski T. Nieborowska-Skorska M. Wlodarski P. Perrotti D. Martinez R. Wasik M.A. Calabretta B. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 13137-13142Crossref PubMed Scopus (75) Google Scholar). Also, v-Abl can up-regulatep19ARFand cause p53-dependent apoptosis in Abelson virus-infected primary preB cells (51Radfar A. Unnikrishnan I. Lee H.W. DePinho R.A. Rosenberg N. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 13194-13199Crossref PubMed Scopus (125) Google Scholar). Unlike preB transformants derived from normal mice, those fromInk4a/Arf −/− mice bypass the crisis that characterizes the transition from primary transformant to established, fully malignant cell line (51Radfar A. Unnikrishnan I. Lee H.W. DePinho R.A. Rosenberg N. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 13194-13199Crossref PubMed Scopus (125) Google Scholar). Dominant negative Rac blocks v-Abl transformation, establishing a requirement for Rac activation in v-Abl transformation (52Renshaw M.W. Lea-Chou E. Wang J.Y. Curr. Biol. 1996; 6: 76-83Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). In this system, ERK and JNK activation was also inhibited by dominant negative Rac, suggesting that these effectors are downstream of v-Abl/Rac (52Renshaw M.W. Lea-Chou E. Wang J.Y. Curr. Biol. 1996; 6: 76-83Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). Rac is not required for v-Abl-dependent induction of c-myc transcription, which depends on p21ras and Raf (20Zou X. Rudchenko S. Wong K. Calame K. Genes Dev. 1997; 11 (654–662): 654-662Crossref PubMed Scopus (60) Google Scholar), but Rac is necessary for activation transcription dependent on serum or 12-O-tetradecanoylphorbol-13-acetate response elements (52Renshaw M.W. Lea-Chou E. Wang J.Y. Curr. Biol. 1996; 6: 76-83Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). Studies with dominant negative Rac also show that Rac is required for BCR-ABL-induced leukemogenesis (53Skorski T. Wlodarski P. Daheron L. Salomoni P. Nieborowska-Skorska M. Majewski M. Wasik M. Calabretta B. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 11858-11862Crossref PubMed Scopus (83) Google Scholar). It is not currently clear whether activation of Rac by v-Abl or BCR-ABL proceeds directly or by activation of p21ras or PI3K, as has been observed in other systems (for review, see Ref. 22Campbell S.L. Khosravi-Far R. Rossman K.L. Clark G.J. Der C.J. Oncogene. 1998; 17: 1395-1413Crossref PubMed Scopus (920) Google Scholar). JNK is activated by both v-Abl and BCR-ABL but by different pathways. v-Abl-dependent JNK activation requires Rac (52Renshaw M.W. Lea-Chou E. Wang J.Y. Curr. Biol. 1996; 6: 76-83Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar), whereas BCR-ABL-dependent JNK activation requires p21ras (41Raitano A.B. Halpern J.R. Hambuch T.M. Sawyers C.L. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 11746-11750Crossref PubMed Scopus (377) Google Scholar). Phosphatases may provide another path to JNK activation because BCR-ABL associates with SHPT1, which regulates JNK activity (54Liedtke M. Pandey P. Kumar S. Kharbanda S. Kufe D. Oncogene. 1998; 17: 1889-1892Crossref PubMed Scopus (26) Google Scholar). Dominant negative c-Jun inhibits BCR-ABL transformation, demonstrating the importance of JNK activation for BCR-ABL transformation (41Raitano A.B. Halpern J.R. Hambuch T.M. Sawyers C.L. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 11746-11750Crossref PubMed Scopus (377) Google Scholar). v-Abl and BCR-ABL, but not c-Abl, associate with and activate PI3K (55Varticovski L. Daley G.Q. Jackson P. Baltimore D. Cantley L.C. Mol. Cell. Biol. 1991; 11: 1107-1113Crossref PubMed Scopus (181) Google Scholar). Interestingly, the accumulation of PI3K products phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate correlates better with v-Abl or BCR-ABL transformation than does association of Abl kinases with PI3K (55Varticovski L. Daley G.Q. Jackson P. Baltimore D. Cantley L.C. Mol. Cell. Biol. 1991; 11: 1107-1113Crossref PubMed Scopus (181) Google Scholar, 56Jain S.K. Susa M. Keeler M.L. Carlesso N. Druker B. Varticovski L. Blood. 1996; 88: 1542-1550Crossref PubMed Google Scholar). v-Abl and BCR-ABL may activate PI3K by more than one pathway because activated p21ras activates PI3K in other systems (57Kauffmann-Zeh A. Rodriguez-Viciana P. Ulrich E. Gilbert C. Coffer P. Downward J. Evan G. Nature. 1997; 385: 544-548Crossref PubMed Scopus (1073) Google Scholar), and recent work suggests activation of Jak1 by v-Abl might contribute to PI3K activation (58Danial N.N. Losman J.A. Lu T. Yip N. Krishnan K. Krolewski J. Goff S.P. Wang J.Y.J. Rothman P.B. Mol. Cell. Biol. 1998; 18: 6795-6804Crossref PubMed Scopus (61) Google Scholar). Inhibition of PI3K blocks proliferation of BCR-ABL-dependent cells, establishing the importance of PI3K for BCR-ABL activity (59Skorski T. Kanakaraj P. Nieborowska-Skorska M. Ratajczak M.Z. Wen S.C. Zon G. Gewirtz A.M. Perussia B. Calabretta B. Blood. 1995; 86: 726-736Crossref PubMed Google Scholar). Akt kinase is an important effector of BCR-ABL-activated PI3K because a dominant negative mutant of Akt inhibits BCR-ABL-dependent transformation of murine bone marrow cells (60Skorski T. Bellacosa A. Nieborowska-Skorska M. Majewski M. Martinez R. Choi J.K. Trotta R. Wlodarski P. Perrotti D. Chan T.O. Wasik M.A. Tsichlis P.N. Calabretta B. EMBO J. 1997; 16: 6151-6161Crossref PubMed Scopus (557) Google Scholar). IL-3-dependent mast cells transformed with a temperature-sensitive form of v-Abl revealed that v-Abl activates phospholipase C-mediated breakdown of phosphatidylcholine, generating diacylglycerol, which then activates PKC (61Owen P.J. Musk P. Evans C.A. Whetton A.D. J. Biol. Chem. 1993; 268: 15696-15703Abstract Full Text PDF PubMed Google Scholar). The anti-apoptotic effect of v-Abl in this system was blocked by inhibiting PKC activity, indicating a functional role for PKC. Subsequent studies in the same cells show that the v-Abl/PKC pathway causes an increase inbcl-XL mRNA, which may be responsible for the anti-apoptotic effect (62Chen Q. Turner J. Watson A.J. Dive C. Oncogene. 1997; 15: 2249-2254Crossref PubMed Scopus (23) Google Scholar). The recent discovery that STAT1, -3, -5, and -6 are constitutively activated in v-Abl-transformed proB or preB cells (58Danial N.N. Losman J.A. Lu T. Yip N. Krishnan K. Krolewski J. Goff S.P. Wang J.Y.J. Rothman P.B. Mol. Cell. Biol. 1998; 18: 6795-6804Crossref PubMed Scopus (61) Google Scholar, 63Danial N.N. Pernis A. Rothman P.B. Science. 1995; 269: 1875-1877Crossref PubMed Scopus (321) Google Scholar) led to the attractive model that constitutive activation of STATs by v-Abl confers cytokine independence and is critical for transformation. In normal cells, nuclear translocation of STATs occurs only in response to cytokine binding to receptor and activation of receptor-associated Janus kinases (Jaks) (for review, see Ref. 64Schindler C. Darnell Jr., J.E. Annu. Rev. Biochem. 1995; 64: 621-651Crossref PubMed Scopus (1650) Google Scholar). Evidence is accumulating to support the constitutive STAT activation model. Jak1 and Jak3 associate directly with v-Abl (58Danial N.N. Losman J.A. Lu T. Yip N. Krishnan K. Krolewski J. Goff S.P. Wang J.Y.J. Rothman P.B. Mol. Cell. Biol. 1998; 18: 6795-6804Crossref PubMed Scopus (61) Google Scholar). Deletion of 200 amino acids in the DNA-binding portion of the v-Abl C terminus (Fig. 1) that are required for association with Jak1 results in a mutant v-Abl, which cannot provide cytokine-independent survival of BAF/3 pro-B lymphoblastoid cells. This provides evidence that Jak binding and STAT activation are important for v-Abl-dependent transformation (58Danial N.N. Losman J.A. Lu T. Yip N. Krishnan K. Krolewski J. Goff S.P. Wang J.Y.J. Rothman P.B. Mol. Cell. Biol. 1998; 18: 6795-6804Crossref PubMed Scopus (61) Google Scholar). Furthermore, in murine tumors resulting fromabl/mycretroviruses, constitutive activation of STAT3 makes the cells IL-6-independent (65Hilbert D.M. Migone T.S. Kopf M. Leonard W.J. Rudikoff S. Immunity. 1996; 5: 81-89Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). However, cytokine independence is not sufficient to cause transformation because a combination of IL-4 and IL-7 signaling cannot substitute for an active v-Abl kinase in transformed pre-B cells (66Banerjee A. Rothman P. J. Immunol. 1998; 161: 4611-4617PubMed Google Scholar). STAT-independent paths from activated Jaks may also be important for v-Abl activity because cytokine-dependent suppression of apoptosis (67Quelle F.W. Wang J. Feng J. Wang D. Cleveland J.L. Ihle J.N. Zambetti G.P. Genes Dev. 1998; 12: 1099-1107Crossref PubMed Scopus (94) Google Scholar) and induction of the anti-apoptotic gene bcl-XL (68Packham G. White E.L. Eischen C.M. Yang H. Parganas E. Ihle J.N. Grillot D.A. Zambetti G.P. Nunez G. Cleveland J.L. Genes Dev. 1998; 12: 2475-2487Crossref PubMed Scopus (100) Google Scholar) result from a Jak-dependent, STAT-independent path in myeloid cells. Contrary to v-Abl, BCR-ABL does not activate STATs by a Jak-dependent pathway. JAK kinases are not consistently activated in BCR-ABL-positive cells (69Carlesso N. Frank D.A. Griffin J.D. J. Exp. Med. 1996; 183: 811-820Crossref PubMed Scopus (433) Google Scholar, 70Chai S.K. Nichols G.L. Rothman P. J. Immunol. 1997; 159: 4720-4728PubMed Google Scholar), and activation of STAT5 by BCR-ABL is not blocked by dominant-negative JAK2 mutants (71Ilaria Jr., R.L. Van Etten R.A. J. Biol. Chem. 1996; 271: 31704-31710Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar). BCR-ABL does not associate with Jaks (71Ilaria Jr., R.L. Van Etten R.A. J. Biol. Chem. 1996; 271: 31704-31710Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar) even though its C-terminal region is identical to that of v-Abl (Fig. 1). Subcellular localization and tyrosine kinase activity differ significantly between the two proteins; the inner plasma membrane localization and/or high tyrosine kinase activity of v-Abl may be critical for Jak association and activation. Nevertheless, STAT1 and STAT5 are constitutively activated in BCR-ABL lines from CML patients (72Shuai K. Halpern J. ten Hoeve J. Rao X. Sawyers C.L. Oncogene. 1996; 13: 247-254PubMed Google Scholar), and primary peripheral blood cells from patients with CML have constitutive activation of STATs (70Chai S.K. Nichols G.L. Rothman P. J. Immunol. 1997; 159: 4720-4728PubMed Google Scholar). Direct association of STAT SH2 domains with phosphorylated tyrosines on BCR-ABL could mediate Jak-independent activation, but no data are available to prove this (69Carlesso N. Frank D.A. Griffin J.D. J. Exp. Med. 1996; 183: 811-820Crossref PubMed Scopus (433) Google Scholar, 71Ilaria Jr., R.L. Van Etten R.A. J. Biol. Chem. 1996; 271: 31704-31710Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar). Other downstream consequences are known to result from the action of either v-Abl or BCR-ABL, but the signaling paths leading to them are poorly understood. v-Abl has been reported to stabilize IκB, thereby blocking activation of NF-κB in preB cells (73Klug C.A. Gerety S.J. Shah P.C. Chen Y.Y. Rice N.R. Rosenberg N. Singh H. Genes Dev. 1994; 8: 678-687Crossref PubMed Scopus (71) Google Scholar). However, the role of NF-κB appears to be different for BCR-ABL. Inhibition of NF-κB by a non-degradable form of IκBα showed that NF-κB is required for BCR-ABL-mediated tumorigenicity in nude mice and transformation of primary bone marrow cells (74Reuther J.Y. Reuther G.W. Cortez D. Pendergast A.M. Baldwin Jr., A.S. Genes Dev. 1998; 12: 968-981Crossref PubMed Scopus (353) Google Scholar). Activation of NF-κB in this system is Ras-dependent. Both v-Abl and BCR-ABL activate proteasome-dependent degradation of specific proteins. In 3T3 fibroblasts, proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27Kip occurs when mitogen-starved or density-arrested cells enter S following v-Abl activation.4 In CML cells expressing BCR-ABL, proteasome-dependent degradation of the inhibitory protein Abi-2 occurs through a Ras-independent pathway (34Dai Z. Quackenbush R.C. Courtney K.D. Grove M. Cortez D. Reuther G.W. Pendergast A.M. Genes Dev. 1998; 12: 1415-1424Crossref PubMed Scopus (103) Google Scholar). Degradation of p27 and Abi-2 may be induced by a common pathway, but this is not yet proven. v-Abl and BCR-ABL affect the expression of genes that regulate apoptosis. v-Abl induces bcl-XL mRNA in pre-mast cells by a PKC-dependent path (62Chen Q. Turner J. Watson A.J. Dive C. Oncogene. 1997; 15: 2249-2254Crossref PubMed Scopus (23) Google Scholar) but causes up-regulation of Bax in myeloid progenitor cells (75Zhu J. Nabissa P.M. Hoffman B. Liebermann D.A. Shore S.K. Blood. 1996; 87: 4368-4375Crossref PubMed Google Scholar). v-Abl induces both Bcl-2 and Bcl-XL in preB cells (66Banerjee A. Rothman P. J. Immunol. 1998; 161: 4611-4617PubMed Google Scholar), but it remains to be shown that this is important for transformation. BCR-ABL induces Bcl-2 mRNA in a Ras-dependent pathway, and Bcl-2 has been shown to be essential for BCR-ABL-mediated transformation (76Sanchez-Garcia I. Grutz G. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5287-5291Crossref PubMed Scopus (196) Google Scholar,77Sanchez-Garcia I. Martin-Zanca D. J. Mol. Biol. 1997; 267: 225-228Crossref PubMed Scopus (68) Google Scholar). The numerous signaling pathways activated by v-Abl are summarized in Fig. 2. The ultimate effect, transformation or apoptosis, is likely to be determined by the relative strength of these signals in different cells. There is much left to learn. With the exception of E2F-dependent genes, few genes have been identified as functionally important final targets of the signaling pathways activated by v-Abl and BCR-ABL. Furthermore, no pathway has been completely characterized and few have been compared in different cell types. Thus, there are likely to be many more connections and many more examples of cross-talk and feedback than we currently understand. There may also be connections that vary in different types of cells. In addition, it is clear that we have little understanding of how a single protein, such as p21ras or E2F-1, may signal multiple downstream effectors and how the relative strength of signaling to different effectors may be determined. v-Abl and BCR-ABL activate a remarkably similar set of signaling pathways including p21ras, Rac, and STATs and induction of c-myc mRNA. However, there are several significant differences. BCR-ABL does not activate ERK but v-Abl does, BCR-ABL does not associate with or activate Jaks but v-Abl does, BCR-ABL associates directly with Grb2 but v-Abl does not, and BCR-ABL activates JNK through Ras whereas v-Abl activates JNK through Rac. It seems likely that the transforming versus apoptotic activities of v-Abl and BCR-ABL result from a delicate balance between many signaling pathways. Many of these, such as induction of c-mycand other E2F-dependent genes, degradation of p27, and activation of JNK, Rac, and PI3K, lead to cell cycle progression. Other signals such as induction of Bcl-XL and Bcl-2 provide anti-apoptotic signals. Finally, it is possible that others, by inducing p19ARF may lead to p53-dependent cell cycle arrest or apoptosis.

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