Abstract
Bcr-Abl plays a critical role in the pathogenesis of Philadelphia chromosome-positive leukemia. Although a large number of substrates and interacting proteins of Bcr-Abl have been identified, it remains unclear whether Bcr-Abl assembles multi-protein complexes and if it does where these complexes are within cells. We have investigated the localization of Bcr-Abl in 32D myeloid cells attached to the extracellular matrix. We have found that Bcr-Abl displays a polarized distribution, co-localizing with a subset of filamentous actin at trailing portions of migrating 32D cells, and localizes on the cortical F-actin and on vesicle-like structures in resting 32D cells. Deletion of the actin binding domain of Bcr-Abl (Bcr-Abl-AD) dramatically enhances the localization of Bcr-Abl on the vesicle-like structures. These distinct localization patterns of Bcr-Abl and Bcr-Abl-AD enabled us to examine the localization of Bcr-Abl substrate and interacting proteins in relation to Bcr-Abl. We found that a subset of biochemically defined target proteins of Bcr-Abl redistributed and co-localized with Bcr-Abl on F-actin and on vesicle-like structures. The co-localization of signaling proteins with Bcr-Abl at its sites of localization supports the idea that Bcr-Abl forms a multi-protein signaling complex, while the polarized distribution and vesicle-like localization of Bcr-Abl may play a role in leukemogenesis.
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Bazzoni G, Carlesso N, Griffin JD and Hemler ME. . 1996 J. Clin. Invest. 98: 521–528.
Bonfini L, Migliaccio E, Pelicci G, Lanfrancone L and Pelicci PG. . 1996 Trends Biochem. Sci. 21: 257–261.
Bouton AH and Burnham MR. . 1997 Hybridoma 16: 403–411.
Cortes JE, Talpaz M and Kantarjian H. . 1996 Am. J. Med. 100: 555–570.
Daley G and Baltimore D. . 1988 Proc. Natl. Acad. Sci. USA 85: 9312–9316.
Daley GQ, Van Etten RA and Baltimore D. . 1990 Science 247: 824–830.
Elefanty AG, Hariharan IK and Cory S. . 1990 EMBO J. 9: 1069–1078.
Enright H and McGlave PB. . 1996 Curr. Opin. Hematol. 3: 303–309.
Goldman JM. . 1997 Curr. Opin. Hematol. 4: 277–285.
Gotoh A and Broxmeyer HE. . 1997 Curr. Opin. Hematol. 4: 3–11.
Hariharan IK, Adams JM and Cory S. . 1988 Oncogene Res. 3: 387–399.
Hariharan IK, Harris AW, Crawford M, Abud H, Webb E, Cory S and Adams JM. . 1989 Mol. Cell. Biol. 9: 2798–2805.
Hawley RG, Lieu FHL, Fong AZC and Hawley TS. . 1995 Gene Therapy 1: 136–138.
Honda H, Fujii T, Takatoku M, Mano H, Witte ON, Yazaki Y and Hirai H. . 1995 Blood 85: 2853–2861.
Honda H, Oda H, Suzuki T, Takahashi T, Witte ON, Ozawa K, Ishikawa T, Yazaki Y and Hirai H. . 1998 Blood 91: 2067–2075.
Kelliher MA, McLaughlin J, Witte ON and Rosenberg N. . 1990 Proc. Natl. Acad. Sci. USA 87: 6649–6653.
Kelliher MA, Weckstein DJ, Knott AG, Wortis HH and Rosenberg N. . 1993 Oncogene 8: 1249–1256.
Laneuville P, Heisterkamp N and Groffen J. . 1991 Oncogene 6: 275–282.
Langdon WY. . 1995 Aust. N.Z. J. Med. 25: 859–864.
Lauffenburger DA and Horwitz AF. . 1996 Cell 84: 359–369.
Lester LB and Scott JD. . 1997 Recent Prog. Horm. Res. 52: 409–429.
Liu J, Campbell M, Guo JQ, Lu D, Xian YM, Andersson BS and Arlinghaus RB. . 1993 Oncogene 8: 101–109.
Liu J, Wu Y, Ma GZ, Lu D, Haataja L, Heisterkamp N, Groffen J and Arlinghaus RB. . 1996 Mol. Cell. Biol. 16: 998–1005.
Lotti LV, Lanfrancone L, Migliaccio E, Zompetta C, Pelicci G, Salcin AE, Falini B, Pelicci PG and Torrisi MR. . 1996 Mol. Cell. Biol. 16: 1946–1954.
Lugo TG, Pendergast A-M, Muller AJ and Witte ON. . 1990 Science 247: 1079–1082.
Lugo TG and Witte ON. . 1989 Mol. Cell. Biol. 9: 1263–1270.
Maru Y and Witte ON. . 1991 Cell 67: 459–468.
McLaughlin J, Chianese E and Witte ON. . 1987 Proc. Natl. Acad. Sci, USA 84: 6558–6562.
McLaughlin J, Chianese E and Witte ON. . 1989 Mol. Cell. Biol. 9: 1866–1874.
McWhirter JR, Gaalasso DL and Wang JYJ. . 1993 Mol. Cell. Biol. 13: 7587–7595.
McWhirter JR and Wang JYJ. . 1993 EMBO J. 12: 1533–1546.
McWhirter JR and Wang JYJ. . 1997 Oncogene 15: 1625–1634.
Melo JV. . 1996 Blood 88: 2375–2384.
Morgenstern JP and Land H. . 1990 Nucl. Acids Res. 18: 3587–3596.
Nakahara H, Mueller SC, Nomizu M, Yamada Y, Yeh Y and Chen WT. . 1998 J. Biol. Chem. 273: 9–12.
Pawson T and Scott JD. . 1997 Science 278: 2075–2080.
Pear WS, Nolan GP, Scott ML and Baltimore D. . 1993 Proc. Natl. Acad. Sci. USA 90: 8392–8396.
Pendergast AM, Quilliam LA, Cripe LD, Bassing CH, Dai Z, Li N, Batzer A, Rabun KM, Der CJ, Schlessinger J and Gishizky ML. . 1993 Cell 75: 175–185.
Puil L, Liu J, Gish G, Mbamalu G, Bowtell D, Pelicci PG, Arlinghaus R and Pawson T. . 1994 EMBO J. 13: 764–773.
Raitano AB, Whang YE and Sawyers CL. . 1997 Biochim. Biophys. Acta 1333: 201–216.
Ren R, Ye Z and Baltimore D. . 1994 Genes Dev. 8: 783–795.
Renshaw MW, McWhirter JR and Wang JYJ. . 1995 Mol. Cell. Biol. 15: 1286–1293.
Salgia R, Li JL, Ewaniuk DS, Pear W, Pisick E, Burky SA, Ernst T, Sattler M, Chen LB and Griffin JD. . 1997 J. Clin. Invest. 100: 46–57.
Sattler M and Salgia R. . 1997 Cytokine Growth Factor Rev. 8: 63–79.
Sawyers C, McLaughlin J, Goga A, Havlik M and Witte O. . 1994 Cell 77: 121–131.
Sawyers CL. . 1997 Baillieres Clin. Haematol. 10: 223–231.
Schlessinger J. . 1994 Curr. Opin. Genet. Dev. 4: 25–30.
Spector I, Shochet NR, Biasberger D and Kashman Y. . 1989 Cell Motil. Cytoskeleton 13: 127–144.
Tanaka S, Neff L, Baron R and Levy JB. . 1995 J. Biol. Chem. 270: 14347–14351.
Van Etten RA, Jackson P and Baltimore D. . 1989 Cell 58: 669–678.
Van Etten RA, Jackson PK, Baltimore D, Sanders M, Matsudaira PT and Janmey PA. . 1993 J. Cell. Biol. 124: 325–340.
Verfaillie CM, Hurley R, Lundell BI, Zhao C and Bhatia R. . 1997 Acta Haematol. 97: 40–52.
Verfaillie CM, McCarthy JB and McGlabe PB. . 1992 J. Clin. Invest. 90: 1232–1239.
Voncken JW, Kaartinen V, Pattengale PK, Germeraad WT, Groffen J and Heisterkamp N. . 1995 Blood 86: 4603–4611.
Wang JYJ. . 1993 Curr. Opin. Genet. Dev. 3: 35–43.
Wetzler M, Talpaz M, Van Etten R, Hirsh-Ginsberg C, Beran M and Kurzrock R. . 1993 J. Clin. Invest. 92: 1925–1939.
Wu C, Butz S, Ying Y and Anderson RGW. . 1997 J. Biol. Chem. 272: 3554–3559.
Wu Y, Lin J and Arlinghaus RB. . 1998 Oncogene 16: 141–146.
Young JC and Witte ON. . 1988 Mol. Cell. Biol. 8: 4079–4087.
Zhang X and Ren R. . 1998 Blood in press.
Acknowledgements
We thank Drs A Bouton, R Salgia, M Lasanti and M Zerial for providing anti-p130Cas, -Crkl, -caveolin, and -Rab7 antibodies, respectively, and X Zhang and A Gross for technical help and critical reading of the manuscript. This work was supported by National Cancer Institute grant CA68008 (to RR). RR is a recipient of American Cancer Society Junior Faculty Research Award.
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Skourides, P., Perera, S. & Ren, R. Polarized distribution of Bcr-Abl in migrating myeloid cells and co-localization of Bcr-Abl and its target proteins. Oncogene 18, 1165–1176 (1999). https://doi.org/10.1038/sj.onc.1202407
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DOI: https://doi.org/10.1038/sj.onc.1202407
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