Effect of Bcr sequences on the cellular function of the Bcr-Abl oncoprotein

McWhirter, John R.; Wang, Jean Yj

doi:10.1038/sj.onc.1201342

Cited by 44 publications

(29 citation statements)

References 32 publications

(57 reference statements)

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“…Actin cytoskeleton staining experiments suggested that disruption of F-actin was observed in a P185-equivalent form of BCR-ABL but not in P210-expressing Rat1 cells, which implies that the DH domain plays a role in stabilization of actin filaments (7). We could never show GDP-GTP exchange activities associated with this region but a report claimed that it activates CDC42, RhoA, and Rac (8,9).…”

mentioning

confidence: 73%

The Dbl Homology Domain of BCR Is Not a Simple Spacer in P210BCR-ABL of the Philadelphia Chromosome

Kin¹,

Li²,

Shibuya³

et al. 2001

Journal of Biological Chemistry

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mentioning

confidence: 73%

The Dbl Homology Domain of BCR Is Not a Simple Spacer in P210BCR-ABL of the Philadelphia Chromosome

Kin¹,

Li²,

Shibuya³

et al. 2001

Journal of Biological Chemistry

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“…Dblhomology domains encode guanine nucleotide exchange factor activity that can activate Rho-type small GTP binding proteins . PH domains, which are often found in tandem with Dbl homology domains, are abundant in proteins involved in signal transduction and may target Dbl to speci®c cytoskeletal locations where it may activate Rho-type small GTP bindings proteins and modulate the cytoskeleton McWhirter and Wang, 1997). At this time we do not know whether these domains play a role in the generation of Bcr-Abl induced dominant phenotypes but it is possible they contribute to the phenotypic di erences observed in P210 and P185 Bcr-Abl expression.…”

Section: Discussionmentioning

confidence: 99%

Dominant effects of the bcr-abl oncogene on Drosophila morphogenesis

Petersen

et al. 1999

Oncogene

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We targeted expression of human/¯y chimeric Bcr-Abl proteins to the developing central nervous system (CNS) and eye imaginal disc of Drosophila melanogaster. Neural expression of human/¯y chimeric P210 Bcr-Abl or P185 Bcr-Abl rescued abl mutant¯ies from pupal lethality, indicating that P210 and P185 Bcr-Abl can substitute functionally for Drosophila Abl during axonogenesis. However, increased levels of neurally expressed P210 or P185 Bcr-Abl but not Drosophila Abl produced CNS defects and lethality. Expression of P210 or P185 in the eye imaginal disc produced a dominant rough eye phenotype that was dependent on dosage of the transgene. Drosophila Enabled, previously identi®ed as a suppressor of the abl mutant phenotype and substrate for Drosophila Abl kinase, had markedly increased phosphotyrosine levels in Bcr-Abl expressing Drosophila, indicating that it is a substrate for Bcr-Abl as well. Drosophila, therefore, is a suitable model system to identify Bcr-Abl interactions important for signal transduction and oncogenesis.

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“…Third, Bcr-Abl is shown to recruit a number of signaling proteins to the vesicle-like structure. Last, it was reported that a mutant form of Bcr-Abl lacking amino acid residue 191 to 923 of the Bcr part of BcrAbl (Bcr/1-191-Abl) disrupted the stress ®bers in ®broblast cells, localized to the cortical F-actin as well as phalloidin negative spots, and displayed an enhanced transforming activity (McWhirter and Wang, 1997). It is not clear whether the vesicle-like structures serve as an alternative signaling docking site, or if the localization of Bcr-Abl onto F-actin and the vesicular structure are both required for Bcr-Abl's full transforming activity.…”

Section: Discussionmentioning

confidence: 99%

Polarized distribution of Bcr-Abl in migrating myeloid cells and co-localization of Bcr-Abl and its target proteins

1999

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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 identi®ed, 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, colocalizing with a subset of ®lamentous 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 BcrAbl (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 de®ned 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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Effect of Bcr sequences on the cellular function of the Bcr-Abl oncoprotein

Cited by 44 publications

References 32 publications

The Dbl Homology Domain of BCR Is Not a Simple Spacer in P210BCR-ABL of the Philadelphia Chromosome

The Dbl Homology Domain of BCR Is Not a Simple Spacer in P210BCR-ABL of the Philadelphia Chromosome

Dominant effects of the bcr-abl oncogene on Drosophila morphogenesis

Polarized distribution of Bcr-Abl in migrating myeloid cells and co-localization of Bcr-Abl and its target proteins

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