Coexistence of phosphotyrosine-dependent and -independent interactions between Cbl and Bcr-Abl

Gaston, Isabelle; Johnson, Kara; Oda, Tsukasa; Bhat, Arun; Reis, Margaret; Langdon, Wallace Y.; Shen, Lei; Deininger, Michael W.; Druker, Brian J.

doi:10.1016/j.exphem.2003.09.018

Cited by 8 publications

(7 citation statements)

References 41 publications

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“…47 Bcr-Abl trafficking, not its proteasomal degradation, appears to underlie the major impact of WP1130 on CML cells and is aligned with previously described activities associated with increased K63-specific ubiquitin polymers on target proteins. 31 Because Ubc13 (E2) is the only known enzyme involved in forming K63-linked polyubiquitin chains, 48 this restricts the number of potential upstream components that provide K63-linked ubiquitin polymers for subsequent transfer to Bcr-Abl.…”

Section: Discussionsupporting

confidence: 51%

Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis

Sun

Kapuria

Peterson

et al. 2011

Blood

109

101

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IntroductionChronic myelogenous leukemia (CML) is associated with a chromosomal abnormality in the hematopoietic stem cell that results in the expression of Bcr-Abl with unregulated tyrosine kinase activity. 1 These observations supported the development and clinical testing of the first Bcr-Abl kinase inhibitor, imatinib, which demonstrated remarkable clinical efficacy in CML patients. Imatinib is the frontline therapy for CML and other Bcr-Ablexpressing leukemias, and most patients treated with imatinib in the chronic phase achieve a complete cytogenetic response. 2,3 However, molecular studies of imatinib-treated patients in remission demonstrated that Bcr-Abl expression is still detectable in most cases, and discontinuation of imatinib therapy often results in disease relapse. 4,5 Limited duration of imatinib response is also common in advanced CML patients, and imatinib resistance can occur at any stage of the disease. 5,6 Acquired imatinib resistance and disease progression are frequently characterized by Bcr-Abl mutations and posttranslational modifications that affect imatinib binding and kinase inhibition. 5,6 Some of the molecular changes in imatinib-resistant disease can be overcome with second-generation tyrosine kinase inhibitors, which bind Bcr-Abl with higher affinity or inhibit imatinib-insensitive kinases associated with resistance. [7][8][9][10][11] However, the activity of these inhibitors can also be limited by mutations and other mechanisms. [12][13][14] These observations suggest that additional approaches and targeting strategies may be needed to provide long-term effective treatment for CML patients.Kinase inhibition by small molecules that bind the ATP or the switch pocket region of Bcr-Abl are effective inhibitors but require continuous treatment because Bcr-Abl protein levels themselves are not directly regulated through kinase inhibition. Some evidence suggests that Bcr-Abl can function as a protein scaffold to organize signaling complexes that are not fully dependent on kinase activity. 15,16 These observations suggest that compounds that modulate Bcr-Abl protein levels may be more effective and appropriate for CML therapy in some settings. In light of that possibility and as a novel approach to overcoming kinase inhibitor resistance, several compounds have been described that affect Bcr-Abl function through mechanisms other than direct kinase inhibition. These include heat shock protein 90 (Hsp90) inhibitors, arsenic trioxide, homoharringtonine, histone deacetylase inhibitors, proteasome inhibitors, PP2A activators, and others. 5,10 All are reported to lead to CML cell death through down-regulation of Bcr-Abl expression or a loss of Bcr-Abl stability. However, most of these compounds reduce Bcr-Abl levels only after extended incubation intervals and display only limited selectivity for Bcr-Abl, which may increase their toxicity and decrease their clinical utility. [17][18][19] Additional compounds that induce rapid changes in Bcr-Abl levels with limited impact on other proteins are ...

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Section: Discussionsupporting

confidence: 51%

Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis

Sun

Kapuria

Peterson

et al. 2011

Blood

109

101

View full text Add to dashboard Cite

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“…It has previously been shown that individual mutations of the Tyr 177 to Phe, and deletion of the SH2 and Proline domains of BCR-ABL do not abolish the associations between BCR-ABL and its substrates [17], [22], [23], [24], [26], nor do they completely abolish the kinase activity [19], [20], [25], [27]. Kinase assays were performed to determine if the kinase activity of BCR-ABL was impaired in the triple mutant.…”

Section: Resultsmentioning

confidence: 99%

A BCR-ABL Mutant Lacking Direct Binding Sites for the GRB2, CBL and CRKL Adapter Proteins Fails to Induce Leukemia in Mice

et al. 2009

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The BCR-ABL tyrosine kinase is the defining feature of chronic myeloid leukemia (CML) and its kinase activity is required for induction of this disease. Current thinking holds that BCR-ABL forms a multi-protein complex that incorporates several substrates and adaptor proteins and is stabilized by multiple direct and indirect interactions. Signaling output from this highly redundant network leads to cellular transformation. Proteins known to be associated with BCR-ABL in this complex include: GRB2, c-CBL, p62DOK, and CRKL. These proteins in turn, link BCR-ABL to various signaling pathways indicated in cellular transformation. In this study we show that a triple mutant of BCR-ABL with mutations of the direct binding sites for GRB2, CBL, p62DOK and CRKL, is defective for transformation of primary hematopoietic cells in vitro and in a murine CML model, while it retains the capacity to induce IL-3 independence in 32D cells. Compared to BCR-ABL, the triple mutant's ability to activate the MAP kinase and PI3-kinase pathways is severely compromised, while STAT5 phosphorylation is maintained, suggesting that the former are crucial for the transformation of primary cells, but dispensable for transformation of factor dependent cell lines. Our data suggest that inhibition of BCR-ABL-induced leukemia by disrupting protein interactions could be possible, but would require blocking of multiple sites.

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“…It has been suggested that tyrosine phosphorylated CBL complexes with the SH2 domain on p210BCR-ABL1 but deletion of the SH2 domain of p210BCR-ABL1 does not inhibit the association which implies that CBL can interact with p210BCR-ABL1 via other mechanisms (Bhat et al, 1997). It has been proposed that an alternative mechanism by which unphosphorylated CBL and p210BCR-ABL1 associate may be via adaptor protein GBR2 (Gaston et al, 2004), which has been shown to activate RAS signaling (Pendergast et al, 1993;Puil et al, 1994). CRKL is an adaptor protein related to the CRK oncogene of the avian viral sarcoma virus (ten Hoeve et al, 1993).…”

Section: Discussionmentioning

confidence: 96%

Detection in primary chronic myeloid leukaemia cells of p210BCR‐ABL1 in complexes with adaptor proteins CBL, CRKL, and GRB2

Patel

Marley

Gordon

2006

Genes Chromosomes & Cancer

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Chronic myeloid leukemia (CML) arises as a consequence of the expression of a chimeric fusion protein, p210BCR-ABL1, which is localized to the cytoplasm and has constitutive protein tyrosine kinase activity. Extensive publications report that p210BCR-ABL1 complexed with multiple cytoplasmic proteins can modulate several cell signaling pathways. However, while altered signaling states can be demonstrated in primary CML material, most of the reported analytical work on complexed proteins has been done in cell lines expressing p210BCR-ABL1. This has been necessary because primary hemopoietic cell lysates contain a degradative activity which rapidly and permanently destroys p210BCR-ABL1, precluding accurate p210BCR-ABL1 quantification by Western blotting or investigation of coimmunoprecipitating proteins in primary cells. This degradative activity has proven intractable to inhibition by conventional protease inhibitors. We show here that the degradative activity in primary cells is associated with cell lysosomes and is most likely to be an acid-dependent hydrolase. By lysing primary hemopoietic cells at high pH, we have demonstrated substantial inhibition of the p210BCR-ABL1-degradative activity and now report, to the best of our knowledge, the first published demonstration by coimmunoprecipitation of the association between p210BCR-ABL1 and cytoplasmic effector proteins in primary CML material.

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Coexistence of phosphotyrosine-dependent and -independent interactions between Cbl and Bcr-Abl

Cited by 8 publications

References 41 publications

Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis

Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis

A BCR-ABL Mutant Lacking Direct Binding Sites for the GRB2, CBL and CRKL Adapter Proteins Fails to Induce Leukemia in Mice

Detection in primary chronic myeloid leukaemia cells of p210BCR‐ABL1 in complexes with adaptor proteins CBL, CRKL, and GRB2

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