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

Kin, Yoshitora; Li, Guang; Shibuya, Masabumi; Maru, Yoshiro

doi:10.1074/jbc.m105484200

Cited by 19 publications

(16 citation statements)

References 40 publications

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“…Although this domain is present in both p160 Bcr and p210 Bcr-Abl, no in vivo functions have been attributed to it in either context. However, the recent observation that the DH/PH domain of p210 Bcr-Abl cannot be functionally replaced with homologous sequences from Cdc24 (a related RhoGEF), or with irrelevant sequences of equivalent size (Kin et al, 2001), suggests that these sequences may in fact contain transforming potential, which would be consistent with what has been observed for multiple members of the RhoGEF family (Whitehead et al, 1997).…”

Section: Introductionsupporting

confidence: 65%

“…However, there have been several recent studies that suggest that this may not be the case. First, replacement of the DH domain of Bcr with a homologous domain from Cdc24, or with irrelevant sequences, diminishes transforming activity in Rat1 cells (Kin et al, 2001). This suggests that p185 Bcr-Abl and p210 Bcr-Abl may possess distinct transforming properties, and that the DH/PH domain may perform a specific function within the context of p210.…”

Section: Discussionmentioning

confidence: 99%

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p38 MAPK-mediated activation of NF-κB by the RhoGEF domain of Bcr

et al. 2002

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Section: Introductionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

p38 MAPK-mediated activation of NF-κB by the RhoGEF domain of Bcr

et al. 2002

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“…To determine whether CSDA S134 phosphorylation is critical for Bcr-Abl-dependent transformation, we generated stable lines expressing empty vector or co-expressing Bcr-Abl and empty vector, CSDA or the CSDAS134A phospho-deficient mutant in Rat1 cells to employ in soft agar colony formation assays. 33, 34 …”

Section: Resultsmentioning

confidence: 99%

Functional phosphoproteomic analysis reveals cold-shock domain protein A to be a Bcr-Abl effector-regulating proliferation and transformation in chronic myeloid leukemia

et al. 2010

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One proposed strategy to suppress the proliferation of imatinib-resistant cells in chronic myeloid leukemia (CML) is to inhibit key proteins downstream of Bcr-Abl. The PI3K/Akt pathway is activated by Bcr-Abl and is specifically required for the growth of CML cells. To identify targets of this pathway, we undertook a proteomic screen and identified several proteins that differentially bind 14-3-3, dependent on Bcr-Abl kinase activity. An siRNA screen of candidates selected by bioinformatics analysis reveals cold-shock domain protein A (CSDA), shown previously to regulate cell cycle progression in epithelial cells, to be a positive regulator of proliferation in a CML cell line. We show that Akt can phosphorylate the serine 134 residue of CSDA but, downstream of Bcr-Abl activity, this modification is mediated through the activation of MEK/p90 ribosomal S6 kinase (RSK) signaling. Inhibition of RSK, similarly to treatment with imatinib, blocked proliferation specifically in Bcr-Abl-positive leukemia cell lines, as well as cells from CML patients. Furthermore, these primary CML cells showed an increase in CSDA phosphorylation. Expression of a CSDA phospho-deficient mutant resulted in the decrease of Bcr-Abl-dependent transformation in Rat1 cells. Our results support a model whereby phosphorylation of CSDA downstream of Bcr-Abl enhances proliferation in CML cells to drive leukemogenesis.

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“…In addition, it has been shown that replacement of the DBL-like domain (and part of the pH domain) with irrelevant sequences abrogates the transformation potential of p210 BCR-ABL , consistent with a positive rather than a negative impact on its transforming potential. 8 The series of patients compiled here is still too small to determine whether e8a2-positive CML is different from 'standard' CML. However, none of the patients who were treated with interferon-a achieved even a minor cytogenetic remission, similar to the rare CML patients with p190 BCR-ABL .…”

mentioning

confidence: 94%