Serine phosphorylation by SYK is critical for nuclear localization and transcription factor function of Ikaros

Uckun, Fatih M.; Ma, Hong; Zhang, Jian; Ozer, Zahide; Dovat, Sinisa; Mao, Cheney; Ishkhanian, Rita; Goodman, Patricia A.; Qazi, Sanjive

doi:10.1073/pnas.1209828109

Cited by 53 publications

(89 citation statements)

References 41 publications

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“…Interestingly, we identified tyrosine residue 96 of Aiolos to be phosphorylated in tonic and activated BCR signaling. Although serine phosphorylation of IKZF1-encoded Ikaros has been shown to control its cellular localization (29), a regulation of Ikaros proteins by tyrosine phosphorylation is hitherto unknown. Therefore, our data might help to understand how BCR-proximal processes are linked to the regulation of this protein family.…”

Section: Bcr Signaling Network In Blmentioning

confidence: 99%

Elucidation of tonic and activated B-cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival

Corso

Pan

Walter

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Burkitt's lymphoma (BL) is a highly proliferative B-cell neoplasm and is treated with intensive chemotherapy that, because of its toxicity, is often not suitable for the elderly or for patients with endemic BL in developing countries. BL cell survival relies on signals transduced by B-cell antigen receptors (BCRs). However, tonic as well as activated BCR signaling networks and their relevance for targeted therapies in BL remain elusive. We have systematically characterized and compared tonic and activated BCR signaling in BL by quantitative phosphoproteomics to identify novel BCR effectors and potential drug targets. We identified and quantified ∼16,000 phospho-sites in BL cells. Among these sites, 909 were related to tonic BCR signaling, whereas 984 phospho-sites were regulated upon BCR engagement. The majority of the identified BCR signaling effectors have not been described in the context of B cells or lymphomas yet. Most of these newly identified BCR effectors are predicted to be involved in the regulation of kinases, transcription, and cytoskeleton dynamics. Although tonic and activated BCR signaling shared a considerable number of effector proteins, we identified distinct phosphorylation events in tonic BCR signaling. We investigated the functional relevance of some newly identified BCR effectors and show that ACTN4 and ARFGEF2, which have been described as regulators of membrane-trafficking and cytoskeletonrelated processes, respectively, are crucial for BL cell survival. Thus, this study provides a comprehensive dataset for tonic and activated BCR signaling and identifies effector proteins that may be relevant for BL cell survival and thus may help to develop new BL treatments.lymphoma | B-cell receptor | phosphoproteome | cancer biology

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Section: Bcr Signaling Network In Blmentioning

confidence: 99%

Elucidation of tonic and activated B-cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival

Corso

Pan

Walter

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Gene expression profiling, immunophenotyping using mAb, confocal imaging, immunoblotting using the ECL detection system (Amersham Pharmacia Biotech), and apoptosis assays were performed, as described in detail in previous publications (40,41,(44)(45)(46) and Supplemental Methods. For bioinformatics analyses of gene expression profiles, we used archived data sets on primary leukemia cells from matchedpair relapse versus diagnosis leukemia specimens from relapsed BPL patients as well as newly diagnosed BPL patients, including those with Philadelphia chromosome (Ph)/BCR-ABL fusion transcript-positive, t(1;19)/E2A-PBX1 fusion transcript-positive, or MLL-rearrangement (R)-positive disease, as detailed in Supplemental Methods.…”

Section: Dr5mentioning

confidence: 99%

Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia

Uckun¹,

Myers²,

Qazi³

et al. 2015

J. Clin. Invest.

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“…PCR, RT-PCR, and qRT-PCR assays as well as Western blots and colony assays were also performed according to standard procedures. 5-8 …”

Section: Methodsmentioning

confidence: 99%

CD22ΔE12 as a molecular target for corrective repair using RNAtrans-splicing: anti-leukemic activity of a rationally designed RNAtrans-splicing molecule

Uckun

Qazi

et al. 2015

Integrative Biology

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Our recent studies have demonstrated that the CD22 exon 12 deletion (CD22ΔE12) is a characteristic genetic defect of therapy-refractory clones in pediatric B-precursor acute lymphoblastic leukemia (BPL) and implicated the CD22ΔE12 genetic defect in the aggressive biology of relapsed or therapy-refractory pediatric BPL. The purpose of the present study was to further evaluate the biologic significance of the CD22ΔE12 molecular lesion and determine if it could serve as a molecular target for corrective repair using RNA trans-splicing therapy. We show that both pediatric and adult B-lineage lymphoid malignancies are characterized by a very high incidence of the CD22ΔE12 genetic defect. We provide experimental evidence that the correction of the CD22ΔE12 genetic defect in human CD22ΔE12+ BPL cells using a rationally designed CD22 RNA trans-splicing molecule (RTM) caused a pronounced reduction of their clonogenicity. The RTM-mediated correction replaced the downstream mutation-rich segment of Intron 12 and remaining segments of the mutant CD22 pre-mRNA with wildtype CD22 Exons 10-14, thereby preventing the generation of the cis-spliced aberrant CD22ΔE12 product. The anti-leukemic activity of this RTM against BPL xenograft clones derived from CD22ΔE12+ leukemia patients provides the preclinical proof-of-concept that correcting the CD22ΔE12 defect with rationally designed CD22 RTMs may provide the foundation for therapeutic innovations that are needed for successful treatment of high-risk and relapsed BPL patients.

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Serine phosphorylation by SYK is critical for nuclear localization and transcription factor function of Ikaros

Cited by 53 publications

References 41 publications

Elucidation of tonic and activated B-cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival

Elucidation of tonic and activated B-cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival

Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia

CD22ΔE12 as a molecular target for corrective repair using RNAtrans-splicing: anti-leukemic activity of a rationally designed RNAtrans-splicing molecule

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