B Cell Receptor-Mediated Syk-Independent Activation of Phosphatidylinositol 3-Kinase, Ras, and Mitogen-Activated Protein Kinase Pathways

Yokozeki, Takeaki; Adler, Kristin; Lankar, Danielle; Bonnerot, Christian

doi:10.4049/jimmunol.171.3.1328

Cited by 27 publications

(19 citation statements)

References 58 publications

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“…ERK was not required for this process, which is in agreement with a previous finding in SYK-deficient mice that activation of the Ras and MAPK pathway can be independent of SYK. 22 We have also shown that the phospho-flow assays can be applied to freezethawed primary lymphoma specimens that demonstrated differential signaling responses to the SYK inhibitor. Together with the data on cell line sensitivities, the profiles of PLC␥2 and AKT showed promise as in vitro biomarkers to predict clinical responses of DLBCL to SYK inhibition.…”

Section: Discussionmentioning

confidence: 89%

SYK inhibition and response prediction in diffuse large B-cell lymphoma

Cheng

Coffey

Zhang

et al. 2011

Blood

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Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the role of SYK in its pathogenesis is not completely understood. Using tissue microarray, we demonstrated for the first time that SYK protein is activated in 27 of 61 (44%) primary human DLBCL tissues. Among DLBCL cell lines, 7 were sensitive and 3 were resistant to a highly specific SYK inhibitor, PRT060318. In sensitive DLBCL cells, SYK inhibition blocked the G 1 -S transition and caused cell-cycle arrest. This effect was reproduced by genetic reduction of SYK using siRNA. A detailed analysis of the BCR signaling pathways revealed that the consequence of SYK inhibition on PLC␥2 and AKT, as opposed to ERK1/2, was responsible for cell-cycle arrest. Genetic knock-down of these key molecules decelerated the proliferation of lymphoma cells. In addition, BCR signaling can be blocked by PRT060318 in primary lymphoma cells. Together, these findings provide insights into cellular pathways required for lymphoma cell growth and support the rationale for considering SYK inhibition as a potentially useful therapy for DLBCL. The results further suggest the possibility of using PLC␥2 and AKT as biomarkers to predict therapeutic response in prospective clinical trials of specific SYK inhibitors. (Blood. 2011;118(24):6342-6352)

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Section: Discussionmentioning

confidence: 89%

SYK inhibition and response prediction in diffuse large B-cell lymphoma

Cheng

Coffey

Zhang

et al. 2011

Blood

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“…Thereafter, Syk binds the dually Src-phosphorylated ITAM [5,24] and plays a critical role in the activation of many downstream signaling enzymes such as phospholipase Cc, PI3 K and MAPK, some of which have been related to other internalization processes (i.e. receptor-mediated phagocytosis, [25,26]). Therefore, the effect of Syk inhibition on BCR-mediated Ag internalization was determined using the Syk inhibitor piceatannol [27].…”

Section: Resultsmentioning

confidence: 99%

Functional and structural requirements for the internalization of distinct BCR‐ligand complexes

et al. 2006

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Antigen (Ag) binding to the BCR rapidly initiates two important events: a phosphorylation cascade that results in the production of secondary signaling intermediaries and the internalization of Ag-BCR complexes. Previous studies using anti-BCR antibodies (Ab) have suggested that BCR signaling is an essential requirement for BCR endocytosis and have further implicated lipid rafts as essential platforms for both BCR functions. However, published data from our laboratory indicate that lipid rafts and consequently raft-mediated signaling are dispensable for BCR-mediated internalization of Ag-specific BCR. Therefore, we investigated the relationship between BCR signaling and endocytosis by defining the role of early kinase signaling in the BCRmediated internalization of a model Ag (haptenated protein). The results demonstrate that Src kinases and Syk-mediated BCR signaling are not essential for BCR-mediated Ag internalization. Moreover, by comparing Ag and Ab, it was determined that while both localize to clathrin-coated pits, the internalization of Ab-BCR complexes is more susceptible to inhibition of signaling and highly sensitive to disruption of lipid rafts and the actin cytoskeleton compared to Ag-BCR complexes. Thus, these results demonstrate that the nature of the ligand ultimately determines the functional requirements and relative contribution of lipid rafts and other membrane structures to the internalization of BCR-ligand complexes.

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“…The JeKo‐1 cell line, bearing Syk overexpression, experienced cell proliferation arrest, growth inhibition and apoptosis at a dose much lower than the remaining MCL cell lines. In B cells, Syk leads to intracellular calcium mobilisation, activation of AKT, mitogen‐activated protein kinases and NF κ B activation (Beitz et al , 1999; Cornall et al , 2000; Yokozeki et al , 2003). The BCR signalling pathway is believed to play a major role in B‐cell lymphoma growth and survival (Kuppers, 2005).…”

Section: Discussionmentioning

confidence: 99%

Genomic and expression profiling identifies the B‐cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma

et al. 2005

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SummaryAmong B-cell lymphomas mantle cell lymphoma (MCL) has the worst prognosis. By using a combination of genomic and expression profiling (Affymetrix GeneChip Mapping 10k Xba131 and U133 set), we analysed 26 MCL samples to identify genes relevant to MCL pathogenesis and that could represent new therapeutic targets. Recurrent genomic deletions and gains were detected. Genes were identified as overexpressed in regions of DNA gain on 3q, 6p, 8q, 9q, 16p and 18q, including the cancer genes BCL2 and MYC. Among the transcripts with high correlation between DNA and RNA, we identified SYK, a tyrosine kinase involved in B-cell receptor signalling. SYK was amplified at DNA level, as validated by fluorescence in situ hybridisation (FISH) analysis, and overexpressed at both RNA and protein levels in the JeKo-1 cell line. Low-level amplification, with protein overexpression of Syk was demonstrated by FISH in a small subset of clinical samples. After treatment with low doses of the Syk inhibitor piceatannol, cell proliferation arrest and apoptosis were induced in the cell line overexpressing Syk, while cells expressing low levels of Syk were much less sensitive. A combination of genomic and expression profiling suggested Syk inhibition as a new therapeutic strategy to be explored in lymphomas.

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B Cell Receptor-Mediated Syk-Independent Activation of Phosphatidylinositol 3-Kinase, Ras, and Mitogen-Activated Protein Kinase Pathways

Cited by 27 publications

References 58 publications

SYK inhibition and response prediction in diffuse large B-cell lymphoma

SYK inhibition and response prediction in diffuse large B-cell lymphoma

Functional and structural requirements for the internalization of distinct BCR‐ligand complexes

Genomic and expression profiling identifies the B‐cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma

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