Human and mouse DOCK10 splicing isoforms with alternative first coding exon usage are differentially expressed in T and B lymphocytes

Alcaraz, María José; Ruiz-Lafuente, Natalia; Sebastián-Ruiz, Silvia; Majado, Maria Juliana; González-García, Consuelo; Bernardo, María Victoria; Álvarez-López, María R.; Parrado, Antonio

doi:10.1016/j.humimm.2011.03.024

Cited by 16 publications

(22 citation statements)

References 24 publications

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“…For most genes, both techniques correlated significantly (p<0.05, Figure S2 ). At the protein level, other authors and ourselves have provided, in previous reports, validation for several IL-4 targets detected in this study, such as CYSLTR1 [31] , IGHE [32] and NFIL3 [33] in B cells, or for DOCK10 in CLL and NBC cells [34] .…”

Section: Resultssupporting

confidence: 64%

The Gene Expression Response of Chronic Lymphocytic Leukemia Cells to IL-4 Is Specific, Depends on ZAP-70 Status and Is Differentially Affected by an NFκB Inhibitor

et al. 2014

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Interleukin 4 (IL-4), an essential mediator of B cell development, plays a role in survival of chronic lymphocytic leukemia (CLL) cells. To obtain new insights into the function of the IL-4 pathway in CLL, we analyzed the gene expression response to IL-4 in CLL and in normal B cells (NBC) by oligonucleotide microarrays, resulting in the identification of 232 non-redundant entities in CLL and 146 in NBC (95 common, 283 altogether), of which 189 were well-defined genes in CLL and 123 in NBC (83 common, 229 altogether) (p<0.05, 2-fold cut-off). To the best of our knowledge, most of them were novel IL-4 targets for CLL (98%), B cells of any source (83%), or any cell type (70%). Responses were significantly higher for 54 and 11 genes in CLL and NBC compared to each other, respectively. In CLL, ZAP-70 status had an impact on IL-4 response, since different sets of IL-4 targets correlated positively or negatively with baseline expression of ZAP-70. In addition, the NFκB inhibitor 6-Amino-4-(4-phenoxyphenethylamino)quinazoline, which reversed the anti-apoptotic effect of IL-4, preferentially blocked the response of genes positively correlated with ZAP-70 (e.g. CCR2, SUSD2), but enhanced the response of genes negatively correlated with ZAP-70 (e.g. AUH, BCL6, LY75, NFIL3). Dissection of the gene expression response to IL-4 in CLL and NBC contributes to the understanding of the anti-apoptotic response. Initial evidence of a connection between ZAP-70 and NFκB supports further exploration of targeting NFκB in the context of the assessment of inhibition of the IL-4 pathway as a therapeutic strategy in CLL, especially in patients expressing bad prognostic markers.

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Section: Resultssupporting

confidence: 64%

The Gene Expression Response of Chronic Lymphocytic Leukemia Cells to IL-4 Is Specific, Depends on ZAP-70 Status and Is Differentially Affected by an NFκB Inhibitor

et al. 2014

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“…Proteins of this subfamily contain a pleckstrin domain that can specifically activate Cdc42 and other closely related GTPases (9). Yelo et al (10) and Alcaraz-Garcia et al (11) have shown that Dock10 is encoded by a gene that is induced by interleukin-4 (IL-4) in chronic lymphocytic leukemia (CLL) cells and in human peripheral blood B lymphocytes but not T lymphocytes (10, 11). The rapid induction of Dock10 after IL-4 stimulation in CLL and normal peripheral blood B cells suggested that Dock10 is important for IL-4-induced B cell activation (10).…”

Section: Introductionmentioning

confidence: 99%

Deletion of Dock10 in B Cells Results in Normal Development but a Mild Deficiency upon In Vivo and In Vitro Stimulations

Gerasimčik

Baptista

et al. 2017

Front. Immunol.

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We sought to identify genes necessary to induce cytoskeletal change in B cells. Using gene expression microarray, we compared B cells stimulated with interleukin-4 (IL-4) and anti-CD40 antibodies that induce B cell spreading, cell motility, tight aggregates, and extensive microvilli with B cells stimulated with lipopolysaccharide that lack these cytoskeletal changes. We identified 84 genes with 10-fold or greater expression in anti-CD40 + IL-4 stimulated B cells, one of these encoded the guanine nucleotide exchange factor (GEF) dedicator of cytokinesis 10 (Dock10). IL-4 selectively induced Dock10 expression in B cells. Using lacZ expression to monitor Dock10 promoter activity, we found that Dock10 was expressed at all stages during B cell development. However, specific deletion of Dock10 in B cells was associated with a mild phenotype with normal B cell development and normal B cell spreading, polarization, motility, chemotaxis, aggregation, and Ig class switching. Dock10-deficient B cells showed lower proliferation in response to anti-CD40 and IL-4 stimulation. Moreover, the IgG response to soluble antigen in vivo was lower when Dock10 was specifically deleted in B cells. Together, we found that most B cell responses were intact in the absence of Dock10. However, specific deletion of Dock10 in B cells was associated with a mild reduction in B cell activation in vitro and in vivo.

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“…We previously reported cloning of the full length coding sequences of the human and mouse Dock10 genes ( Yelo et al, 2008 ; Alcaraz-García et al, 2011 ). Two isoforms, designated Dock10.1 and Dock10.2, arise from alternative transcription start site usage.…”

Section: Introductionmentioning

confidence: 99%

Dock10, a Cdc42 and Rac1 GEF, induces loss of elongation, filopodia, and ruffles in cervical cancer epithelial HeLa cells

et al. 2015

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Dock10 is one of the three members of the Dock-D family of Dock proteins, a class of guanine nucleotide exchange factors (GEFs) for Rho GTPases. Its homologs Dock9 and Dock11 are Cdc42 GEFs. Dock10 is required for maintenance of rounded morphology and amoeboid-type movement. Full-length isoforms of Dock10 have been recently cloned. Here, we address GTPase specificity and GEF activity of Dock10. In order of decreasing intensity, Dock10 interacted with nucleotide-free Rac1, Cdc42, and Rac3, and more weakly with Rac2, RhoF, and RhoG. Inducible expression of Dock10 in HeLa epithelial cells promoted GEF activity on Cdc42 and Rac1, and a morphologic change in two-dimensional culture consisting in loss of cell elongation, increase of filopodia, and ruffles. Area in contact with the substrate of cells that spread with non-elongated morphology was larger in cells expressing Dock10. Inducible expression of constitutively active mutants of Cdc42 and Rac1 in HeLa cells also induced loss of elongation. However, Cdc42 induced filopodia and contraction, and Rac1 induced membrane ruffles and flattening. When co-expressed with Dock10, Cdc42 potentiated filopodia, and Rac1 potentiated ruffles. These results suggest that Dock10 functions as a dual GEF for Cdc42 and Rac1, affecting cell morphology, spreading and actin cytoskeleton protrusions of adherent HeLa cells.

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Human and mouse DOCK10 splicing isoforms with alternative first coding exon usage are differentially expressed in T and B lymphocytes

Cited by 16 publications

References 24 publications

The Gene Expression Response of Chronic Lymphocytic Leukemia Cells to IL-4 Is Specific, Depends on ZAP-70 Status and Is Differentially Affected by an NFκB Inhibitor

The Gene Expression Response of Chronic Lymphocytic Leukemia Cells to IL-4 Is Specific, Depends on ZAP-70 Status and Is Differentially Affected by an NFκB Inhibitor

Deletion of Dock10 in B Cells Results in Normal Development but a Mild Deficiency upon In Vivo and In Vitro Stimulations

Dock10, a Cdc42 and Rac1 GEF, induces loss of elongation, filopodia, and ruffles in cervical cancer epithelial HeLa cells

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