Modulation of proximal signaling in normal and transformed B cells by transmembrane adapter Cbp/PAG

Kalland, Maria Elisabeth; Solheim, Silje; Skånland, Sigrid S.; Taskén, Kjetil; Berge, Torunn

doi:10.1016/j.yexcr.2012.05.014

Cited by 9 publications

(9 citation statements)

References 34 publications

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“…33–35 PAG1 has also been identified as a putative Ras signaling inhibitor 36 , and to have a negative regulatory function in proximal B-cell receptor signaling. 37 …”

Section: Resultsmentioning

confidence: 99%

The genomic landscape of hypodiploid acute lymphoblastic leukemia

Holmfeldt¹,

Wei²,

et al. 2013

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The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole genome and exome sequencing of 40 cases, identified two subtypes that differ in severity of aneuploidy, transcriptional profile and submicroscopic genetic alterations. Near haploid cases with 24–31 chromosomes harbor alterations targeting receptor tyrosine kinase- and Ras signaling (71%) and the lymphoid transcription factor IKZF3 (AIOLOS; 13%). In contrast, low hypodiploid ALL with 32–39 chromosomes are characterized by TP53 alterations (91.2%) which are commonly present in non-tumor cells, and alterations of IKZF2 (HELIOS; 53%) and RB1 (41%). Both near haploid and low hypodiploid tumors exhibit activation of Ras- and PI3K signaling pathways, and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.

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“…33–35 PAG1 has also been identified as a putative Ras signaling inhibitor 36 , and to have a negative regulatory function in proximal B-cell receptor signaling. 37 …”

Section: Resultsmentioning

confidence: 99%

The genomic landscape of hypodiploid acute lymphoblastic leukemia

Holmfeldt¹,

Wei²,

et al. 2013

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“…PAG1 also inhibits the SRC kinase Lyn following B-cell receptor signaling and B-cell activation. 13 In contrast, PAG1 in mast cells acts as a feedbackloop inhibitor. Following FcεRI activation on mast cells, SRC kinases hyperphosphorylate PAG1.…”

Section: Introductionmentioning

confidence: 99%

“…However, whether PAG1 expression affects the development of T H 2 responses is not known. PAG1 also inhibits the SRC kinase Lyn following B‐cell receptor signaling and B‐cell activation . In contrast, PAG1 in mast cells acts as a feedback‐loop inhibitor.…”

Section: Introductionmentioning

confidence: 99%

PAG1 limits allergen‐induced type 2 inflammation in the murine lung

Ullah

Vicente

Collinson

et al. 2019

Allergy

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Background Phosphoprotein associated with glycosphingolipid‐enriched microdomains 1 (PAG1) is a transmembrane adaptor protein that affects immune receptor signaling in T and B cells. Evidence from genome‐wide association studies of asthma suggests that genetic variants that regulate the expression of PAG1 are associated with asthma risk. However, it is not known whether PAG1 expression is causally related to asthma pathophysiology. Here, we investigated the role of PAG1 in a preclinical mouse model of house dust mite (HDM)‐induced allergic sensitization and allergic airway inflammation. Methods Pag1‐deficient (Pag1−/−) and wild‐type (WT) mice were sensitized or sensitized/challenged to HDM, and hallmark features of allergic inflammation were assessed. The contribution of T cells was assessed through depletion (anti‐CD4 antibody) and adoptive transfer studies. Results Type 2 inflammation (eosinophilia, eotaxin‐2 expression, IL‐4/IL‐5/IL‐13 production, mucus production) in the airways and lungs was significantly increased in HDM sensitized/challenged Pag1−/− mice compared to WT mice. The predisposition to allergic sensitization was associated with increased airway epithelial high‐mobility group box 1 (HMGB1) translocation and release, increased type 2 innate lymphoid cells (ILC2s) and monocyte‐derived dendritic cell numbers in the mediastinal lymph nodes, and increased T‐helper type 2 (TH2)‐cell differentiation. CD4+ T‐cell depletion studies or the adoptive transfer of WT OVA‐specific CD4+ T cells to WT or Pag1−/− recipients demonstrated that the heightened propensity for TH2‐cell differentiation was both T cell intrinsic and extrinsic. Conclusion PAG1 deficiency increased airway epithelial activation, ILC2 expansion, and TH2 differentiation. As a consequence, PAG1 deficiency predisposed toward allergic sensitization and increased the severity of experimental asthma.

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“…2A ). It has been determined that CBP/PAG is expressed as a tyrosine-phosphorylated protein and serves a negative role in signal transduction in lymphoid cell lines ( 23 ). To identify whether this was the case in the transfected Jurkat cells, proliferation and apoptosis in the two cell lines was examined.…”

Section: Resultsmentioning

confidence: 99%

Overexpression of Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomains induces cluster of differentiation 59-mediated apoptosis in Jurkat cells

Cong

Gao

et al. 2018

Exp Ther Med

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Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomains (CBP/PAG) is a membrane-bound adaptor protein that downregulates the activation of Src family kinases present in lipid rafts. To elucidate the role of CBP/PAG in human T cell activation, a cell line overexpressing CBP/PAG was constructed and the function of CBP/PAG in Jurkat cells was examined. The present study revealed that increased CBP/PAG expression in T cells significantly enhanced their apoptosis and reduced cellular activation and proliferation. Overexpression of CBP/PAG suppressed the growth of Jurkat cells by recruiting c-Src and its negative regulator, C-terminal Src kinase (CSK), to lipid rafts. The negative regulation of CBP/PAG was enhanced in the presence of anti-cluster of differentiation (CD)59 monoclonal antibodies. In addition, a significant association was revealed between the location of CBP/PAG and CD59, which were co-expressed in the same region of the cell membrane, implicating a potential overlap of the elicited signaling pathways. These results indicate that CBP/PAG functions as a negative regulator of cell signal transduction and suggest that CD59 may strengthen the role of negative feedback regulation.

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Modulation of proximal signaling in normal and transformed B cells by transmembrane adapter Cbp/PAG

Cited by 9 publications

References 34 publications

The genomic landscape of hypodiploid acute lymphoblastic leukemia

The genomic landscape of hypodiploid acute lymphoblastic leukemia

PAG1 limits allergen‐induced type 2 inflammation in the murine lung

Overexpression of Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomains induces cluster of differentiation 59-mediated apoptosis in Jurkat cells

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