Essential role of the adaptor protein Nck1 in Jurkat T cell activation and function

Yiemwattana, Ichaya; Ngoenkam, Jatuporn; Paensuwan, Pussadee; Kriangkrai, R; Chuenjitkuntaworn, Boontharika; Pongcharoen, Sutatip

doi:10.1111/j.1365-2249.2011.04494.x

Cited by 16 publications

(29 citation statements)

References 39 publications

(51 reference statements)

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“…2) with opposing associations in CLL ( P 1-tailed = 1.97 × 10 −8 ) and HL ( P 1-tailed = 3.31 × 10 −3 ). rs11715604 maps to intron 1 of NCK1, which is integral to T-cell activation3839 and regulates the PI3K/Akt pathway40. We also identified a number of promising associations that did not reach genome-wide significance, but exhibited moderate effects in the different BCM (Supplementary Table 2).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci

Law

Sud

Mitchell

et al. 2017

Sci Rep

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B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10 −9 ) with opposing effects between CLL (P = 1.97 × 10 −8 ) and HL (P = 3.31 × 10 −3 ). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10 −12 ) was associated with increased CLL and HL risk (P = 4.68 × 10 −12 ), and reduced MM risk (P = 1.12 × 10 −2 ), and Gly70 in HLA-DQB1 (P = 3.15 × 10 −10 ) showed opposing effects between CLL (P = 3.52 × 10 −3 ) and HL (P = 3.41 × 10 −9 ). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell

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Section: Resultsmentioning

confidence: 99%

Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci

Law

Sud

Mitchell

et al. 2017

Sci Rep

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“…The siRNA sequence targeting Nck1 used in this study was 5 -GGGTTCTCTGTCAGAGAAA -3 . The siRNA transfection was performed as previously described 14 . Briefly, 2 × 10 5 Jurkat cells were harvested, washed with D-PBS (Invitrogen) and resuspended in 10 µl solution R plus 50 pmol of stealth RNAi siRNA duplexes specific for Nck1.…”

Section: Nck Sirna Transfectionmentioning

confidence: 99%

“…In many cell types, Nck links phosphotyrosine signals and regulates actin cytoskeletal rearrangements 7 . In T cells activated via their T cell antigen receptor (TCR), Nck is essential in regulating actin rearrangement and immunological synapse formation [8][9][10][11][12][13][14] . Interestingly, our recent data have shown that silencing of Nck1 by transfection of siRNA to Jurkat T cell results in abrogation of T cell activation as indicated by decreased interleukin-2 (IL-2) secretion and CD69 expression 14 .…”

Section: Introductionmentioning

confidence: 99%

RNAi down-regulation of Nck1 adaptor protein in Jurkat T cells

Paensuwan¹,

Ngoenkam²,

Sanguansermsri³

et al. 2014

ScienceAsia

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RNA interference (RNAi) is a potent gene delivery system for studying the regulation of gene expression in a wide variety of eukaryotic cells. In the present study, different RNAi approaches, namely, synthetic small interfering RNA (siRNA) and plasmid-and lentivirus-based short hairpin RNA (shRNA) were investigated to assess the down-regulation of Nck1 protein efficiency in the Jurkat T cell line. Jurkat T cells treated with these three different systems substantially and specifically reduced the expression of the Nck1 protein but not that of the Nck2 protein. Although the three systems showed a similar Nck1 knockdown efficiency, they led to different T cell activation outcomes. After stimulation, CD69 expression and IL-2 production were impaired in Nck1-siRNA and plasmid-based Nck1-shRNA transfected Jurkat cells. However, these T cell activation outcomes were increased in lentiviral vector based Nck1-shRNA transfected cells. These data suggest that the outcomes from transfection with the shRNA based lentiviral vector differ from those of siRNA and shRNA-based plasmids although they provide the same gene silencing efficiency. The verification of suitable RNAi strategies to silence target genes is therefore necessary before using it in experiments.

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“…Bone marrow reconstitution with CD3ε PRS mutants in CD3ε-deficient mice, Nck overexpression in primary T cells, Nck knockout mice, and PRS knockin (KI) mice have all been used to study the role of the PRS and Nck in T cell development and mature T cell activation (14)(15)(16)(17)(18)(19)(20). Some experiments have suggested that the PRS is important for thymic maturation, but not for mature T cell activation in vitro (15), although experiments with bone marrow chimeras indicate that the PRS is important to activate mature T cells by weak, but not by strong, agonists in vitro (19).…”

mentioning

confidence: 99%

Relevance of Nck–CD3ε Interaction for T Cell Activation In Vivo

Borroto

Arellano

Blanco

et al. 2014

The Journal of Immunology

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On TCR ligation, the adaptor Nck is recruited through its src homology 3.1 domain to a proline-rich sequence (PRS) in CD3ε. We have studied the relevance of this interaction for T cell activation in vitro and in vivo by targeting the interaction sites in both partners. The first approach consisted of studying a knockin (KI) mouse line (KI-PRS) bearing a conservative mutation in the PRS that makes the TCR incompetent to recruit Nck. This deficiency prevents T cell activation by Ag in vitro and inhibited very early TCR signaling events including the tyrosine phosphorylation of CD3ζ. Most important, KI-PRS mice are partly protected against the development of neurological symptoms in an experimental autoimmune encephalitis model, and show a deficient antitumoral response after vaccination. The second approach consisted of using a high-affinity peptide that specifically binds the src homology 3.1 domain and prevents the interaction of Nck with CD3ε. This peptide inhibits T cell proliferation in vitro and in vivo. These data suggest that Nck recruitment to the TCR is fundamental to mount an efficient T cell response in vivo, and that the Nck–CD3ε interaction may represent a target for pharmacological modulation of the immune response.

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Essential role of the adaptor protein Nck1 in Jurkat T cell activation and function

Cited by 16 publications

References 39 publications

Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci

Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci

RNAi down-regulation of Nck1 adaptor protein in Jurkat T cells

Relevance of Nck–CD3ε Interaction for T Cell Activation In Vivo

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