SYK and ZAP70 kinases in lymphocyte selection

SYK 和 ZAP70 激酶在淋巴细胞选择中的作用

基本信息

  • 批准号:
    10557882
  • 负责人:
  • 金额:
    $ 61.73万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-02-01 至 2027-01-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT While B-cells are under intense selective pressure to eliminate autoreactive and pre-malignant clones, we identified SYK as central kinase to set the thresholds for negative selection. SYK and its highly homologous relative ZAP70 initiate B-cell receptor (BCR) and T-cell receptor (TCR) signaling in B- and T-lymphocytes, respectively. Even though the two kinases are almost identical and serve analogous functions, their expression in B- and T-cells is strictly segregated throughout evolution. Whereas the reason for separation of the two kinases is not known, aberrant coexpression of Syk and Zap70 was previously reported in B-cell chronic lymphocytic leukemia (CLL) and in peripheral T-cell lymphoma (PTCL). Our group recently demonstrated that aberrant ZAP70 expression is a common feature in pre- germinal center (GC) B-cell malignancies (B-ALL, CLL, MCL; Sadras et al., Mol Cell 2021). In genetic mouse models for B-ALL and B-CLL, inducible coexpression of Zap70 accelerated disease onset, while genetic deletion impaired malignant transformation. Likewise, inducible expression of Zap70 during early B-cell development subverted negative selection of autoreactive B-cells to promote pervasive autoantibody production. Mechanistically, ZAP70 competes with SYK and exerts a dominant-negative effect on SYK-dependent Ca2+-signaling. By occupying but not phosphorylating BLNK, BTK and PLC2 substrates upstream of calcium signaling, ZAP70 dramatically reduces the frequency of autonomous Ca2+-oscillations. Fast oscillations in the sole presence of SYK (4.5 mHz) are decoded by NFATC1 and result in anergy and cell death. In contrast, slow Ca2+-oscillations in the presence of ZAP70 (0.25 mHz) promote selective activation of NF-B and B-cell survival and proliferation. We test here the central hypothesis that B-cells sense pathological signaling downstream of an autoreactive BCR or a transforming oncogene through SYK-dependent high-frequency Ca2+- oscillations. At high frequencies, Ca2+-oscillations activate NFATC1 to initiate B-cell anergy and clonal deletion. Conversely, ZAP70 slows down Ca2+-oscillations to activate NF-B instead of NFATC1 and enables autoreactive and premalignant B-cell clones to persist and eventually give rise to autoimmune disease or pre-GC B-cell malignancies. We are proposing three Aims to (1) elucidate the mechanisms by which ZAP70 slows down SYK- dependent high-frequency Ca2+-oscillations, to (2) determine how coexpression of ZAP70 subverts negative selection of autoreactive B-cells in autoimmune disease and (3) to uncover how ZAP70 enables oncogenic signaling and overt malignant transformation of pre-malignant B-cells.
摘要

项目成果

期刊论文数量(0)
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Eric Meffre其他文献

Eric Meffre的其他文献

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{{ truncateString('Eric Meffre', 18)}}的其他基金

Elucidating the immunology of autoantibody formation and function in COVID-19
阐明 COVID-19 中自身抗体形成和功能的免疫学
  • 批准号:
    10639707
  • 财政年份:
    2023
  • 资助金额:
    $ 61.73万
  • 项目类别:
SYK and ZAP70 kinases in lymphocyte selection
SYK 和 ZAP70 激酶在淋巴细胞选择中的作用
  • 批准号:
    10467215
  • 财政年份:
    2022
  • 资助金额:
    $ 61.73万
  • 项目类别:
Impact of regulatory T cells on human peripheral B cell tolerance
调节性 T 细胞对人外周 B 细胞耐受的影响
  • 批准号:
    8424216
  • 财政年份:
    2012
  • 资助金额:
    $ 61.73万
  • 项目类别:
Impact of regulatory T cells on human peripheral B cell tolerance
调节性 T 细胞对人外周 B 细胞耐受的影响
  • 批准号:
    8302578
  • 财政年份:
    2012
  • 资助金额:
    $ 61.73万
  • 项目类别:
Loss of B cell tolerance in rheumatoid arthritis
类风湿性关节炎 B 细胞耐受性丧失
  • 批准号:
    8091761
  • 财政年份:
    2010
  • 资助金额:
    $ 61.73万
  • 项目类别:
Autoreactive B Cell Development in Autoimmune Disease
自身免疫性疾病中自身反应性 B 细胞的发育
  • 批准号:
    7687682
  • 财政年份:
    2009
  • 资助金额:
    $ 61.73万
  • 项目类别:
Loss of B Cell Tolerance in Rheumatoid Arthritis
类风湿性关节炎 B 细胞耐受性丧失
  • 批准号:
    8811079
  • 财政年份:
    2006
  • 资助金额:
    $ 61.73万
  • 项目类别:
Loss of B Cell Tolerance in Rheumatoid Arthritis
类风湿性关节炎 B 细胞耐受性丧失
  • 批准号:
    8586459
  • 财政年份:
    2006
  • 资助金额:
    $ 61.73万
  • 项目类别:
Loss of B Cell Tolerance in Rheumatoid Arthritis
类风湿性关节炎 B 细胞耐受性丧失
  • 批准号:
    8968799
  • 财政年份:
    2006
  • 资助金额:
    $ 61.73万
  • 项目类别:
Loss of B cell tolerance in rheumatoid arthritis
类风湿性关节炎 B 细胞耐受性丧失
  • 批准号:
    7446808
  • 财政年份:
    2006
  • 资助金额:
    $ 61.73万
  • 项目类别:

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