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
- 来源:
- 关键词:AblationAccelerationAcuteAllelesAntibodiesAutoantibodiesAutoimmune DiseasesB lymphoid malignancyB-Cell Acute Lymphoblastic LeukemiaB-Cell Antigen ReceptorB-Cell DevelopmentB-Cell LymphomasB-Cell NeoplasmB-LymphocytesBLNK geneBiological MarkersCalcium SignalingCell DeathCell ProliferationCell SurvivalCellsChronic Lymphocytic LeukemiaClonal DeletionClone CellsDevelopmentDominant-Negative MutationEngineeringEtiologyEvolutionFlareFrequenciesGeneticGenetic studyHumanImpairmentKnock-inLymphocyteMalignant - descriptorMediatingMusOncogenesOncogenicOnset of illnessOutputPIK3CG genePathologicPatientsPeripheralPhosphoric Monoester HydrolasesPhosphotransferasesPreclinical TestingProductionProtein AnalysisReceptor SignalingReportingReverse Transcriptase Polymerase Chain ReactionRheumatoid ArthritisSYK geneSignal TransductionStructure of germinal center of lymph nodeSystemic Lupus ErythematosusT-Cell DevelopmentT-Cell LymphomaT-Cell ReceptorT-LymphocyteTestingZAP-70 Geneanaloganergyautoreactive B cellautoreactivitycell transformationhumanized mouseinducible gene expressionloss of functionmouse modelmutantnoveloptogeneticspatient derived xenograft modelpharmacologicphosphoproteomicspremalignantpressurepreventpromoterremote controlsegregationsingle cell proteinssmall molecule inhibitorstoichiometry
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 PLC2 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
虽然B细胞处于强烈的选择压力下,以消除自身反应和癌前克隆,
我们将SYK鉴定为中枢激酶以设定阴性选择的阈值。SYK及其高度
同源相对ZAP 70在B-和
T淋巴细胞。尽管这两种激酶几乎相同,
由于它们的功能,它们在B细胞和T细胞中的表达在整个进化过程中是严格分离的。而
分离这两种激酶的原因尚不清楚,Syk和Zap 70的异常共表达是由于
先前在B细胞慢性淋巴细胞白血病(CLL)和外周T细胞淋巴瘤中报告
(PTCL)。我们的研究小组最近证明,ZAP 70的异常表达是前乳腺癌的一个共同特征。
老年中心(GC)B细胞恶性肿瘤(B-ALL,CLL,MCL; Sadras等,Mol Cell 2021)。遗传
在B-ALL和B-CLL小鼠模型中,Zap 70的可诱导共表达加速了疾病的发作,
基因缺失损害恶性转化。同样地,Zap 70的诱导型表达在
早期B细胞发育破坏了自身反应性B细胞的阴性选择,
自身抗体产生。
从机制上讲,ZAP 70与SYK竞争,并对SYK依赖性细胞发挥显性-负性作用。
Ca 2+信号转导。通过占据但不磷酸化BLNK、BTK和PLC的上游底物,
在钙信号传导中,ZAP 70显著降低自主Ca 2+振荡的频率。快速
在SYK(4.5 mHz)单独存在的情况下的振荡被NFATC 1解码,并导致无反应性,
细胞死亡相比之下,在ZAP 70(0.25 mHz)存在下的缓慢Ca 2+振荡促进选择性的细胞分裂。
NF-κ B B的活化和B细胞存活和增殖。
我们在这里测试的核心假设,即B细胞的感觉病理信号下游的一个
自身反应性BCR或通过SYK依赖性高频Ca 2 +-
振荡在高频率下,Ca 2+振荡激活NFATC 1以启动B细胞无反应性和克隆形成。
删除。相反,ZAP 70减慢Ca 2+振荡以激活NF-κ B B而不是NFATC 1,
使自身反应性和癌前B细胞克隆持续存在,并最终引起自身免疫性
疾病或GC前B细胞恶性肿瘤。
我们提出了三个目标:(1)阐明ZAP 70减缓SYK的机制,
依赖于高频Ca 2+振荡,以(2)确定ZAP 70的共表达如何颠覆
自身免疫性疾病中自身反应性B细胞的阴性选择和(3)揭示ZAP 70
使致癌信号和明显的恶性转化前B细胞。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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:
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