Negative regulation of mast cell proliferation by Fc-γRIIB
Negative regulation of mast cell proliferation by Fc-γRIIB
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DOI：
10.1016/s0161-5890(02)00078-0
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发表时间：
2002-09-01
影响因子：
3.6
通讯作者：
Daëron, M
中科院分区：
文献类型：
--
作者：
Malbec, O;Attal, JP;Daëron, M
Fc γ RIIB是IgG抗体的Fc部分的单链低亲和力受体，其由造血细胞（包括肥大细胞）广泛表达。我们先前证明Fc γ RIIB负调节由具有免疫受体酪氨酸基活化基序（ITAM）的受体（包括高亲和力IgE受体（Fc ε RI））触发的细胞活化。Fc γ RIIB具有基于免疫受体酪氨酸的抑制基序（ITAM），其缺失或突变消除抑制。当与Fc受体RI共聚集时，Fc γ RIIB ITIM被src家族蛋白酪氨酸激酶林恩酪氨酰-磷酸化，并募集含有SH 2结构域的肌醇5-磷酸酶SHIP，其导致细胞活化的抑制。胸苷掺入被抑制，细胞不进入细胞周期的G1期，细胞周期蛋白D2、D3和A的诱导被抑制，MAP激酶Erk 1/2、JNK和p38的活化被降低，Akt磷酸化被抑制，SHIP与Fc γ RIIB共沉淀。尽管在SHIP-/-细胞中Akt磷酸化和Erk活化的抑制被废除，但胸苷掺入的抑制仅部分减少。然而，Fc γ RIIB对Kit介导的肥大细胞增殖的依赖性抑制被其胞质内结构域被SHIP的催化结构域取代的Fc γ RIIB模拟。我们还发现，Fc γ RIIB可以抑制增殖被赋予生长因子非依赖性的细胞的增殖，因为它们表达突变形式的Kit，该突变形式的Kit赋予该RTK组成性活化。基于这些结果，我们开发了旨在使用Fc γ RIIB作为与肥大细胞活化相关的疾病（如过敏）和与肥大细胞增殖相关的疾病（如肥大细胞增多症）的新治疗方法的靶标的模型。肥大细胞瘤或肥大细胞白血病。(C)2002爱思唯尔科技有限公司版权所有。
FcgammaRIIB are single-chain low-affinity receptors for the Fc portion of IgG antibodies that are widely expressed by hematopoietic cells including mast cells. We previously demonstrated that FcgammaRIIB negatively regulate cell activation triggered by receptors that possess Immunoreceptor Tyrosine-based Activation Motifs (ITAMs) including high-affinity IgE receptors (FcepsilonRI). FcgammaRIIB possess an Immunoreceptor Tyrosine-based Inhibition Motif (ITAM) whose deletion or mutation abolishes inhibition. When coaggregated with FcepsilonRI, the FcgammaRIIB ITIM is tyrosyl-phosphorylated by the src family protein tyrosine kinase lyn, and recruits the SH2 domain-containing inositol 5-phosphatase SHIP that accounts for inhibition of cell activation.We found recently that, when coaggregated with Kit, FcgammaRIIB can also inhibit mast cell proliferation: thymidine incorporation is inhibited, cells do not enter the G1 phase of the cell cycle, the induction of cyclins D2, D3 and A is inhibited, the activation of the MAP kinases Erk1/2, JNK and p38 is decreased, Akt phosphorylation is inhibited, and SHIP coprecipitates with FcgammaRIIB. Although inhibition of Akt phosphorylation and Erk activation was abrogated in SHIP-/- cells, inhibition of thymidine incorporation was only partially reduced. FcgammaRIIB-dependent inhibition of Kit-mediated mast cell proliferation was however mimicked by FcgammaRIIB whose intracytoplasmic domain was replaced by the catalytic domain of SHIP. We also found that Fc-yRIIB can inhibit the proliferation of cells whose proliferation was rendered growth factor-independent because they express a mutated form of Kit that renders this RTK constitutively activated.Based on these results we developed models aiming at using FcgammaRIIB as targets for new therapeutic approaches of disease associated with mast cell activation such as allergies and diseases associated with mast cell proliferation such as mastocytosis, mastocytomas or mast cell leukemias. (C) 2002 Elsevier Science Ltd. All rights reserved.