CD19 amplifies B lymphocyte signal transduction by regulating Src-family protein tyrosine kinase activation.
CD19 amplifies B lymphocyte signal transduction by regulating Src-family protein tyrosine kinase activation.
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DOI：
10.4049/jimmunol.162.12.7088
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发表时间：
1999-06
影响因子：
4.4
通讯作者：
Manabu Fujimoto;J. Poe;Paul J. Jansen;S. Sato;Thomas F. Tedder
中科院分区：
文献类型：
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作者：
Manabu Fujimoto;J. Poe;Paul J. Jansen;S. Sato;Thomas F. Tedder
B细胞Ag受体（BCR）的连接通过刺激src家族蛋白酪氨酸激酶（PTKs）磷酸化BCR复合物的成员来诱导细胞活化。随后，src家族PTKs，特别是Lyn，被提出磷酸化并结合CD19， CD19是一种调节成熟B细胞活化的细胞表面共刺激分子。在这里，我们发现cd19缺陷小鼠的B细胞在BCR连接后，Lyn激酶活性和BCR磷酸化降低。在cd19缺失的B细胞中，其他src家族PTKs的酪氨酸磷酸化也降低。在野生型B细胞中，CD19与Vav、Lyn和其他src家族PTKs组成性络合，BCR连接后CD19磷酸化及其与Lyn和Vav的关联增加。因此，组成性CD19/Lyn/Vav复合体信号可能负责在Ag受体连接之前在B细胞中建立基线信号阈值，除了加速BCR接合后的信号传导或其他跨膜信号。用纯化的CD19和纯化的Lyn进行体外激酶实验发现，当与CD19共孵育时，Lyn的激酶活性显著提高。因此，组成型和诱导型CD19/Lyn复合物可能通过放大Lyn和其他src家族PTKs的激酶活性来调节基础信号阈值和BCR信号传导。这些体内和体外研究结果证明了CD19调节B淋巴细胞信号转导的新机制。CD19/ src家族激酶扩增环的缺失可能是CD19缺陷B细胞低反应表型的原因。
Ligation of the B cell Ag receptor (BCR) induces cellular activation by stimulating Src-family protein tyrosine kinases (PTKs) to phosphorylate members of the BCR complex. Subsequently, Src-family PTKs, particularly Lyn, are proposed to phosphorylate and bind CD19, a cell-surface costimulatory molecule that regulates mature B cell activation. Herein, we show that B cells from CD19-deficient mice have diminished Lyn kinase activity and BCR phosphorylation following BCR ligation. Tyrosine phosphorylation of other Src-family PTKs was also decreased in CD19-deficient B cells. In wild-type B cells, CD19 was constitutively complexed with Vav, Lyn, and other Src-family PTKs, with CD19 phosphorylation and its associations with Lyn and Vav increased after BCR ligation. Constitutive CD19/Lyn/Vav complex signaling may therefore be responsible for the establishment of baseline signaling thresholds in B cells before Ag receptor ligation, in addition to accelerating signaling following BCR engagement or other transmembrane signals. In vitro kinase assays using purified CD19 and purified Lyn revealed that the kinase activity of Lyn was significantly increased when coincubated with CD19. Thus, constitutive and induced CD19/Lyn complexes are likely to regulate basal signaling thresholds and BCR signaling by amplifying the kinase activity of Lyn and other Src-family PTKs. These in vivo and in vitro findings demonstrate a novel mechanism by which CD19 regulates signal transduction in B lymphocytes. The absence of this CD19/Src-family kinase amplification loop may account for the hyporesponsive phenotype of CD19-deficient B cells.