The tyrosine kinases Syk and Lyn exert opposing effects on the activation of protein kinase Akt PKB in B lymphocytes
The tyrosine kinases Syk and Lyn exert opposing effects on the activation of protein kinase Akt PKB in B lymphocytes
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DOI：
10.1073/pnas.96.12.6890
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发表时间：
1999-06-08
影响因子：
11.1
通讯作者：
Puré, E
中科院分区：
文献类型：
--
作者：
Li, HL;Davis, WW;Puré, E
蛋白激酶 Akt/PKB 是响应有丝分裂信号的细胞存活的关键调节因子。 v-akt（Akt/PKB 的一种致癌形式）激酶活性的增加会导致小鼠 T 细胞淋巴瘤，而 Akt/PKB 的过度表达与人类多种肿瘤类型的进展相关。在这项研究中，我们证明B细胞抗原受体（BCR）的连接会导致B淋巴细胞中Akt/PKB的激活，BCR诱导的Akt/PKB激活需要酪氨酸激酶Syk，而此前我们并不知道该酪氨酸激酶Syk可以调节Akt/PKB，相反，与野生型B细胞相比，Lyn缺陷的B细胞的BCR交联导致Akt/PKB的过度磷酸化和激活显着增强，表明该Src家族激酶起作用作为 BCR 诱导的 Akt/PKB 激活的内源性拮抗剂。 Lyn 与冈田酸敏感的内源磷酸酶相加抑制 Akt/PKB，突变细胞中外源 Lyn 的表达恢复了正常的 BCR 诱导的 Akt/PKB 磷酸化，Lyn 对 Akt/PKB 的负调节不依赖于蛋白磷酸酶 SHP-1、SHP-2 或 SHIP。我们的结果表明，Lyn 提供了一种负调节机制，并反对 Syk 对 BCR 介导的 Akt/PKB 激活的影响，Akt/PKB 的失调与 BCR 交联刺激的 Lyn 缺陷小鼠的 B 细胞高反应性相关，并可能导致 Lyn 缺陷动物中发生的自身免疫综合征。
The protein kinase Akt/PKB is a crucial regulator of cell survival in response to mitogenic signals. The increased kinase activity of v-akt, an oncogenic form of Akt/PKB, causes mouse T cell lymphoma, and overexpression of Akt/PKB is associated with progression of several tumor types in human. In this study, we demonstrate that ligation of B cell antigen receptor (BCR) leads to activation of Akt/PKB in B lymphocytes, BCR-induced activation of Akt/PKB required the tyrosine kinase Syk, which was not previously known to regulate Akt/PKB, In contrast, BCR crosslinking of Lyn-deficient B cells resulted in markedly enhanced hyperphosphorylation and activation of Akt/PKB compared with wild-type B cells, indicating that this Src-family kinase acts as an endogenous antagonist of BCR-induced Akt/PKB activation. Lyn inhibited Akt/PKB additively with an okadaic acid-sensitive endogenous phosphatase(s), Expression of exogenous Lyn in mutant cells restored normal BCR-induced phosphorylation of Akt/PKB, Negative regulation of Akt/PKB by Lyn was not dependent on the protein phosphatases SHP-1, SHP-2, or SHIP. Our results show that Lyn provides a mechanism for negative regulation and opposes the effect of Syk on BCR-mediated activation of Akt/PKB, Deregulation of Akt/PKB correlates with the hyperresponsiveness of B cells from Lyn-deficient mice stimulated by BCR crosslinking and may contribute to the autoimmune syndrome that develops in Lyn-deficient animals.