A function for tyrosine phosphorylation of type 1 inositol 1,4,5-trisphosphate receptor in lymphocyte activation.
A function for tyrosine phosphorylation of type 1 inositol 1,4,5-trisphosphate receptor in lymphocyte activation.
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DOI：
10.1083/jcb.200708200
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发表时间：
2007-12-03
期刊：
影响因子：
--
通讯作者：
Marks AR
中科院分区：
文献类型：
--
作者：
deSouza N;Cui J;Dura M;McDonald TV;Marks AR
淋巴细胞活化需要通过Ca 2+释放激活的Ca 2+通道持续升高细胞内钙。持续的Ca 2+内流需要内质网（ER）Ca 2+耗竭和肌醇1，4，5-三磷酸受体（IP 3R）/Ca 2+释放通道的延长激活。然而，淋巴细胞ER中的一种主要亚型IP 3 R1会受到胞浆Ca 2+水平升高的抑制，并且使淋巴细胞活化所需的IP 3 R1延长活化的机制尚不清楚。我们发现，IP 3R 1结合到活化的T细胞的支架蛋白接头，并在活化过程中与T细胞受体共定位，导致IP 3R 1在Tyr 353处持续磷酸化。这种磷酸化增加了通道对IP 3激活的敏感性，并使通道对Ca 2+诱导的失活不太敏感。突变型IP 3R 1-Y353 F通道在淋巴细胞中的表达导致Ca 2+信号传导缺陷和活化T细胞活化的核因子降低。因此，IP 3R 1-Y353的酪氨酸磷酸化可能在维持淋巴细胞活化过程中升高的胞质Ca 2+水平方面具有重要功能。
Sustained elevation of intracellular calcium by Ca2+ release–activated Ca2+ channels is required for lymphocyte activation. Sustained Ca2+ entry requires endoplasmic reticulum (ER) Ca2+ depletion and prolonged activation of inositol 1,4,5-trisphosphate receptor (IP3R)/Ca2+ release channels. However, a major isoform in lymphocyte ER, IP3R1, is inhibited by elevated levels of cytosolic Ca2+, and the mechanism that enables the prolonged activation of IP3R1 required for lymphocyte activation is unclear. We show that IP3R1 binds to the scaffolding protein linker of activated T cells and colocalizes with the T cell receptor during activation, resulting in persistent phosphorylation of IP3R1 at Tyr353. This phosphorylation increases the sensitivity of the channel to activation by IP3 and renders the channel less sensitive to Ca2+-induced inactivation. Expression of a mutant IP3R1-Y353F channel in lymphocytes causes defective Ca2+ signaling and decreased nuclear factor of activated T cells activation. Thus, tyrosine phosphorylation of IP3R1-Y353 may have an important function in maintaining elevated cytosolic Ca2+ levels during lymphocyte activation.
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