Phosphorylation of PITSLRE p110 isoforms accompanies their processing by caspases during Fas-mediated cell death
Phosphorylation of PITSLRE p110 isoforms accompanies their processing by caspases during Fas-mediated cell death
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DOI：
10.1074/jbc.273.26.16601
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发表时间：
1998-06-26
影响因子：
4.8
通讯作者：
Kidd, VJ
中科院分区：
文献类型：
--
作者：
Tang, DM;Gururajan, R;Kidd, VJ
许多细胞蛋白已被确定为caspase在细胞死亡过程中的靶点，包括PITSLRE蛋白激酶。这些靶标通常可分为三类：1)其他半胱天冬酶；2)在细胞凋亡过程中失活的蛋白质；3)执行细胞死亡程序所需的蛋白质。然而，并不是所有的蛋白质在细胞凋亡过程中都被半胱天冬酶切割。为什么在细胞死亡过程中只有特定的蛋白质被半胱天冬酶处理，目前还不清楚。本研究表明，在fas诱导的Jurkat t细胞凋亡过程中，多种caspase样活性参与了PITSLRE p110亚型的加工。三个p110 caspase裂解位点已被定位到p110的氨基末端结构域，并通过位点定向诱变进行了验证。奇怪的是，诱变研究表明，在体内细胞死亡过程中，两个并列的caspase位点的切割对于该蛋白的完整加工是必要的。最后，我们证明了PITSLRE p110蛋白在fas诱导的Jurkat细胞凋亡过程中被快速磷酸化，并且该蛋白的氨基末端部分的磷酸化可能会增强该区域的半胱天冬酶裂解。
A number of cellular proteins have been identified as caspase targets during cell death, including the PITSLRE protein kinases. These targets generally fall into one of three possible categories: 1) other caspases, 2) proteins that are inactivated during apoptosis, and 3) proteins that are required for execution of the cell death program. However, not all proteins are cleaved by caspases during apoptosis. Why only specific proteins are destined to be processed by caspases during cell death is currently not clear. Here we show that multiple caspase-like activities are involved in the processing of the PITSLRE p110 isoforms during Fas-induced apoptosis in Jurkat T-cells. Three p110 caspase cleavage sites have been mapped to the amino-terminal domain of p110 and verified by site-directed mutagenesis. Curiously, the mutagenesis studies revealed that cleavage of two juxtaposed caspase sites is necessary for the complete processing of this protein during cell death in vivo. Finally, we demonstrate that the PITSLRE p110 protein is rapidly phosphorylated during Fas-induced apoptosis in Jurkat cells and that phosphorylation of an aminoterminal portion of the protein may enhance caspase cleavage in this region.