The lysophosphatidic acid 2 receptor mediates down-regulation of Siva-1 to promote cell survival
The lysophosphatidic acid 2 receptor mediates down-regulation of Siva-1 to promote cell survival
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DOI：
10.1074/jbc.m705025200
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发表时间：
2007-12-28
影响因子：
4.8
通讯作者：
Lin, Weei-Chin
中科院分区：
文献类型：
--
作者：
Lin, Fang-Tsyr;Lai, Yun-Ju;Lin, Weei-Chin
Lysophosphatidic acid (LPA) promotes cell survival through the activation of G protein-coupled LPA receptors. However, whether different LPA receptors activate distinct anti-apoptotic signaling pathways is not yet clear. Here we report a novel mechanism by which the LPA(2) receptor targets the proapoptotic Siva-1 protein for LPA-dependent degradation, thereby attenuating Siva-1 function in DNA damage response. The carboxylterminal tail of the LPA2 receptor, but not LPA(1) or LPA(3) receptor, specifically associates with the carboxyl cysteine-rich domain of Siva-1. Prolonged LPA stimulation promotes the association of Siva-1 with the LPA(2) receptor and targets both proteins for ubiquitination and degradation. As a result, adriamycin-induced Siva-1 protein stabilization is attenuated by LPA in an LPA(2)-dependent manner, and the function of Siva-1 in promoting DNA damage-induced apoptosis is inhibited by LPA pretreatment. Consistent with this result, inhibition of the LPA2 receptor expression increases Siva-1 protein levels and augments adriamycin-induced caspase-3 cleavage and apoptosis. Together, these findings reveal a critical and specific role for the LPA(2) receptor through which LPA directly inactivates a critical component of the death machinery to promote cell survival.
