PMID:17965021
| Citation |
Lin, FT, Lai, YJ, Makarova, N, Tigyi, G and Lin, WC (2007) The lysophosphatidic acid 2 receptor mediates down-regulation of Siva-1 to promote cell survival. J. Biol. Chem. 282:37759-69 |
|---|---|
| Abstract |
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 carboxyl-terminal tail of the LPA(2) 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 LPA(2) 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. |
| Links |
PubMed PMC3496872 Online version:10.1074/jbc.M705025200 |
| Keywords |
Amino Acid Sequence; Animals; Apoptosis; Apoptosis Regulatory Proteins; Caspase 3/metabolism; Down-Regulation; Gene Expression Regulation; Humans; Intracellular Signaling Peptides and Proteins/chemistry; Intracellular Signaling Peptides and Proteins/physiology; Lysophospholipids/chemistry; Mice; Models, Biological; Molecular Sequence Data; NIH 3T3 Cells; Receptors, Lysophosphatidic Acid/physiology; Sequence Homology, Amino Acid |
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