Lysophosphatidic acid prevents apoptosis in fibroblasts via Gi-protein-mediated activation of mitogen-activated protein kinase
Lysophosphatidic acid prevents apoptosis in fibroblasts via Gi-protein-mediated activation of mitogen-activated protein kinase
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DOI：
10.1042/0264-6021:3520135
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发表时间：
2000-11-15
影响因子：
4.1
通讯作者：
Mills, GB
中科院分区：
文献类型：
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作者：
Fang, XJ;Yu, SX;Mills, GB
溶血磷脂酸（LPA）是一种天然存在的磷脂，具有多种生物学功能。在本研究中，我们证明，除了有丝分裂活性外，LPA是一种有效的生存因子，可以防止血清剥夺诱导的成纤维细胞和其他细胞类型的凋亡。LPA的增殖作用和存活活性均对百日咳毒素（PTX）的作用敏感，表明这两个过程均由G(i)蛋白介导。因此，我们专注于G(i)蛋白介导的信号事件在LPA促进细胞存活中的作用。除了激活丝裂原活化蛋白激酶（MAPK）外，LPA还刺激了一种模式：st ptx敏感的丝氨酸/苏氨酸激酶Akt的磷酸化/激活，Akt是磷酸肌肽3激酶（PI3K）下游的生存介质。ly294002或wortmannin抑制PI3K可显著抑制LPA诱导的DNA合成，但LPA的存活活性仅下降20- 30%，表明PI3K- akt级联在LPA诱导的细胞存活中输入有限。相反，MEK-1抑制剂PD 98059抑制MAPK的激活，可以阻断LPA的增殖和存活作用。这些结果表明，LPA主要通过G(i)-蛋白介导的ERK1/ERK2或MAPK家族中其他PD 98059敏感成员的激活来促进细胞存活。
Lysophosphatidic acid (LPA) is a naturally occurring phospholipid with multiple biological functions. In the present study, we demonstrate that, besides its mitogenic activity, LPA is a potent survival factor, preventing serum-deprivation-induced apoptosis in fibroblasts and other cell types. Both the proliferative effect and survival activity of LPA are sensitive to the action of pertussis toxin (PTX), indicating that both processes are mediated by G(i) protein(s). We therefore focused on the role of G(i)-protein-mediated signalling events in the promotion of cell survival by LPA. In addition to activation of mitogen-activated protein kinase (MAPK), LPA stimulates a mode:st PTX-sensitive phosphorylation/activation of the serine/threonine kinase Akt, a survival mediator downstream of phosphoinositide 3-kinase (PI3K). Inhibition of PI3K with LY 294002 or wortmannin resulted in a marked inhibition of LPA-induced DNA synthesis, and yet the survival activity of LPA decreased by only 20-30 %, suggesting a limited input of the PI3K-Akt cascade in LPA-induced cell survival. In contrast, inhibition of MAPK activation by the MEK-1 inhibitor, PD 98059, blocked both the proliferative and survival effects of LPA. These results indicate that LPA promotes cell survival largely via G(i)-protein-mediated activation of ERK1/ERK2, or other PD 98059-sensitive member(s) of the MAPK family.