Lysophosphatidic acid signals through mitogen-activated protein kinase-extracellular signal regulated kinase in ovarian theca cells expressing the LPA1/edg2-receptor:: Involvement of a nonclassical pathway?
Lysophosphatidic acid signals through mitogen-activated protein kinase-extracellular signal regulated kinase in ovarian theca cells expressing the LPA1/edg2-receptor:: Involvement of a nonclassical pathway?
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DOI：
10.1210/me.2002-0371
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发表时间：
2003-08-01
影响因子：
--
通讯作者：
Mukhopadhyay, AK
中科院分区：
文献类型：
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作者：
Budnik, LT;Brunswig-Spickenheier, B;Mukhopadhyay, AK
我们研究了溶血磷脂酸（LPA）在卵巢卵泡膜细胞中的信号转导机制，并观察到这种生物活性脂质的刺激显著增强MAPK ERK 1/2的Thr/Tyr磷酸化。ERK的激活是短暂的，在5分钟后出现峰值，此后下降，并且与伴随的酶核转位无关，这表明胞质酪氨酸磷酸酶可能负责关闭信号。在相同的细胞系统中，表皮生长因子（EGF）诱导的酶活化更迅速（豌豆王在1分钟），可持续至少60分钟，并且可以通过百日咳毒素或Ras受体蛋白的非竞争性抑制剂manumycin A的预先处理来抑制。然而，这种对Gi或Ras的功能抑制未能影响LPA诱导的ERK磷酸化。令人惊讶的是，在C3外毒素脂质转染的细胞中，Rho-GTdR的功能抑制显著降低了LPA刺激的ERK磷酸化，而不影响EGF诱导的MAPK刺激。用抗LPA 1/edg 2型抗体标记的卵泡膜细胞显示出明显的细胞表面标记，这反映在（LPA 1）型LPA受体在mRNA和蛋白水平的表达上。研究结果表明，LPA瞬时刺激MAPK ERK在LPA 1/edg 2表达卵泡膜细胞，并提出了一种替代机制，调节ERK的激活，不同于典型的EGF-Ras-MAPK激酶途径。
We investigated the mechanism of lysophosphatidic acid (LPA) signaling in ovarian theca cells and observed that stimulation with this bioactive lipid markedly enhanced Thr/Tyr phosphorylation of the MAPK ERK1/2. Activation of ERK was transient, showing a peak at 5 min that declined thereafter, and was not associated with a concomitant nuclear translocation of the enzyme, suggesting that a cytosolic tyrosine phosphatase may be responsible for switching off the signal. Epidermal growth factor (EGF)-induced activation of the enzyme in the same cell system was more rapid (pea king at 1 min), sustainable for at least 60 min, and could be suppressed by prior treatment with either pertussis toxin or a noncompetitive inhibitor of Ras acceptor protein, manumycin A. This functional inhibition of either Gi or Ras failed, however, to affect the LPA-induced ERK-phosphorylation. Surprisingly, functional inhibition of Rho-GTPase, in C3-exotoxin-lipofected cells, markedly reduced LPA-stimulated phosphorylation of ERK, without affecting the EGF-induced stimulation of MAPK. Theca cells labeled with anti-LPA1/edg2-type antibody showed a distinct cell surface labeling, which is reflected in the expression of (LPA1)-type LPA receptors at both mRNA and protein levels. The findings indicate that LPA transiently stimulates MAPK ERK in LPA1/edg2-expressing theca cells and suggest an alternative mechanism regulating the activation of ERK that differs from the canonical EGF-Ras-MAPK kinase pathway.