Rho-dependent, Rho kinase-independent inhibitory regulation of Rac and cell migration by LPA1 receptor in Gi-inactivated CHO cells
Rho-dependent, Rho kinase-independent inhibitory regulation of Rac and cell migration by LPA1 receptor in Gi-inactivated CHO cells
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DOI：
10.1016/j.yexcr.2006.02.020
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发表时间：
2006-06-10
影响因子：
3.7
通讯作者：
Takuwa, Yoh
中科院分区：
文献类型：
--
作者：
Sugimoto, Naotoshi;Takuwa, Noriko;Takuwa, Yoh
溶血磷脂酸（LPA）是一种主要的血清溶血磷脂，它刺激包括卵巢癌细胞在内的多种细胞类型的细胞迁移。我们在此报告，在缺乏G（i）功能的情况下，LPA诱导抑制，而不是刺激，细胞的Rac活性，板状伪足的形成，和细胞迁移响应胰岛素样生长因子I（IGF-I）在中国仓鼠卵巢（CHO）细胞，其中只表达LPA（1）作为LPA受体。LPA的抑制作用被G α（13）C-末端肽或C3毒素预处理的表达废除，但不是Rho激酶抑制剂。在没有PTX预处理的情况下，LPA刺激Rac和细胞迁移，但类似地激活Rho，表明Rho激活本身不足以抑制细胞迁移。相反，显性负性Rac突变体的表达充分模拟了LPA对细胞迁移的抑制。LPA以依赖于Rho激酶的方式抑制IGF I诱导的Akt活化仅40%。这些结果表明，Gi功能的抑制将LPA对Rac和细胞迁移的调节转化为抑制模式，其由G（13）和Rho而不是Rho激酶介导，并提高了Gi作为LPA依赖性肿瘤进展的新治疗靶点的可能性。(c)2006年爱思唯尔公司All rights reserved.
Lysophosphatidic acid (LPA) is a major serum lysophospholipid that stimulates cell migration in diverse cell types including ovarian cancer cells. We report here that in the absence of G(i) function, LPA induces inhibition, rather than stimulation, of cellular Rac activity, lamellipodium formation, and cell migration in response to insulin like growth factor I (IGF-I) in Chinese hamster ovary (CHO) cells, which solely express LPA(1) as a LPA receptor. The inhibitory effects of LPA are abrogated by the expression of either G alpha(13) C-terminal peptide or C3 toxin pretreatment, but not a Rho kinase inhibitor. Without PTX pretreatment, LPA stimulates Rac and cell migration yet similarly activates Rho, indicating that Rho activation by itself is not sufficient for inhibition of cell migration. Conversely, the expression of a dominant negative Rac mutant sufficiently mimics the LPA inhibition of cell migration. LPA inhibits IGF I-induced Akt activation by only 40% in a manner dependent on Rho kinase. These results demonstrate that inhibition of Gi function converts LPA regulation on Rac and cell migration to an inhibitory mode, which is mediated by G(13) and Rho but not Rho kinase, and raise a possibility of Gi as a new therapeutic target for LPA-dependent tumor progression. (c) 2006 Elsevier Inc. All rights reserved.