Centaurin-α1 is a phosphatidylinositol 3-kinase-dependent activator of ERK1/2 mitogen-activated protein kinases
Centaurin-α1 is a phosphatidylinositol 3-kinase-dependent activator of ERK1/2 mitogen-activated protein kinases
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DOI：
10.1074/jbc.m505905200
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发表时间：
2006-01-20
影响因子：
4.8
通讯作者：
Nishida, E
中科院分区：
文献类型：
--
作者：
Hayashi, H;Matsuzaki, O;Nishida, E
Centaurin-α(1)是一种磷脂酰肌醇-3，4，5-三磷酸(PIP3)结合蛋白，具有两个Pleckstrin同源结构域和一个ADP核糖化因子GTP酶激活蛋白结构域。然而，积木素-α(1)的生理功能仍不清楚。在这里，我们已经证明了在COS-7细胞中瞬时表达Centaurin-α(1)导致了ERK的特异性激活，并且这种激活被显性的阴性形式的RAS的共同表达所抑制。我们还发现，不能与PIP3结合的积雪草素-α(1)的突变形式未能诱导ERK激活，磷脂酰肌醇3-激酶抑制剂LY294002抑制依赖于积雪草素-α(1)的ERK激活。此外，在表皮生长因子刺激T-Rex 293细胞后，小干扰RNA瞬时敲除Centaurin-α(1)会导致ERK活性降低。这些结果表明，Centaurin-α(1)通过与PIP3相互作用，将PI3K途径与ERK丝裂原活化蛋白激酶途径联系起来，从而参与了生长因子信号转导中ERK的激活。
Centaurin-alpha(1) is known to be a phosphatidylinositol 3,4,5triphosphate (PIP3)-binding protein that has two pleckstrin homology domains and a putative ADP ribosylation factor GTPase-activating protein domain. However, the physiological function of centaurin-alpha(1) is still not understood. Here we have shown that transient expression of centaurin-alpha(1) in COS-7 cells results in specific activation of ERK, and the activation is inhibited by co-expression of a dominant negative form of Ras. We have also found that a mutant form of centaurin-alpha(1) that is unable to bind PIP3 fails to induce ERK activation and that a phosphatidylinositol 3-kinase inhibitor LY294002 inhibits centaurin-alpha(1)-dependent ERK activation. Furthermore, transient knockdown of centaurin-alpha(1) by small interfering RNAs results in reduced ERK activation after epidermal growth factor stimulation in T-REx 293 cells. These results suggest that centaurin-alpha(1) contributes to ERK activation in growth factor signaling, linking the PI3K pathway to the ERK mitogen-activated protein kinase pathway through its ability to interact with PIP3.