Casein kinase 2-interacting protein-1, a novel Akt pleckstrin homology domain-interacting protein, down-regulates PI3K/Akt signaling and suppresses tumor growth in vivo
Casein kinase 2-interacting protein-1, a novel Akt pleckstrin homology domain-interacting protein, down-regulates PI3K/Akt signaling and suppresses tumor growth in vivo
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DOI：
10.1158/0008-5472.can-07-1050
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Tsuruo, Takashi
中科院分区：
文献类型：
--
作者：
Tokuda, Emi;Fujita, Naoya;Tsuruo, Takashi
丝氨酸/苏氨酸激酶Akt在细胞存活和增殖中起核心作用。它的激活与几种人类癌症的肿瘤发生有关。虽然许多Akt底物已被阐明，但调控Akt功能的Akt结合蛋白仍不清楚。我们在此报道已经鉴定出酪蛋白激酶2-相互作用蛋白-1 （CKIP- 1）作为Akt pleckstrin同源（PH）结构域结合蛋白，具有Akt抑制功能。CKIP-1通过其NH2末端与Akt各亚型（Akt1、Akt2和Akt3）形成复合物。通过COOH末端的亮氨酸拉链（LZ）基序，CKIP-1的二聚化被发现与Akt失活有关，因为LZ基序的缺失消除了Akt的抑制功能，尽管它仍然可以与Akt结合。表达NH2末端缺失的含有LZ基序但缺乏Akt结合能力的CKIP-1突变体，通过隔离内源性CKIP-1与Akt结合的能力，诱导Akt磷酸化和活化。稳定表达CKIP-1导致Akt失活，抑制细胞生长。此外，稳定的CKIP-1转染物移植到裸鼠体内的生长速度比模拟转染物慢。这些结果表明CKIP-1是一种新的Akt PH结构域相互作用蛋白，可能是一种具有抑制Akt功能的肿瘤抑制因子。
The serine/threonine kinase Akt plays a central role in cell survival and proliferation. Its activation is linked to tumorigenesis in several human cancers. Although many Akt substrates have been elucidated, the Akt-binding proteins that regulate Akt function remain unclear. We report herein having identified casein kinase 2-interacting protein-1 (CKIP- 1) as an Akt pleckstrin homology (PH) domain-binding protein with Akt inhibitory function. CKIP-1 formed a complex with each Akt isoform (Akt1, Akt2, and Akt3) via its NH2 terminus. Dimerization of CKIP-1 via its leucine zipper (LZ) motif at the COOH terminus was found to be associated with Akt inactivation because deletion of the LZ motif eliminated Akt inhibitory function, although it could still bind to Akt. Expression of the NH2 terminus-deleted CKIP-1 mutant containing the LZ motif, but lacking Akt-binding ability, induced Akt phosphorylation and activation by sequestering the ability of endogenous CKIP-1 to bind to Akt. Stable CKIP-1 expression caused Akt inactivation and cell growth inhibition in vitro. In addition, the growth of stable CKIP-1 transfectants xenografted into nude mice was slower than that of mock transfectants. These results indicate that CKIP-1, a novel Akt PH domain-interacting protein, would be a candidate of tumor suppressor with an Akt inhibitory function.