The Lipid Kinase PI4KIIIβ Is Highly Expressed in Breast Tumors and Activates Akt in Cooperation with Rab11a
The Lipid Kinase PI4KIIIβ Is Highly Expressed in Breast Tumors and Activates Akt in Cooperation with Rab11a
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DOI：
10.1158/1541-7786.mcr-13-0604
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发表时间：
2014-10-01
影响因子：
5.2
通讯作者：
Lee, Jonathan M.
中科院分区：
文献类型：
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作者：
Morrow, Anne A.;Alipour, Mohsen Amir;Lee, Jonathan M.
新出现的证据表明，磷脂酰肌醇4-激酶（PI 4K），从磷脂酰肌醇（PtdIns）产生PI（4）P的酶，与癌症有关。在这项研究中，我们研究了PI 4KIII β，四种哺乳动物PI 4Ks之一，在乳腺癌中的作用。尽管PI 4KIII β蛋白水平在正常乳腺组织中较低，但我们发现大约20%的原发性人类乳腺肿瘤过度表达PI 4KIII β。然而，PI 4KIII β的激酶失活形式也导致Akt活化增加，并且在PI 4KIII β过表达细胞中未检测到PI（4）P或PI（4，5）P-2脂质丰度的变化。这意味着PI 4KIII β调节PI（3，4，5）P-3和Akt，而不依赖于PI（4）P的产生。我们发现，PI 4KIII β结合蛋白Rab 11 a，一种调节内体再循环的小GTdR，参与PI 4KIII β介导的Akt激活，因为Rab 11 a的RNAi消耗损害Akt激活。此外，异位PI 4KIII β表达改变细胞Rab 11 a分布，并增强PI 4KIII β和Rab 11 a向再循环内体的募集。这项工作表明，PI 4KIII β通过Rab 11 a和内体运输影响PI 3 K/Akt信号传导，与其脂质激酶活性无关。因此，PI 4KIII β可能在乳腺癌发生中起作用，Rab 11 a和PI 4KIII β之间的合作代表了一种新的Akt激活途径。（C）2014年AACR。
Emerging evidence now implicates phosphatidylinositol 4-kinases (PI4K), enzymes that generate PI(4)P from phosphatidylinositol (PtdIns), in cancer. In this study, we investigate the role of PI4KIII beta, one of four mammalian PI4Ks, in breast cancer. Although PI4KIII beta protein levels are low in normal breast tissue, we find that approximately 20% of primary human breast tumors overexpress it. Expression of PI4KIII beta in breast carcinoma cells leads to increased Akt activation, dependent on increased PI(3,4,5)P-3 production. However, a kinase-inactive version of PI4KIII beta also led to increased Akt activation, and no changes in PI(4)P or PI(4,5)P-2 lipid abundance were detected in the PI4KIII beta-overexpressing cells. This implies that PI4KIII beta regulates PI(3,4,5)P-3 and Akt independent of PI(4)P production. We find that the PI4KIII beta-binding protein, Rab11a, a small GTPase that regulates endosomal recycling, is involved in PI4KIII beta-mediated activation of Akt, as RNAi depletion of Rab11a impairs Akt activation. Furthermore, ectopic PI4KIII beta expression alters cellular Rab11a distribution and enhances recruitment of PI4KIII beta and Rab11a to recycling endosomes. This work suggests that PI4KIII beta affects PI3K/Akt signaling through Rab11a and endosomal trafficking, independent of its lipid kinase activity. Thus, PI4KIII beta likely plays a role in breast oncogenesis and that cooperation between Rab11a and PI4KIII beta represents a novel Akt activation pathway. (C)2014 AACR.