The LINK-A lncRNA interacts with PtdIns(3,4,5)P(3) to hyperactivate AKT and confer resistance to AKT inhibitors.
The LINK-A lncRNA interacts with PtdIns(3,4,5)P(3) to hyperactivate AKT and confer resistance to AKT inhibitors.
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DOI：
10.1038/ncb3473
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发表时间：
2017-03
影响因子：
21.3
通讯作者：
Yang L
中科院分区：
文献类型：
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作者：
Lin A;Hu Q;Li C;Xing Z;Ma G;Wang C;Li J;Ye Y;Yao J;Liang K;Wang S;Park PK;Marks JR;Zhou Y;Zhou J;Hung MC;Liang H;Hu Z;Shen H;Hawke DH;Han L;Zhou Y;Lin C;Yang L
磷脂酰肌醇-3，4，5-三磷酸（PIP 3）作为第二信使响应细胞外信号而介导信号传导途径。虽然磷脂和RNA的原始功能已被假设在“RNA世界”，生理RNA磷脂相互作用和它们参与基本的细胞过程仍然是一个谜。我们阐明了脂质结合长非编码RNA（lncRNA）在癌细胞中的作用。其中，用于激酶激活的长基因间非编码RNA（LINK-A）在单核苷酸水平上直接与AKT普列克底物蛋白同源结构域和PIP 3相互作用，促进AKT-PIP 3相互作用和随后的酶激活。LINK-A依赖性AKT超活化导致肿瘤发生和对AKT抑制剂的抗性。LINK-A PIP 3结合基序的基因组缺失显著地使乳腺癌细胞对AKT抑制剂敏感。此外，荟萃分析显示LINK-A表达与SNP（rs 12095274：A>G）发生率、AKT磷酸化状态以及乳腺癌和肺癌患者预后不良之间存在相关性。PIP 3结合lncRNA调节AKT活化，具有广泛的临床意义。
Phosphatidylinositol-3,4,5-trisphosphate (PIP3) mediates signaling pathways as a second messenger in response to extracellular signals. Although primordial functions of phospholipids and RNAs have been hypothesized in the “RNA world”, physiological RNA-phospholipid interactions and their involvement in essential cellular processes has remained a mystery. We explicate the contribution of lipid-binding long non-coding RNAs (lncRNAs) in cancer cells. Among them, Long Intergenic Noncoding RNA for Kinase Activation (LINK-A) directly interacts with AKT pleckstrin homology domain and PIP3 at the single nucleotide level, facilitating AKT-PIP3 interaction and consequent enzymatic activation. LINK-A-dependent AKT hyperactivation leads to tumorigenesis and resistance to AKT inhibitors. Genomic deletions of the LINK-A PIP3-binding motif dramatically sensitized breast cancer cells to AKT inhibitors. Furthermore, meta-analysis showed the correlation between LINK-A expression and incidence of a SNP (rs12095274: A>G), AKT phosphorylation status, and poor outcomes for breast and lung cancer patients. PIP3-binding lncRNA modulates AKT activation with broad clinical implications.