The LINK-A lncRNA interacts with PtdIns(3,4,5)P3 tohyperactivate AKTand confer resistance to AKTinhibitors. Academic Article uri icon

abstract

  • Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3 or PIP3) mediates signalling 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 have remained a mystery. We explicate the contribution of lipid-binding long non-coding RNAs (lncRNAs) in cancer cells. Among them, long intergenic non-coding RNA for kinase activation (LINK-A) directly interacts with the AKT pleckstrin homology domain and PIP3 atthe 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 single nucleotide polymorphism (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.

published proceedings

  • Nat Cell Biol

altmetric score

  • 27.096

author list (cited authors)

  • Lin, A., Hu, Q., Li, C., Xing, Z., Ma, G., Wang, C., ... Yang, L.

citation count

  • 160

complete list of authors

  • Lin, Aifu||Hu, Qingsong||Li, Chunlai||Xing, Zhen||Ma, Guolin||Wang, Cheng||Li, Jun||Ye, Yin||Yao, Jun||Liang, Ke||Wang, Shouyu||Park, Peter K||Marks, Jeffrey R||Zhou, Yan||Zhou, Jianwei||Hung, Mien-Chie||Liang, Han||Hu, Zhibin||Shen, Hongbing||Hawke, David H||Han, Leng||Zhou, Yubin||Lin, Chunru||Yang, Liuqing

publication date

  • March 2017