The LINK-A lncRNA interacts with PtdIns(3,4,5)P3 to hyperactivate AKT and confer resistance to AKT inhibitors.

Journal Article (Journal Article)

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 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 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.

Full Text

Duke Authors

Cited Authors

  • 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, M-C; Liang, H; Hu, Z; Shen, H; Hawke, DH; Han, L; Zhou, Y; Lin, C; Yang, L

Published Date

  • March 2017

Published In

Volume / Issue

  • 19 / 3

Start / End Page

  • 238 - 251

PubMed ID

  • 28218907

Pubmed Central ID

  • PMC5332298

Electronic International Standard Serial Number (EISSN)

  • 1476-4679

Digital Object Identifier (DOI)

  • 10.1038/ncb3473


  • eng

Conference Location

  • England