Format

Send to:

Choose Destination
See comment in PubMed Commons below
Mol Cell. 2014 Feb 20;53(4):577-90. doi: 10.1016/j.molcel.2013.12.018. Epub 2014 Jan 23.

Phosphoproteomics screen reveals akt isoform-specific signals linking RNA processing to lung cancer.

Author information

  • 1Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
  • 2Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA; Division of Digestive Diseases, Center for Systems Biomedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • 3Department of Biostatistics and Computational Biology, Center for Cancer Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 4Cell Signaling Technology, Danvers, MA 01923, USA.
  • 5Division of Digestive Diseases, Center for Systems Biomedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • 6Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA. Electronic address: ptsichlis@tuftsmedicalcenter.org.

Abstract

The three Akt isoforms are functionally distinct. Here we show that their phosphoproteomes also differ, suggesting that their functional differences are due to differences in target specificity. One of the top cellular functions differentially regulated by Akt isoforms is RNA processing. IWS1, an RNA processing regulator, is phosphorylated by Akt3 and Akt1 at Ser720/Thr721. The latter is required for the recruitment of SETD2 to the RNA Pol II complex. SETD2 trimethylates histone H3 at K36 during transcription, creating a docking site for MRG15 and PTB. H3K36me3-bound MRG15 and PTB regulate FGFR-2 splicing, which controls tumor growth and invasiveness downstream of IWS1 phosphorylation. Twenty-one of the twenty-four non-small-cell-lung carcinomas we analyzed express IWS1. More importantly, the stoichiometry of IWS1 phosphorylation in these tumors correlates with the FGFR-2 splicing pattern and with Akt phosphorylation and Akt3 expression. These data identify an Akt isoform-dependent regulatory mechanism for RNA processing and demonstrate its role in lung cancer.

Copyright © 2014 Elsevier Inc. All rights reserved.

Comment in

PMID:
24462114
[PubMed - indexed for MEDLINE]
PMCID:
PMC3947584
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk