Phosphoproteomics Screen Reveals Akt Isoform-Specific Signals Linking RNA Processing to Lung Cancer

Sanidas, I, Polytarchou, C ORCID: 0000-0002-1948-7934, Hatziapostolou, M, Ezell, SA, Kottakis, F, Hu, L, Guo, A, Xie, J, Comb, MJ, Iliopoulos, D and Tsichlis, PN, 2014. Phosphoproteomics Screen Reveals Akt Isoform-Specific Signals Linking RNA Processing to Lung Cancer. Molecular Cell, 53 (4), pp. 577-590. ISSN 1097-2765

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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.

Item Type: Journal article
Publication Title: Molecular Cell
Creators: Sanidas, I., Polytarchou, C., Hatziapostolou, M., Ezell, S.A., Kottakis, F., Hu, L., Guo, A., Xie, J., Comb, M.J., Iliopoulos, D. and Tsichlis, P.N.
Publisher: Elsevier
Date: 2014
Volume: 53
Number: 4
ISSN: 1097-2765
Divisions: Schools > School of Science and Technology
Depositing User: Linda Sullivan
Date Added: 16 Nov 2015 15:57
Last Modified: 09 Jun 2017 13:57

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