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

Area of Science:

• Molecular Biology
• Cancer Research
• Epigenetics

Background:

• The three Akt isoforms (Akt1, Akt2, Akt3) exhibit distinct functions.
• Differences in Akt isoform phosphoproteomes suggest isoform-specific target engagement.
• RNA processing is a key cellular function differentially regulated by Akt isoforms.

Purpose of the Study:

• To investigate the isoform-specific phosphoproteomes of Akt.
• To elucidate the role of Akt-mediated phosphorylation in RNA processing and its implications in lung cancer.

Main Methods:

• Phosphoproteomic analysis to identify Akt isoform-specific targets.
• Investigating the phosphorylation of IWS1 by Akt1 and Akt3.
• Analyzing the recruitment of SETD2, histone modifications, and splicing factor interactions.
• Examining FGFR-2 splicing patterns in non-small-cell lung carcinoma (NSCLC) tissues.

Main Results:

• Akt isoforms display distinct phosphoproteomes, indicating differences in target specificity.
• IWS1, an RNA processing regulator, is phosphorylated by Akt1 and Akt3 at Ser720/Thr721.
• This phosphorylation event is crucial for recruiting SETD2 to the RNA Pol II complex, leading to H3K36 trimethylation.
• H3K36me3 facilitates MRG15 and PTB binding, regulating FGFR-2 splicing and downstream tumor growth.
• IWS1 phosphorylation stoichiometry in NSCLC tumors correlates with FGFR-2 splicing, Akt phosphorylation, and Akt3 expression.

Conclusions:

• Identified an Akt isoform-dependent regulatory pathway for RNA processing.
• Demonstrated the critical role of this pathway in lung cancer pathogenesis through FGFR-2 splicing.
• Established a link between Akt signaling, RNA processing, and tumor characteristics in NSCLC.