Phosphoproteomics screen reveals akt isoform-specific signals linking RNA processing to lung cancer.
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.
Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
Ioannis
I
Sanidas
Molecular 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.
Christos
C
Polytarchou
Molecular 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.
Maria
M
Hatziapostolou
Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
Scott A
SA
Ezell
Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
Filippos
F
Kottakis
Department of Biostatistics and Computational Biology, Center for Cancer Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Lan
L
Hu
Cell Signaling Technology, Danvers, MA 01923, USA.
Ailan
A
Guo
Cell Signaling Technology, Danvers, MA 01923, USA.
Jianxin
J
Xie
Cell Signaling Technology, Danvers, MA 01923, USA.
Michael J
MJ
Comb
Division of Digestive Diseases, Center for Systems Biomedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Dimitrios
D
Iliopoulos
Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA. Electronic address: ptsichlis@tuftsmedicalcenter.org.
Philip N
PN
Tsichlis
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D016601:RNA-Binding Proteins; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013997:Time Factors; D014157:Transcription Factors
D006657:Histones; C587920:IWS1 protein, mouse; C510636:Iws1 protein, human; D010750:Phosphoproteins; D020033:Protein Isoforms; D011506:Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D012313:RNA; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; C587921:SETD2 protein, mouse; C496353:FGFR2 protein, human; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2; C494918:AKT1 protein, human; C491754:AKT3 protein, human; C514862:Akt1 protein, mouse; C491753:Akt3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt