PI3K-alpha translocation mediates nuclear PtdIns(3,4,5)P(3) effector signaling in colorectal cancer
- Author(s)
- Palmieri, M; Catimel, B; Mouradov, D; Sakthianandeswaren, A; Kapp, E; Ang, CS; Williamson, NA; Nowell, CJ; Christie, M; Desai, J; Gibbs, P; Burgess, AW; Sieber, OM;
- Journal Title
- Molecular & Cellular Proteomics
- Publication Type
- epub ahead of print
- Abstract
- The canonical view of phosphatidylinositol 3-kinase alpha (PI3Kalpha) signaling describes PtdIns(3,4,5)P(3) generation and activation of downstream effectors at the plasma membrane or at microtubule-bound endosomes. Here, we show that colorectal cancer (CRC) cell lines exhibit a diverse plasma membrane-nuclear distribution of PI3Kalpha, controlling corresponding levels of subcellular PtdIns(3,4,5)P(3) pools. PI3Kalpha nuclear translocation was mediated by the importin beta-dependent nuclear import pathway. By PtdIns(3,4,5)P(3) affinity capture mass spectrometry done in the presence of SDS on CRC cell lines with PI3Kalpha nuclear localization, we identified 867 potential nuclear PtdIns(3,4,5)P(3) effector proteins. Nuclear PtdIns(3,4,5)P(3) interactome proteins were characterized by non-canonical PtdIns(3,4,5)P(3) binding domains and showed overrepresentation for nuclear membrane, nucleolus and nuclear speckles. The nuclear PtdIns(3,4,5)P(3) interactome was enriched for proteins related to RNA metabolism, with splicing reporter assays and SC-35 foci staining suggesting a role of EGF-stimulated nuclear PI3Kalpha signaling in modulating pre-mRNA splicing. In patient tumors, nuclear p110alpha staining was associated with lower T stage and mucinous histology. These results indicate that PI3Kalpha translocation mediates nuclear PtdIns(3,4,5)P(3) effector signaling in human CRC, modulating signaling responses.
- Publisher
- Elsevier
- Research Division(s)
- Personalised Oncology
- PubMed ID
- 36931626
- Publisher's Version
- https://doi.org/10.1016/j.mcpro.2023.100529
- Open Access at Publisher's Site
https://doi.org/10.1016/j.mcpro.2023.100529- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-03-29 08:34:06
Last Modified: 2023-03-29 08:56:45