PI3Kα Translocation Mediates Nuclear PtdIns(3,4,5) P3 Effector Signaling in Colorectal Cancer

The canonical view of PI3K alpha signaling describes phos-phatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) gen-eration 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 PI3K alpha, controlling corresponding levels of subcellular PtdIns(3,4,5)P3 pools. PI3K alpha nuclear translocation was mediated by the importin beta-dependent nuclear import pathway. By PtdIns(3,4,5)P3 affinity capture mass spec-trometry done in the presence of SDS on CRC cell lines with PI3K alpha nuclear localization, we identified 867 potential nuclear PtdIns(3,4,5)P3 effector proteins. Nuclear PtdIns(3,4,5)P3 interactome proteins were characterized by noncanonical PtdIns(3,4,5)P3-binding domains and showed overrepresentation for nuclear membrane, nucleolus, and nuclear speckles. The nuclear PtdIns(3,4,5) P3 interactome was enriched for proteins related to RNA metabolism, with splicing reporter assays and SC-35 foci staining suggesting a role of epidermal growth factor- stimulated nuclear PI3K alpha signaling in modulating pre-mRNA splicing. In patient tumors, nuclear p110 alpha staining was associated with lower T stage and mucinous histol-ogy. These results indicate that PI3K alpha translocation me-diates nuclear PtdIns(3,4,5)P3 effector signaling in human CRC, modulating signaling responses.