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

Abstract

The canonical view of PI3Kα signaling describes phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P₃) 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 PI3Kα, controlling corresponding levels of subcellular PtdIns(3,4,5)P₃ pools. PI3Kα nuclear translocation was mediated by the importin β-dependent nuclear import pathway. By PtdIns(3,4,5)P₃ affinity capture mass spectrometry done in the presence of SDS on CRC cell lines with PI3Kα 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 PI3Kα signaling in modulating pre-mRNA splicing. In patient tumors, nuclear p110α staining was associated with lower T stage and mucinous histology. These results indicate that PI3Kα translocation mediates nuclear PtdIns(3,4,5)P₃ effector signaling in human CRC, modulating signaling responses.

Keywords: PI3Kα; PtdIns(3,4,5)P(3) interactome; colorectal cancer; nuclear import pathway; pre-mRNA splicing.