Phosphatidylinositol Phosphate 5-Kinase Iγi2 in Association with Src Controls Anchorage-independent Growth of Tumor Cells

Background: PIPKI isoforms play roles in cell migration, polarization, and membrane trafficking and are overexpressed in triple-negative breast cancers, indicating protumorigenic functions. Results: PIPKIi2 associates with the C terminus of Src, and this interaction interdependently controls their functioning. Conclusion: PIPKIi2 and Src synergistically control anchorage-independent tumor cell growth. Significance: This study shows unexpected mechanisms for a phosphatidylinositol 4,5-biphosphate-generating enzyme that synergizes with the proto-oncogene Src to regulate oncogenic signaling. A fundamental property of tumor cells is to defy anoikis, cell death caused by a lack of cell-matrix interaction, and grow in an anchorage-independent manner. How tumor cells organize signaling molecules at the plasma membrane to sustain oncogenic signals in the absence of cell-matrix interactions remains poorly understood. Here, we describe a role for phosphatidylinositol 4-phosphate 5-kinase (PIPK) Ii2 in controlling anchorage-independent growth of tumor cells in coordination with the proto-oncogene Src. PIPKIi2 regulated Src activation downstream of growth factor receptors and integrins. PIPKIi2 directly interacted with the C-terminal tail of Src and regulated its subcellular localization in concert with talin, a cytoskeletal protein targeted to focal adhesions. Co-expression of PIPKIi2 and Src synergistically induced the anchorage-independent growth of nonmalignant cells. This study uncovers a novel mechanism where a phosphoinositide-synthesizing enzyme, PIPKIi2, functions with the proto-oncogene Src, to regulate oncogenic signaling.