Phosphatidylinositol Phosphate 5-Kinase I{gamma} and PI3K/Akt Signaling Couple to Promote Oncogenic Growth [Signal Transduction]

June 12th, 2015 by Thapa, N., Choi, S., Tan, X., Wise, T., Anderson, R. A.

The assembly of signaling complexes at the plasma membrane is required for the initiation and propagation of cellular signaling upon cell activation. The class I phosphoinositide 3-kinases (PI3K) and the serine/threonine-specific protein kinase Akt signaling pathways (PI3K/AKT) are often activated in tumors. These pathways are initiated by the generation of phosphatidylinositol 3,4,5-triphosphate (PIP3) by PI3K-mediated phosphorylation of phosphatidylinositol 4,5-phosphate (PIP2), synthesized by phosphatidylinositol 4-phosphate 5-kinase (PIPKI) enzymes. The mechanism of how tumor cells recruit and organize the PIP2-synthesizing enzymes with PI3K in the plasma membrane for activation of PI3K/Akt signaling is not defined. Here, we demonstrated a role for the phosphatidylinositol 4-phosphate 5-kinase Iγ (PIPKIγ) in PI3K/Akt signaling. PIPKIγ is over-expressed in triple-negative breast cancers. Loss of PIPKIγ or its focal adhesion-targeting variant, PIPKIγi2, impaired PI3K/Akt activation upon stimulation with growth factors or ECM proteins in different tumor cells. PIPKIγi2 assemble into a complex containing Src and PI3K; Src was required for the recruitment of PI3K enzyme into the complex. PIPKIγi2 interaction with Src and its lipid kinase activity were required for promoting PI3K/Akt signaling. These results define a mechanism, where PIPKIγi2 and PI3K are integrated into a complex regulated by Src, resulting in the spatial generation of PIP2 that is the substrate PI3K required for PIP3 generation and subsequent Akt activation. This study elucidates the mechanism by which PIP2-generating enzyme controls Akt activation upstream of PI3K enzyme. This pathway may represent a signaling nexus required for the survival and growth of metastasizing and circulating tumor cells in vivo.