title: Phosphatidylinositol Phosphate 5-Kinase Iγ and Phosphoinositide 3-Kinase/Akt Signaling Couple to Promote Oncogenic Growth.
abstract: 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 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-biphosphate (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 overexpressed 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 extracellular matrix proteins in different tumor cells. PIPKIγi2 assembles 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 by which PIPKIγi2 and PI3K are integrated into a complex regulated by Src, resulting in the spatial generation of PIP2, which 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 a PI3K enzyme. This pathway may represent a signaling nexus required for the survival and growth of metastasizing and circulating tumor cells in vivo.
authors.affiliation: From the Molecular and Cellular Pharmacology Program, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin 53706.
authors.forename: Narendra
authors.initials: N
authors.lastname: Thapa
authors.affiliation: From the Molecular and Cellular Pharmacology Program, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin 53706.
authors.forename: Suyong
authors.initials: S
authors.lastname: Choi
authors.affiliation: From the Molecular and Cellular Pharmacology Program, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin 53706.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Tan
authors.affiliation: From the Molecular and Cellular Pharmacology Program, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin 53706.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wise
authors.affiliation: From the Molecular and Cellular Pharmacology Program, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin 53706 raanders@wisc.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
mesh_terms: D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000378:metabolism; D010716:Phosphatidylinositols / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Akt PKB; PIPKIgamma; PIPKIgammai2; Src; oncogenic growth; phosphatidylinositide 3-kinase (PI3K); phosphatidylinositol kinase (PI kinase); phosphoinositide