A p53–phosphoinositide signalosome regulates nuclear AKT activation View Full Text


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Article Info

DATE

2022-07-07

AUTHORS

Mo Chen, Suyong Choi, Tianmu Wen, Changliang Chen, Narendra Thapa, Jeong Hyo Lee, Vincent L. Cryns, Richard A. Anderson

ABSTRACT

The tumour suppressor p53 and PI3K–AKT pathways have fundamental roles in the regulation of cell growth and apoptosis, and are frequently mutated in cancer. Here, we show that genotoxic stress induces nuclear AKT activation through a p53-dependent mechanism that is distinct from the canonical membrane-localized PI3K–AKT pathway. Following genotoxic stress, a nuclear PI3K binds p53 in the non-membranous nucleoplasm to generate a complex of p53 and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), which recruits AKT, PDK1 and mTORC2 to activate AKT and phosphorylate FOXO proteins, thereby inhibiting DNA damage-induced apoptosis. Wild-type p53 activates nuclear AKT in an on/off fashion following stress, whereas mutant p53 dose-dependently stimulates high basal AKT activity. The p53–PtdIns(3,4,5)P3 complex is dephosphorylated to p53–phosphatidylinositol 4,5-bisphosphate by PTEN to inhibit AKT activation. The nuclear p53–phosphoinositide signalosome is distinct from the canonical membrane-localized pathway and insensitive to PI3K inhibitors currently in the clinic, which underscores its therapeutic relevance. More... »

PAGES

1099-1113

References to SciGraph publications

  • 2019-11-04. The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism in NATURE REVIEWS CANCER
  • 2021-01-23. Assessing In Situ Phosphoinositide–Protein Interactions Through Fluorescence Proximity Ligation Assay in Cultured Cells in PHOSPHOINOSITIDES
  • 2016-11-21. Agonist-stimulated phosphatidylinositol-3,4,5-trisphosphate generation by scaffolded phosphoinositide kinases in NATURE CELL BIOLOGY
  • 2019-06-24. The Specificity of EGF-Stimulated IQGAP1 Scaffold Towards the PI3K-Akt Pathway is Defined by the IQ3 motif in SCIENTIFIC REPORTS
  • 2013-01. p53 mutations in cancer in NATURE CELL BIOLOGY
  • 2011-05-06. Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis in MODERN PATHOLOGY
  • 2013-03-29. Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis in CELL DEATH & DIFFERENTIATION
  • 2017-12-14. DNA damage causes rapid accumulation of phosphoinositides for ATR signaling in NATURE COMMUNICATIONS
  • 2012-01. FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage in NATURE COMMUNICATIONS
  • 2008-02. A PtdIns4,5P2-regulated nuclear poly(A) polymerase controls expression of select mRNAs in NATURE
  • 2020-11-02. Phosphatidylinositol 3-kinase signalling is spatially organized at endosomal compartments by microtubule-associated protein 4 in NATURE CELL BIOLOGY
  • 2019-03-18. A nuclear phosphoinositide kinase complex regulates p53 in NATURE CELL BIOLOGY
  • 2012-07-23. Histone H2AX Phosphorylation: A Marker for DNA Damage in DNA REPAIR PROTOCOLS
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41556-022-00949-1

    DOI

    http://dx.doi.org/10.1038/s41556-022-00949-1

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1149303025

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/35798843


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