STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells

Elife. 2020 Jan 8;9:e53003. doi: 10.7554/eLife.53003.

Abstract

Alterations involving serine-threonine phosphatase PP2A subunits occur in a range of human cancers, and partial loss of PP2A function contributes to cell transformation. Displacement of regulatory B subunits by the SV40 Small T antigen (ST) or mutation/deletion of PP2A subunits alters the abundance and types of PP2A complexes in cells, leading to transformation. Here, we show that ST not only displaces common PP2A B subunits but also promotes A-C subunit interactions with alternative B subunits (B''', striatins) that are components of the Striatin-interacting phosphatase and kinase (STRIPAK) complex. We found that STRN4, a member of STRIPAK, is associated with ST and is required for ST-PP2A-induced cell transformation. ST recruitment of STRIPAK facilitates PP2A-mediated dephosphorylation of MAP4K4 and induces cell transformation through the activation of the Hippo pathway effector YAP1. These observations identify an unanticipated role of MAP4K4 in transformation and show that the STRIPAK complex regulates PP2A specificity and activity.

Keywords: MAP4K4; PP2A; STRIPAK; cancer biology; human; small t; transformation.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Calmodulin-Binding Proteins / genetics
  • Calmodulin-Binding Proteins / metabolism
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism*
  • Female
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Heterografts
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • Transcription Factors / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Calmodulin-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • STRN4 protein, human
  • Transcription Factors
  • YAP1 protein, human
  • MAP4K4 protein, human
  • Protein-Serine-Threonine Kinases
  • Phosphoprotein Phosphatases

Associated data

  • GEO/GSE118272