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Methods to Study Mrp4-containing Macromolecular Complexes in the Regulation of Fibroblast Migration
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STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells

Jong Wook Kim1,2,3,4, Christian Berrios2,5, Miju Kim1,2

  • 1Broad Institute of Harvard and MIT, Cambridge, United States.

Elife
|January 9, 2020
PubMed

Insights

The SV40 Small T antigen (ST) hijacks cancer-driving protein phosphatase 2A (PP2A) by engaging the STRIPAK complex. This interaction promotes cell transformation via MAP4K4 dephosphorylation and YAP1 activation.

Area of Science:

  • Molecular biology
  • Cell biology
  • Oncology

Background:

  • Alterations in serine-threonine phosphatase PP2A subunits are implicated in human cancers, contributing to cell transformation.
  • The SV40 Small T antigen (ST) can disrupt PP2A function by displacing regulatory B subunits, leading to cellular transformation.

Purpose of the Study:

  • To investigate the interaction between ST, PP2A, and alternative PP2A subunits.
  • To elucidate the role of the Striatin-interacting phosphatase and kinase (STRIPAK) complex in ST-induced cell transformation.

Main Methods:

  • Investigated the association of ST with PP2A subunits and the STRIPAK complex.
  • Utilized STRN4 knockdown to assess its requirement for ST-PP2A-induced transformation.
  • Analyzed PP2A-mediated dephosphorylation of MAP4K4 and YAP1 activation.

Main Results:

  • ST displaces common PP2A B subunits and promotes interactions with alternative B subunits (B''', striatins) within the STRIPAK complex.
  • STRN4, a STRIPAK component, is essential for ST-induced cell transformation.
  • ST recruits STRIPAK to facilitate PP2A-mediated dephosphorylation of MAP4K4, activating YAP1 and driving cell transformation.

Conclusions:

  • The STRIPAK complex regulates PP2A specificity and activity, playing a critical role in ST-induced cell transformation.
  • MAP4K4 is identified as a novel factor in cellular transformation through its regulation by PP2A within the STRIPAK complex.
  • ST exploits the STRIPAK-PP2A-MAP4K4-YAP1 axis to promote cancer development.
Keywords:
MAP4K4PP2ASTRIPAKcancer biologyhumansmall ttransformation

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