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FAM122A inhibition of PP2A-B55 through a bipartite binding mechanism

Iker Benavides-Puy1,2, Suzanne Vigneron3, Arminja N Kettenbach4,5

  • 1Center for Epigenetic Cell Memory, Danish Cancer Institute, 2100 Copenhagen, Denmark.

Journal of Cell Science
|July 3, 2026
PubMed

Insights

FAM122A regulates cell division by inhibiting PP2A-B55 phosphatase. Its binding and inhibitory activity are controlled by a novel C-terminal region and phosphorylation of Ser158 during the cell cycle.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • FAM122A protein regulates cell cycle progression by inhibiting the PP2A-B55 phosphoprotein phosphatase.
  • Previous studies identified N-terminal helical elements in FAM122A critical for PP2A-B55 binding.
  • The regulatory mechanism of FAM122A's inhibitory activity on PP2A-B55 remained unclear.

Purpose of the Study:

  • To systematically analyze the interaction between FAM122A and PP2A-B55 in cellular contexts.
  • To identify novel regions and regulatory mechanisms governing FAM122A's inhibition of PP2A-B55.
  • To elucidate the role of Ser158 phosphorylation in FAM122A function during the cell cycle.

Main Methods:

  • Systematic cellular analysis of FAM122A-PP2A-B55 interactions.
  • Amino acid resolution scans of the FAM122A C-terminus (residues 150-170).
  • Functional assays in human cells and Xenopus laevis egg extracts to assess mitotic entry and phosphatase inhibition.

Main Results:

  • A novel C-terminal region (residues 150-170) of FAM122A is essential for PP2A-B55 binding, complementing the N-terminal helices for a bipartite binding mechanism.
  • Amino acid scans identified key residues within the C-terminus, including Ser158, that contribute to binding.
  • Ser158 phosphorylation is crucial for PP2A-B55 inhibition in human cells and mitotic entry stimulation in Xenopus, with phosphorylation levels correlating with cell cycle stages.

Conclusions:

  • FAM122A employs a bipartite binding mechanism involving both N-terminal and C-terminal regions for PP2A-B55 interaction.
  • Serine 158 phosphorylation acts as a key regulatory switch for FAM122A's inhibitory activity on PP2A-B55.
  • This study provides insights into the cell cycle-dependent regulation of FAM122A's function, impacting cell cycle progression.
Keywords:
Cell cycleFAM122APP2A-B55Phosphorylation

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