The Functional Study Of Newly Identified Cellular PP2A Inhibitor FAM122A

Protein phosphatase 2A(PP2A)has an important roles in embryonic development,cell proliferation,transformation,and fate determination.Although cellular PP2A inhibitors with oncogenic activity have been identified,its embryogenesis-involving endogenous regulators are greatly unclear.With the application of proteomics,cellular and molecular technologies,we describe a cellular inhibitor of PP2A which is essential for embryogenesis.The highly conserved protein in mammals,designated FAM122A,directly interacts with PP2A-A?and B55 rather than B56 subunits,and potentiates degradation of catalytic subunit of PP2A complex by the poly-ubiquitin/proteosome,thus inhibiting the phosphatase activity of PP2A-A?/B55/C?complex with alteration of phosphorylation of B55-specific substrate Akt.Further,we found that three lysine residues respectively localized in 8,29 and 283 amino acids of PP2A-C?protein are possible ubiquitation sites.Correspondingly,the homozygous deletion of the FAM122A gene in mouse results in a delayed embryonic lethality,that displayed the enhanced PP2A-C?protein and apoptosis effect when compared with the wild-type and heterozygous embryos.In agreement,the heterozygous FAM122A^+/-MEFs or transforming cell lines with FAM122A silencing have the inhibiting growing and colony-forming ability.FAM122A silencing cells are more sensitive to Etoposide,demonstrating the increased DNA damge and apoptosis induction.Thus,our data show that as a specific PP2A inhibitor,FAM122A is an essential early embryonic development-related protein.