Reference: Stefansson B and Brautigan DL (2006) Protein phosphatase 6 subunit with conserved Sit4-associated protein domain targets IkappaBepsilon. J Biol Chem 281(32):22624-34

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Abstract

Protein Ser/Thr phosphatases (PPP) comprise a family that includes type-2 PP2A, PP4 and PP6, each with essential functions. The human PP6 gene rescues sit4ts mutants of S. cerevisiae and Sit4 phosphatase function depends on multiple SAP (Sit4 Associated Protein) proteins. We report here finding a SAPS sequence domain encoded in only a single gene each in S. pombe, C. elegans and Drosophila but in three distinct open reading frames in Xenopus, M. musculus and H. sapiens. The SAPS proteins are more divergent in sequence than PP6. Northern hybridization showed differential distribution of the human SAPS-related mRNA in multiple human tissues, named as PP6R1, PP6R2 and PP6R3. Antibodies were generated and distribution of endogenous PP6, PP6R1, PP6R2 and PP6R3 proteins was examined by immunoblotting and abundance of mRNA and protein in various tissues did not match. FLAG-tagged PP6R1 and PP6R2 expressed in HEK293 cells co-precipitated endogenous PP6, but not PP2A or PP4, showing specificity for recognition of phosphatases. The SAPS domain of PP6R1 alone was sufficient for association with PP6 and this predicts that conserved sequence motifs in the SAPS domain account for the specificity. FLAG-PP6R1 and FLAG-PP6R2 co-precipitated HA-IkappaBepsilon. Knock-down of PP6 or PP6R1 but not PP6R3 with siRNA significantly enhanced degradation of endogenous IkappaBepsilon in response to Tumor Necrosis Factor-alpha. The results show SAPS domain subunits recruit substrates such as IkappaBepsilon as one way to determine specific functions for PP6.

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Journal Article
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Stefansson B, Brautigan DL
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