Protein phosphatase PP4 is overexpressed in human breast and lung tumors

Reversible protein phosphorylation by kinases and phosphatases is one of the most common mechanisms in controlling most, if not all, cellular processes ¹. Dephosphorylation of serine/threonine residues is regulated by two distinct groups of functionally diverse serine/threonine protein phosphatases, the PPM family (which includes PP2C) and the PPP family, which includes the type 1 (PP1) and the type 2A (PP2A, PP2B, PP3, PP4, PP5, PP6, and PP7) protein phosphatases. Members of the type 2A group of phosphatases (PP2A, PP4, and PP6) are the most closely related in sequence. They are sensitive to inhibition by low doses of okadaic acid (OA) or fostriecin, which distinguishes them from PP1 ¹. The regulation and function of PP2A have been thoroughly investigated. PP2A is composed of a core complex containing the catalytic subunit (C) and the scaffold subunit (A), which interacts with a wide variety of regulatory subunits and interacting proteins that target the AC core dimer to specific substrates and subcellular locations ¹. The assembly of many different types of heterotrimeric holoenzymes accounts for the ability of PP2A, and, possibly, PP4 and PP6, to regulate a wide range of biological processes.

Protein phosphatases 4 catalytic subunit (PP4C) plays an important role in microtubule growth/organization ², apoptosis ^{3, 4}, tumor necrosis factor signaling ⁵, and pre-T-cell receptor signaling ⁴. The ablation of PP4 leads to embryonic lethality in mice ⁴. The human PP4 phosphatase complex, PP4C-PP4R2-PP4R3, was recently identified through mammalian TAP-tagging technique and mass spectrometry ⁶. In Saccharomyces cerevisiae, the pph3 (PP4 orthologue), psy2 (PP4R2 orthologue), and yb1046w (PP4R3 orthologue) mutants, but not the pph22 (PP2A orthologue) mutant, are hypersensitive to cisplatin treatment ^{6, 7}. Since cisplatin is a replication-dependent DNA-damaging agent ⁸, this suggests that PP4 is involved in DNA damage signaling and/or repair. Indeed, we recently found that PP4C dephosphorylates γ-H2AX generated during DNA replication ⁹, while PP2A dephosphorylates γ-H2AX generated in response to exogenous DNA damaging agents ¹⁰.

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