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Emerging roles of nuclear protein phosphatases

Key Points

  • Genomics has provided an inventory of the catalytic subunits of human protein phosphatases, which can be classified into three groups: Ser and Thr phosphatases (comprising the phosphoprotein phosphatase (PPP) and protein phosphatase, Mg2+ or Mn2+ dependent (PPM) families); the protein Tyr phosphatase (PTP) superfamily; and Asp-based protein phosphatases.

  • Various members from each phosphatase group are enriched or exclusive to the nucleus and often have associated regulatory subunits that have a targeting role.

  • In the DNA-damage response, PP2Cδ (also known as WIP1) has emerged as a key nuclear phosphatase that regulates the activities of the DNA-damage-response proteins ataxia telangiectasia mutated (ATM), CHK1, CHK2, p53, p38 MAPK and uracil DNA glycosylase.

  • Cell-cycle progression is highly regulated by protein phosphorylation events and involves the phosphatases CDC25, CDC14, PP1 and PP2A.

  • The roles of PP1, PP2A and PP2Cγ and PP2Cδ in pre-mRNA maturation are presented, along with recent progress in understanding how the phosphatases TFIIF-associating C-terminal domain (CTD) phosphatase-1 (FCP1), the small CTD phosphatases (SCPs), PP1 and Ssu72 control the phosphorylation state of RNA polymerase II CTD in the nucleus.

  • A functional genomics screen for phosphatases that regulate C-terminal dephosphorylation of SMAD2 and SMAD3 revealed that nuclearly localized PP2Cα has a key role in transforming growth factor-β (TGFβ) and bone-morphogenetic protein (BMP) signalling. Additional searches for the N-terminal and linker-region phosphatases uncovered the SCPs as the enzymes that target these regions of the SMADs.

Abstract

The phosphorylation state of any protein represents a balance of the actions of specific protein kinases and protein phosphatases. Many protein phosphatases are highly enriched in, or exclusive to, the nuclear compartment, where they dephosphorylate key substrates to regulate various nuclear processes. In this review we will discuss recent findings that define the role of nuclear protein phosphatases in controlling transforming growth factor-β (TGFβ) and bone-morphogenetic protein (BMP) signalling, the DNA-damage response, RNA processing, cell-cycle progression and gene transcription.

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Figure 1: The localization and activity of PP1 are regulated by a pool of targeting subunits.
Figure 2: PP2Cδ and the DNA-damage response.
Figure 3: Nuclear protein phosphatases in spliceosome assembly and catalysis.
Figure 4: The phosphorylation state of the C-terminal domain of RNA polymerase II controls transcript maturation.
Figure 5: PP2Cα attenuates TGFβ signalling in the nucleus.

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Acknowledgements

Work in the group of G.B.G.M. is supported by the Natural Sciences and Engineering Research Council of Canada. L.T.M. is funded by the Wellcome Trust.

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Correspondence to Greg B. G. Moorhead.

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Glossary

SILAC

A mass-spectrometry-based quantitative proteomics method that uses stable-isotope labelling with amino acids in cell culture.

HEAT repeat

A tandemly repeated module, 37–47 amino acids in length, that is present in a number of proteins, including the four proteins that gave the module its name: huntingtin, elongation factor-3 (EF3), the A subunit of PP2A and target of rapamycin kinase-1 (TOR1).

TOR signalling

Signal-transduction events that are mediated through the target of rapamycin (TOR) protein complexes.

LC–MS/MS

Liquid chromatography coupled with tandem mass spectrometry. This involves the separation of peptides by high-pressure liquid chromatography and their detection by an interfaced mass spectrometer. Peptides are then selected, fragmented and the products are detected by a second mass spectrometer.

TPR domain

(Tetratricopeptide repeat). A motif that consists of tandem repeats of a degenerate sequence of 34 amino acids and that functions as an interaction scaffold in proteins.

Calmodulin

(CaM). A Ca2+-binding protein that can bind to and regulate a large number of different protein targets and is considered a major transducer of Ca2+ signals in the cell.

EF-hand domain

An EF-hand has two nearly perpendicular α-helices that are connected by a loop, forming a single Ca2+-binding site. EF-hand units generally, but not always, bind Ca2+. EF-hand-containing proteins include CaM, recoverin and the B subunit of PP2B.

Spliceosome

A large nuclear complex of RNA and protein subunits that catalyses the removal of the non-coding introns from unprocessed mRNA.

BRCT domain

A phosphopeptide-binding module that recognizes specific phosphorylation motifs and occurs as a single module or as multiple repeats.

Base-excision repair

(BER). The main DNA-repair pathway that is responsible for the repair of apurinic and apyrimidinic (AP) sites in DNA. BER is catalysed in four consecutive steps: a DNA glycosylase removes the damaged base; an AP endonuclease processes the abasic site; a DNA polymerase inserts the new nucleotide(s); and DNA ligase rejoins the DNA strand.

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Moorhead, G., Trinkle-Mulcahy, L. & Ulke-Lemée, A. Emerging roles of nuclear protein phosphatases. Nat Rev Mol Cell Biol 8, 234–244 (2007). https://doi.org/10.1038/nrm2126

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