Essential, Overlapping and Redundant Roles of the Drosophila Protein Phosphatase 1α and 1β Genes

Abstract

Protein serine/threonine phosphatase type 1 (PP1) has been found in all eukaryotes examined to date and is involved in the regulation of many cellular functions, including glycogen metabolism, muscle contraction, and mitosis. In Drosophila, four genes code for the catalytic subunit of PP1 (PP1c), three of which belong to the PP1a subtype. PP1b9C (flapwing) encodes the fourth PP1c gene and has a specific and nonredundant function as a nonmuscle myosin phosphatase. PP1a87B is the major form and contributes $80% of the total PP1 activity. We describe the first mutant alleles of PP1a96A and show that PP1a96A is not an essential gene, but seems to have a function in the regulation of nonmuscle myosin. We show that overexpression of the PP1a isozymes does not rescue semilethal PP1b9C mutants, whereas overexpression of either PP1a96A or PP1b9C does rescue a lethal PP1a87B mutant combination, showing that the lethality is due to a quantitative reduction in the level of PP1c. Overexpression of PP1b9C does not rescue a PP1a87B, PP1a96A double mutant, suggesting an essential PP1a-specific function in Drosophila.

The selective inhibition of protein phosphatase-1 results in mitotic catastrophe and impaired tumor growth

“…A knockdown approach was not an attractive option because of the redundancy between PP1 isoforms, which enables PIPs to form functional complexes with other PP1 isoforms once their preferred isozyme is removed (Gibbons et al, 2007;Kirchner et al, 2007;TrinkleMulcahy et al, 2006;Varmuza et al, 1999). In addition, none of the available small-molecule, cell-permeable inhibitors of PPP-type phosphatases is specific for PP1, making a chemical genetics approach unfeasible (De Munter et al, 2013;Gehringer, 2004;Kelker et al, 2009).…”

“…Another problem stems from the functional redundancy between PP1 isoforms, making knockdown experiments of individual isoforms rather uninformative (Cheng et al, 2000;Kirchner et al, 2007;Trinkle-Mulcahy et al, 2006;Varmuza et al, 1999). We have delineated the global role of PP1 in cell cycle progression using cell lines that inducibly overexpress nuclear inhibitor of PP1 (NIPP1; also known as PPP1R8).…”

PNUTS/PP1 Regulates RNAPII-Mediated Gene Expression and Is Necessary for Developmental Growth

“…In Drosophila , PP1 is found at multiple sites on chromosomes where it has been postulated to play important roles in regulating developmentally controlled gene expression [17], [18]. However, analysing the role of PP1 in transcriptional regulation has been complicated by its pleiotropic roles [19] and broad in vitro substrate specificity. In vivo , PP1 has been shown to associate with different targeting subunits that restrict its activity towards particular substrates [20].…”

Protein Phosphatase 1 β Paralogs Encode the Zebrafish Myosin Phosphatase Catalytic Subunit

“…We cannot exclude a role for other related targeting subunits such as Mypt2, Mypt3 and TIMAP (reviewed in 5) or yet other unidentified targeting subunits, and a further analysis of PP1 binding proteins in early development may be warranted. Additionally, given the considerable functional redundancy between PP1 isoforms observed in other organisms [15,33–35], it could be quite informative to characterize overlapping functions with other zebrafish PP1 genes such as ppp1caa , ppp1cab and ppp1cc . Such an analysis may uncover additional roles for ppp1cba and ppp1cbb .…”

“…Interestingly, zebrafish have five PP1 genes: two genes similar to PP1α, two genes similar to PP1β and one gene related to PP1γ. Genetic experiments in flies and mice have indicated that PP1 isoforms have both unique isoform-specific functions and other roles that overlap with the other PP1 isoforms [33,34]. While all three mammalian PP1 isoforms can partially complement the single essential PP1 catalytic subunit in S.…”