Academic journal article Genetics

Wide-Ranging Effects of the Yeast Ptc1 Protein Phosphatase Acting through the MAPK Kinase Mkk1

Academic journal article Genetics

Wide-Ranging Effects of the Yeast Ptc1 Protein Phosphatase Acting through the MAPK Kinase Mkk1

Article excerpt

PROTEIN kinases play an essential role in nearly every aspect of cell physiology, and the activity of these key players is frequently modulated by phosphorylation. Therefore, protein phosphatases (PPases) are important regulators of protein kinases and cellular homeostasis. Among them, type 2C Ser/Thr PPases constitute an evolutionarily conserved group that,incontrasttootherPPasefamilies,aremonomericenzymes apparently lacking regulatory subunits. In the yeast Saccharomyces cerevisiae, seven members (Ptc1-Ptc7) have been identified and at least partially characterized [see Arino et al. (2011) for a review].

Ptc1 is the closest homolog of human Wip1, a phosphatase involved in the regulation of stress-induced and DNA damage-induced networks in diverse physiologic and pathologic conditions (Le Guezennec and Bulavin 2010; Zhu and Bulavin 2012) and by far the most widely studied yeast isoform. Both the large number of characteristic phenotypes and the specific changes in the transcriptomic profile (Gonzalez et al. 2006) derived from deletion of the gene suggest that this phosphatase is involved in a large variety of cellular processes not shared by other Ptc family members. Early evidence indicated that Ptc1 was involved in the negative regulation of the high-osmolarity glycerol (HOG) pathway (Maeda et al. 1993; Maeda et al. 1994), and subsequent work demonstrated that Ptc1 could dephosphorylate the Hog1 MAPK in vitro and in vivo (Warmka et al. 2001). Ptc1 physically interacts with the N-terminal domain of Nbp2,anSH3domain- containing protein that serves as an adaptor for the recruitment of Ptc1 to the Pbs2-Hog1 complex, and this interaction is necessary for Ptc1 to participate in the regulation of HOGmediated signaling (Uetz et al. 2000; Ito et al. 2001; Mapes and Ota 2004).

Cells lacking Ptc1 display many phenotypes that cannot be explained by a Hog1-dependent role of this phosphatase. For instance, these cells are sensitive to diverse cations, including calcium (likely by hyperactivation of calcineurin phosphatase), zinc, and cesium (Gonzalez et al. 2006), as well as to alkaline pH (Serrano et al. 2004). These are traits commonly found in mutants with impaired vacuolar function, and indeed, the ptc1 mutant displays fragmented vacuoles, mimicking those of class B vps (vacuolar protein-sorting) mutants (Bonangelino et al. 2002; Seeley et al. 2002; Sambade et al. 2005; Gonzalez et al. 2006). Deletion of PTC1 confers a lithium (but not sodium)-sensitive phenotype. This can be attributed, at least in part, to a less effective cation extrusion, likely due to a Hog1-independent decrease in the expression of the Na+-ATPase ENA1 gene (Ruiz et al. 2006).

Ptc1 is required for the correct inheritance of organelles such as vacuoles, mitochondria, cortical endoplasmic reticulum (ER), peroxisomes, and secretory vesicles. These effects are independent of Hog1 dephosphorylation (Roeder et al. 1998; Du et al. 2006; Jin et al. 2009). Moreover, lack of Ptc1 results in additional phenotypic traits, such as defects in transfer RNA (tRNA) splicing and growth in nonfermentable media (Robinson et al. 1994) and, in haploid strains, cell separation defects and a random budding pattern at 37^ (Gonzalez et al. 2006). A link between Ptc1 and the targetof-rapamycin (TOR) pathway was suggested by the increased sensitivity of ptc1 cells to rapamycin, an inhibitor of the TORC1 complex (Parsons et al. 2004; Xie et al. 2005). Subsequent work demonstrated that Ptc1 is required for normal TOR signaling by regulating, in a HOG-independent manner, a step upstream of the Sit4 phosphatase (Gonzalez et al. 2009). Recently, Ptc1 has been shown to dephosphorylate the Snf1 protein kinase at Thr 210 in vivo (Ruiz et al. 2013).

Early work showed that mutations in PTC1 could suppress phenotypes derived from hypoactive pkc1 alleles (Huang and Symington 1995), thus pointing to a link between Ptc1 and the cell-wall integrity (CWI) pathway. This pathway is composed of several membrane sensors that signal through the small GTPase Rho1 to the Pkc1 kinase. …

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