Type 2C Protein Phosphatases in Fungi

Abstract

Type 2C Ser/Thr phosphatases are a remarkable class of protein phosphatases, which are conserved in eukaryotes and involved in a large variety of functional processes. Unlike in other Ser/Thr phosphatases, the catalytic polypeptide is not usually associated with regulatory subunits, and functional specificity is achieved by encoding multiple isoforms. For fungi, most information comes from the study of type 2C protein phosphatase (PP2C) enzymes in Saccharomyces cerevisiae, where seven PP2C-encoding genes (PTC1 to -7) with diverse functions can be found. More recently, data on several Candida albicans PP2C proteins became available, suggesting that some of them can be involved in virulence. In this work we review the available literature on fungal PP2Cs and explore sequence databases to provide a comprehensive overview of these enzymes in fungi.Reversible phosphorylation of proteins is a major mechanism regulating many biological processes such as metabolism, gene transcription, or cell cycle. It is an extremely common event in signal transduction, and it is considered the main mechanism of posttranslational modification leading, for instance, to a change in enzyme activity. The phosphorylation state of a protein results from the balance of protein kinases and protein phosphatases activities. Alterations in the phosphorylation state of proteins are a cause of various diseases, such as cancer, diabetes, rheumatoid arthritis, or hypertension. The importance of this regulatory mechanism is evident when it is considered that it affects around 30% of the proteome of Saccharomyces cerevisiae (72) and that the number of genes encoding phosphatases and kinases represents 2 to 4% of all genes in a typical eukaryotic genome (60).Most phosphorylation events in eukaryotes involve transfer of phosphate to Ser and Thr residues. Removal of this phosphate is catalyzed by Ser/Thr protein phosphatases. Members of this large family of enzymes were initially classified, using enzymological criteria, as type 1 (PP1) and type 2 (PP2) phosphatases. PP2 enzymes were subsequently divided into three groups on the basis of the requirements for metal ions: 2A (not requiring metal ions), 2B (activated by calcium), and 2C (Mg 2ϩ dependent) (10). The molecular cloning of a number of cDNAs and genes from diverse organisms allowed the establishment of three major subfamilies: PPP (phosphoprotein phosphatases), including type 1, 2A, and 2B phosphatases, among others; PPM (metal-dependent protein phosphatases), including type 2C enzymes (PP2C), which are the subject of this review; and the catalytically Asp-based subfamily, represented by HAD and FCP/SCP (see reference 89 for a review).Although PP2C proteins are distantly related in primary sequence to PPP enzymes, their tridimensional structure and catalytic mechanisms appear to be quite similar. Type 2C phosphatases are widely represented in bacteria, fungi, plants, insects, and mammals (83), suggesting that they are involved in key cellular processes, such as proliferation, metabolism, and cell...

PPM1H Is a p27 Phosphatase Implicated in Trastuzumab Resistance

“…The yeast PP2C family members (PTC2 and 3) are also described as negative regulators of growth by dephosphorylating and inactivating Cdc28, a primary regulator of cell-cycle progression (18). Other family members such as PTC1 are negative regulators of osmotic stress signaling pathways (36). Very little is known about PPM1H, although it was originally identified as a negative regulator of neurite outgrowth (21).…”

Ptc1 Protein Phosphatase 2C Contributes to Glucose Regulation of SNF1/AMP-activated Protein Kinase (AMPK) in Saccharomyces cerevisiae

“…20). Ptc1 is implicated in MAPK pathways such as the high-osmolarity glycerol and cell wall integrity pathways, the TOR (target of rapamycin) pathway, cation homeostasis, inheritance of cellular organelles, and other functions (20). Analysis of the ptc1⌬ mutant using DNA microarrays showed no significant effects on expression of glucoseregulated genes (21,22).…”

“…Ptc1 is the best characterized, and it is structurally and functionally distinct from the others, although it may share some functions (for review, see ref. 20). Ptc1 is implicated in MAPK pathways such as the high-osmolarity glycerol and cell wall integrity pathways, the TOR (target of rapamycin) pathway, cation homeostasis, inheritance of cellular organelles, and other functions (20).…”

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

“…Among them, type 2C Ser/Thr PPases constitute an evolutionarily conserved group that, in contrast to other PPase families, are monomeric enzymes 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.…”

“…Among them, type 2C Ser/Thr PPases constitute an evolutionarily conserved group that, in contrast to other PPase families, are monomeric enzymes 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].…”