Atypical Protein Phosphatases: Emerging Players in Cellular Signaling

Abstract

It has generally been considered that protein phosphatases have more diverse catalytic domain structures and mechanisms than protein kinases; however, gene annotation efforts following the human genome project appeared to have completed the whole array of protein phosphatases. Ser/Thr phosphatases are divided into three subfamilies that have different structures from each other, whereas Tyr phosphatases and dual-specificity phosphatases targeting Tyr, Ser and Thr belong to a single large family based on their common structural features. Several years of research have revealed, however, the existence of unexpected proteins, designated here as “atypical protein phosphatases”, that have structural and enzymatic features different from those of the known protein phosphatases and are involved in important biological processes. In this review, we focus on the identification and functional characterization of atypical protein phosphatases, represented by eyes absent (EYA), suppressor of T-cell receptor signaling (Sts) and phosphoglycerate mutase family member 5 (PGAM5) and discuss their biological significance in cellular signaling.

Protein phosphorylation and its role in archaeal signal transduction

“…Investigations in Eukaryotes also revealed the presence of atypical PPs, which were, so far, not detected in Prokaryotes (Sadatomi et al. 2013). …”

A Conserved Motif Mediates both Multimer Formation and Allosteric Activation of Phosphoglycerate Mutase 5

“…In humans, the 12 members of the phosphoglycerate mutase (PGAM) 2 family are defined by the presence of a catalytic domain of ϳ200 amino acids containing a canonical motif of RHGE in which the His residue is critically required for enzymatic activity (1). Although most PGAM members catalyze the dephosphorylation/phosphorylation of small metabolites, three members of the PGAM family, STS1, STS2 and PGAM5, are protein phosphatases (1)(2)(3).…”

“…Although most PGAM members catalyze the dephosphorylation/phosphorylation of small metabolites, three members of the PGAM family, STS1, STS2 and PGAM5, are protein phosphatases (1)(2)(3). The tyrosine phosphatase activity of the closely related STS1 and STS2 proteins underlies their involvement in T-cell receptor signaling (2), and the serine/threonine phosphatase activity of PGAM5 has been implicated in mitochondrial fragmentation and cell death (4).…”

Identification of PGAM5 as a Mammalian Protein Histidine Phosphatase that Plays a Central Role to Negatively Regulate CD4 + T Cells

“…Many members of this family function as mutases in metabolic pathways and catalyze the transfer of a phosphate group from one position to another on the same metabolite molecule via a phosphohistidine intermediate formed on a conserved histidine residue in the PGAM domain. In contrast, PGAM5 along with STS-1 and 2 are divergent and do not exhibit mutase activity but rather have been shown to function respectively as serine/threonine and tyrosine phosphatases (Carpino et al, 2004; Sadatomi et al, 2013; Wang et al, 2012). PGAM5 and STS-1 and STS-2 utilize a conserved histidine as a phospho-acceptor, with subsequent hydrolyis of the phosphohistidine releasing the free phosphate.…”