Molecules in focus
Protein phosphatase 5

https://doi.org/10.1016/j.biocel.2007.08.010Get rights and content

Abstract

Protein phosphatase 5 (PP5) is a unique member of the PPP family of serine/threonine phosphatases based on the presence of tetratricopeptide repeat (TPR) domains within its structure. Since its discovery, PP5 has been implicated in wide ranging cellular processes, including MAPK-mediated growth and differentiation, cell cycle arrest and DNA damage repair via the p53 and ATM/ATR pathways, regulation of ion channels via the membrane receptor for atrial natriuretic peptide, the cellular heat shock response as mediated by heat shock transcription factor, and steroid receptor signaling, especially glucocorticoid receptor (GR). Given this diversity of effects, the recent development of viable PP5-deficient mice was surprising and suggests that PP5 is a modulatory, rather than essential, factor in phosphorylation pathways. Here, we review the signaling involvement of PP5 in light of new findings and relate these activities to the structural features of the protein.

Introduction

Although PP5 is the commonly accepted name of this important phosphatase, alternative names can be found in the literature, including Ppp5 (Yong et al., 2007; Zeke, Morrice, Vazquez-Martin, & Cohen, 2005) and phosphoprotein phosphatase 5 (Russell, Whitt, Chen, & Chinkers, 1999). Identification of PP5 came late compared to other members of the PPP family of serine/threonine-specific phosphatases, such as PP1, PP2A, and PP2B—most likely due to its low-basal phosphatase activity (Chen & Cohen, 1997). Using different methods, three laboratories are credited for the discovery of PP5 in 1994 (Becker, Kentrup, Klumpp, Schultz, & Joost, 1994; Chen et al., 1994, Chinkers, 1994); the Cohen laboratory provided the nomenclature, PP5 (Chen et al., 1994). Sequencing of PP5, and its yeast homolog PPT, showed the presence of TPR domains within their structures. Although many proteins use TPR domains as protein–protein interaction motifs, PP5 and PPT are the only phosphatases known to contain these structures. Not surprisingly, PP5 was later found to interact with Heat Shock Protein 90 (HSP90) (Chen, Silverstein, Pratt, & Chinkers, 1996), a molecular chaperone known to bind other TPR-containing proteins, such as FKBP52, FKBP51 and Cyp40 (for review see Pratt & Toft, 1997). As a well-known function of HSP90 is to control the early stages of steroid receptor (SR) activity, PP5 has been actively studied with respect to its actions on steroid receptors. In this context, it should be noted that HSP90, although it exists as a dimer in SR complexes, only generates one TPR-binding site per receptor complex (Pratt & Toft, 1997). Thus, multiple SR complexes are known to exist based on TPR protein content. Therefore, PP5 is best viewed as part of a modulatory cartel of distinct TPR-containing HSP90 complexes whose principal and unique roles in regulation of SRs and other clients are still largely unknown.

Section snippets

Structure

A diagram showing pertinent features of PP5 and its isoforms is seen in Fig. 1. The phosphatase domain resides in the C-terminal region and contains all the relevant motifs of the PPP family of phosphatases (Becker et al., 1994, Chen et al., 1994, Chinkers, 1994). Key residues in the phosphatase domain responsible for binding the phosphate moiety of substrates are R275, N303, H304 and R400 (Swingle, Honkanen, & Ciszak, 2004). Interestingly, sequence homology is low (approximately 40%) when

Biological function

A delicate balance of phosphorylation and dephosphorylation is essential to the maintenance of cellular responsiveness. In the 13 years since its discovery, it is evident that PP5 is a multi-tasking regulator of this balance. Cellular functions impacted by PP5 include proliferation, migration, differentiation, electrolyte balance, apoptosis, survival, and DNA damage repair. Not surprisingly, PP5 is expressed in virtually all mammalian tissues, with particularly high levels in brain and neurons (

Acknowledgement

This work was supported in part by a National Institutes of Health (USA) grant (DK70127) to ERS. The authors thank Dr. Michael Chinkers (University of South Alabama) for critical review of the manuscript.

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