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Protein phosphatase 5 in signal transduction

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Abstract

Protein phosphatase 5 (PP5) possesses unique biochemical properties, which include its tetratricopeptide repeat (TPR) targeting/regulatory domain and its ability to be activated by lipids. PP5 has been studied as a paradigm for TPR protein structure and function. Roles for PP5 in signal transduction are emerging: from cell cycle regulation and signaling by nuclear receptors, to possible regulation of membrane receptors and ion channels.

Section snippets

PP5 structure: a tetratricopeptide repeat (TPR) protein

Many protein Ser/Thr phosphatases consist of catalytic subunits whose subcellular localization, enzymatic activity and substrate specificity vary according to the regulatory subunits with which they are associated 9. By contrast, PP5 contains catalytic, regulatory and subcellular targeting functions within a single polypeptide chain. The catalytic domain of PP5 is closely related to the catalytic subunits of PP1, PP2A and PP2B, being 42–43% identical to each in amino acid sequence 10. PP5, like

Autoinhibition and arachidonic acid activation

The low basal activity of PP5 (11., 20.) is a consequence of the autoinhibitory role of its TPR domain. Partial proteolysis of the enzyme led to concomitant removal of the TPR domain and up to a 50-fold increase in phosphatase activity 20., 21.. An additional twofold activation was correlated with the cleavage of the ten C-terminal amino acids by subtilisin. This led to the identification of another autoinhibitory role for these residues 21 (Fig. 1c). In the intact cell, PP5 is presumably not

Hsp90 and the glucocorticoid response

Once the sequence of PP5 had been reported, it was noted that its TPR domain was most closely related to the TPR domains of proteins that bind to hsp90 in steroid receptor heterocomplexes 2. Hsp90 is a chaperone required for the proper folding, trafficking, stability and function of steroid receptors and other proteins involved in signal transduction (reviewed in 23., 24.). It was subsequently demonstrated that PP5 binds to hsp90 via its TPR domain and that PP5 is a major component of

PP5 and the cell cycle

In Saccharomyces cerevisiae, deletion of the PP5 homolog PPT results in no obvious change in phenotype 5, although a recent genomic two-hybrid screen suggested interactions between PPT and two other proteins: PPG, a phosphatase that regulates glycogen metabolism; and ADR1, a transcription factor 31. By contrast, in cultured human cells, treatment with a PP5 antisense oligonucleotide resulted in G1 growth arrest 32. Growth arrest was correlated with the induction of p21WAF1/Cip1, an inhibitor of

Regulation of potassium channels?

The functions of many types of ion channels are regulated by phosphorylation 34, and several different types of K+ channels have been shown to be regulated by an okadaic acid-sensitive phosphatase that is stimulated by arachidonic acid 22., 35., 36., 37.. One such channel, which perhaps best illustrates the case for this phosphatase being PP5, will be discussed here. In rat pituitary GH4C1 cells, Armstrong and co-workers have extensively characterized the regulation of large-conductance Ca2+-

Does PP5 have rhythm?

Another intriguing observation is the association of PP5 with mammalian cryptochromes, CRY1 and CRY2. These proteins were initially identified as mammalian homologs of Arabidopsis proteins that act as blue-light photoreceptors, and are expressed in the retina as well as other tissues 41., 42.. Like their plant homologs, CRY1 and CRY2 appear to be blue-light photoreceptors involved in the regulation of circadian rhythm. In a yeast two-hybrid screen, both proteins interacted with the TPR domain

Concluding remarks

Our understanding of the role and regulation of PP5 is growing rapidly. PP5 has been implicated in several signal transduction pathways using three general approaches: (1) the identification of PP5-binding proteins; (2) the inhibition of PP5 activity by recombinant DNA approaches, and (3) blocking arachidonic acid-stimulated cellular processes with protein phosphatase inhibitors. Important challenges now include identifying the natural activator of PP5 and dissecting the mechanisms by which PP5

Acknowledgements

I thank Sandra Rossie, David Armstrong, William Pratt, Adam Silverstein, Richard Honkanen, Dan Donoghue and Tricia Cohen for helpful discussions. I thank Linda Touart and Frank Vogtner for assistance with artwork. Research on PP5 in my laboratory is supported by NIH grants HL 47063 and DK 55877.

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