Phosphatase modulator

Details Phosphatase modulator Phosphatase modulator

1998-09-28

2000-12-12

Slobodyansky, Elizabeth

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving hydrolase

435 6, 435196, C12Q 142, C12Q 168, C12N 916

Patent

active

06159704&

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a modulator of protein phosphatase 2A (PP2A). In particular, the invention relates to the involvement of eRF1 in PP2A regulation and the use of modulators of the eRF1-PP2A interaction for the regulation of intracellular signalling and protein synthesis.
Protein phosphatase 2A (PP2A) is implicated in the regulation of many cellular processes including metabolism, signal transduction, growth, development, cell cycle progression and transformation (reviewed in Mumby, M. C. and Walter, G. (1993) Physiol. Rev, 73, 673-699; Mayer-Jaekel, R. E. and Hemmings, B. A. (1994) Trends Cell Biol., 4, 287-291). PP2A is a family of trimeric holoenzymes which consist of a 36-kDa catalytic subunit (PP2Ac) bound to the constant regulatory subunit of 65 kDa (PR65/A) which then further associate with the third, variable regulatory subunit. Several trimeric PP2A holoenzymes have been purified which contain different variable subunits of either 54, 55, 72 or 74 kDa.
As documented by in vitro reconstitution assays and by analysing yeast and Drosophila mutants deficient in regulatory proteins, both constant and variable subunits are important for controlling PP2A activity and substrate specificity. For instance, PP2A activity from brain extracts of Drosophila aar.sup.r mutants, in which the gene encoding PR55 has been disrupted by P-element insertion, is several fold lower towards histone H1 and caldesmon phosphorylated by p342.sup.cdc2 as compared to wild type flies. In contrast, phosphorylase phosphatase activity of PP2A is similar in aar.sup.1 and control flies. The variable regulatory subunits also represent targets for potential second messengers and viral proteins. It has been demonstrated that ceramide activates only trimeric PP2A containing the PR55 subunit whereas the PP2Ac-PR65 dimer is unaffected. Recent data, however, show that neither the constant nor variable regulatory subunits are required for ceramide stimulation of PP2A activity, since both PP2Ac and PP2Ac-PR65 dimer could be stimulated by ceramide in a manner similar to that of the trimeric holoenzyme, suggesting that PP2Ac itself is a target of ceramide action. Furthermore, PP2A has also been shown to associate with transforming antigens of certain DNA tumour viruses, such as polyomavirus small t and middle T and SV40 small t. It is believed that these oncoproteins act to alter PP2A activity by displacing the normal cellular variable regulatory subunits from the trimeric holoenzyme. Some viral proteins interact only with specific forms of PP2A holoenzymes, e.g. SV40 small t antigen is able to replace only the B subunit (PR55), but not the B' subunit from trimeric PP2A. It was also shown that adenovirus E4orf4 binds to the trimeric PP2A holoenzyme that contains PR55. Taken together, these examples illustrate that activity of PP2Ac is tightly controlled in vivo by regulatory proteins.
Many components of the eukaryotic translational apparatus are known to be phosphorylated and in some cases phosphorylation has been shown to control the rate of translation. Furthermore, elongation and termination factors that directly function in maintaining translational accuracy are phosphorylated. Phosphorylation levels are also implicated in the control of translational fidelity in Schizosaccharomyces pombe since the allosuppressor gene, sal3, is allelic to cdc25, which is now known to encode a dual specificity protein phosphatase. Other examples of the involvement of protein phosphatases in the maintaining the accuracy of translation have been reported, most remarkable in this respect is the yeast translational allosuppressor SAL6, which has recently been identified as a serine/threonine protein phosphatase, termed PPQ.
A fundamental question in signal transduction is how protein kinases and protein phosphatases are regulated to phosphorylate/dephosphorylate the correct target proteins rapidly and preferentially at the correct time and place. The targeting hypothesis of Hubbard and Cohen, (1993) Trends Biochem. Sci., 81, 172-177, postulates that

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