Localization of protein Ser/Thr phosphatase 5 in rat brain

Bahl, Rimple; Bradley, Katherine C.; Thompson, Kenira J.; Swain, Rodney A.; Rossie, Sandra; Meisel, Robert L.

doi:10.1016/s0169-328x(01)00089-4

Cited by 36 publications

(36 citation statements)

References 21 publications

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“…2B). This is consistent with the fact that the PP5 antiserum recognizes the linker region between the TPR and catalytic domains rather than catalytic domain of PP5 (35). We then studied the kinetics of brain PP5 toward P-tau and found that the K m values of rat brain PP5 and human brain PP5 were similar to that of recombinant rat PP5 (Fig.…”

Section: Dephosphorylation Of Tau By Protein Phosphatasesupporting

confidence: 75%

“…It is ubiquitously expressed in all types of mammalian tissue, with a relatively high level in the brain (34,35). PP5 contains a C-terminal catalytic domain structurally related to the PP1/PP2A/PP2B family and an N-terminal regulatory domain consisting of three tetratricopeptide repeats (TPRs) that usually mediate protein-protein interaction.…”

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confidence: 99%

“…The phosphorylation-independent tau antibodies 92e and R134d and anti-PP5 antibody were raised in rabbits as described previously (35,44,45). [␥-32 P]ATP was bought from ICN Biomedicals (Costa Mesa, CA).…”

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Dephosphorylation of Tau by Protein Phosphatase 5

Liu

Iqbal

Grundke‐Iqbal

et al. 2005

Journal of Biological Chemistry

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116

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Protein phosphatase (PP) 5 is highly expressed in the mammalian brain, but few physiological substrates have yet been identified. Here, we investigated the kinetics of dephosphoryation of phospho-tau by PP5 and found that PP5 had a K m of 8 -13 M toward tau, which is similar to that of PP2A, the major known tau phosphatase. This K m value is within the range of intraneuronal tau concentration in human brain, suggesting that tau could be a physiological substrate of both PP5 and PP2A. PP5 dephosphorylated tau at all 12 Alzheimer's disease (AD)-associated abnormal phosphorylation sites studied, with different efficiency toward each site. Tau protein is a major microtubule-associated protein in neurons. The known biological function of tau protein is to stimulate and stabilize microtubule formation from tubulin subunits. In human brain, there are six tau isoforms generated by alternative mRNA splicing from a single gene (1, 2). Tau is a phosphoprotein that normally contains 2-3 phosphates/molecule, but it is abnormally hyperphosphorylated with a stoichiometry of 9 -10 moles of phosphate per mole of protein in Alzheimer's disease (AD) 1 brain (3, 4). To date, more than 30 phosphorylation sites have been identified in AD hyperphosphorylated tau, some of which are not phosphorylated in normal tau (for review, see Refs. 5 and 6). The abnormally hyperphosphorylated tau is the major component of paired helical filaments (PHFs) (7-10), which form neurofibrillary tangles, a histopathological hallmark brain lesion of AD and several other tauopathies.The hyperphosphorylation of tau appears to be responsible for the loss of its biological function, gain of its toxicity, and aggregation into PHFs (11-16). However, the molecular mechanism by which tau becomes abnormally hyperphosphorylated in AD brain is not yet well understood. Theoretically, the abnormal hyperphosphorylation of tau could be the result of up-regulation of tau kinases or down-regulation of tau phosphatases. Several studies have shown that three major protein phosphatases (PPs), PP1, PP2A, and PP2B, dephosphorylate tau in vitro (17-23). Among these, PP2A appears to be the major phosphatase that regulates tau phosphorylation in the brain (23-28). The activity of PP2A was found to be decreased in AD brain (29 -33). Nevertheless, PP2A does not dephosphorylate all the phosphorylation sites of tau, and down-regulation of PP2A in animal brain could not produce PHFs (26,28). These studies suggest that in addition to PP2A, other phosphatases or factors might also participate in the regulation of tau phosphorylation.PP5 is a 58-KDa phosphoseryl/phosphothreonyl protein phosphatase. It is ubiquitously expressed in all types of mammalian tissue, with a relatively high level in the brain (34,35). PP5 contains a C-terminal catalytic domain structurally related to the PP1/PP2A/PP2B family and an N-terminal regulatory domain consisting of three tetratricopeptide repeats (TPRs) that usually mediate protein-protein interaction. It has been demonstrated that PP5 interacts with mul...

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Section: Dephosphorylation Of Tau By Protein Phosphatasesupporting

confidence: 75%

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confidence: 99%

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Dephosphorylation of Tau by Protein Phosphatase 5

Liu

Iqbal

Grundke‐Iqbal

et al. 2005

Journal of Biological Chemistry

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116

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“…PPP has four subfamilies, which are protein phosphatases 1 (PP1), protein phosphatases 2A (PP2A), protein phosphatases 2B (PP2B, calcineurin) and protein phosphatases 5 (PP5). 18,19 We hypothesized that PP5, a 58-kDa Ser/Thr protein phosphatase, was among the likely candidate as it is ubiquitously expressed in all types of mammalian tissue, with a relatively high level in the brain, 20,21 and the transduction efficiency of AAV vectors is particularly high in the brain. 22 Furthermore, although PP5 is present in both nuclear and cytoplasmic compartments, its subcellular localization predominates in the nucleus, 19,23 a site where dephosphorylation of FKBP52 is most likely to occur.…”

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Adeno-associated virus 2-mediated gene transfer: role of a cellular serine/threonine protein phosphatase in augmenting transduction efficiency

Zhao

Zhong

et al. 2006

Gene Ther

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We have documented that a cellular chaperone protein, FKBP52, when phosphorylated at tyrosine and/or serine/ threonine (Ser/Thr) residues, interacts with the D-sequence in the inverted terminal repeats of the adeno-associated virus 2 (AAV) genome, inhibits the viral second-strand DNA synthesis, and leads to inefficient transgene expression from recombinant AAV vectors in certain cell types. We have also demonstrated that FKBP52 is dephosphorylated at tyrosine residues by T-cell protein tyrosine phosphatase (TC-PTP), and that deliberate overexpression of TC-PTP leads to more efficient viral second-strand DNA synthesis, and increased transgene expression. However, the identity of the putative Ser/Thr protein phosphatase that dephosphorylates FKBP52 at Ser/Thr residues has remained elusive. Using known inhibitors of Ser/Thr phosphatases, we have now identified protein phosphatase 5 (PP5) to be a candidate enzyme.Deliberate overexpression of PP5 in 293 cells, which does not influence cellular growth, leads to B5-fold increase in the transduction efficiency of conventional single-stranded AAV vectors, but no significant enhancement in the transduction efficiency of self-complementary AAV vectors, suggesting that PP5 plays a role in AAV second-strand DNA synthesis. Electrophoretic mobility-shift assays show that in cells overexpressing PP5, the extent of the complex formation between FKBP52 and the AAV D-sequence is significantly reduced. These studies suggest that PP5-mediated dephosphorylation of FKBP52 at Ser/Thr residues augments viral second-strand DNA synthesis and enhances AAV transduction efficiency, which has implications in the optimal use of these vectors in human gene therapy.

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“…In recent years, however, studies using phosphatase inhibitors revealed that these enzymes exert a major influence on synaptic plasticity in the cerebellum (11)(12)(13)(14)(15) and other brain structures (16,17). In the cerebellum, investigation of AMPAR regulation by PP at the GC-PC synapse represents a challenge as PCs abundantly express at least five major types of serine͞threonine PPs: PP-1, PP-2A, PP-2B, PP-2C, and PP-5 (18)(19)(20)(21)(22). In addition, PCs have the distinctive property of expressing G substrate, a PP-1, PP-2A (23)(24)(25), and possibly PP-5 inhibitory protein.…”

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confidence: 99%