Liu F, Iqbal K, Grundke-Iqbal I, Rossie S, Gong CX.
Dephosphorylation of tau by protein phosphatase 5: impairment in Alzheimer's disease.
J Biol Chem. 2005 Jan 21;280(3):1790-6.
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Of the diverse range of posttranslational modifications of tau (reviewed by us in Chen et al., 2004), serine/threonine-directed phosphorylation and truncations are among the most intensely studied, yet the role of their relative contribution to the tau pathology in Alzheimer disease is not entirely understood. Additional light is shed on them by four recent publications which now appear in JBC (in press). These publications deal with the dephosphorylation of tau by PP5 (Gong and coworkers), Gα12-stimulated PP2A activity and dephosphorylation of tau (Brad Denker and coworkers), thrombin-mediated cleavage of tau (Patrick McGeer and coworkers), and tau phosphorylation and cleavage during apoptosis (Faraj Terro and coworkers). A combination of studies with recombinant proteins, tissue culture experiments and the analysis of human brain section aims to dissect the role of these modifications (and the enzymes responsible for them) under both physiologic and pathologic conditions. As several enzymes seem able to phosphorylate or truncate tau (although to different degrees at different sites), questions remain. For example, how specific are these reactions and how do enzymatic activities overlap? As Gong and coworkers point out for activities of the two phosphatases PP2A and PP5 with respect to tau, "these studies suggest that tau phosphorylation can be regulated by more than one phosphatase, and that each phosphatase may regulate tau phosphorylation at different sites with a certain preference." This even points to the possibility that conditions may vary for different cell types and different metabolic conditions, a question not much addressed in the past. In addition, in the living organism, the situation may be different from those in tissue culture or cell-free extracts. When we used a dominant negative mutant approach to interfere with PP2A function, we found that only two epitopes, the AT8 and the pS422 epitope, were hyperphosphorylated, much different from the in vitro situation (Kins et al., 2001). We recently confirmed these findings with a new transgenic mouse strain. In addition, PP2A (and possibly also PP5) may not only act directly on tau, but also indirectly, by activating distinct kinases (Pei et al., 2003 and Kins et al., 2003).
The identification of Gα12 as a PP2A interactor is particularly interesting because Gα12 has been shown also to interact with cadherin, thereby affecting β-catenin signaling. PP2A itself is part of the wnt signaling complex composed of axin, APC, and GSK3. That the tau protease thrombin binds to Gα12 points to a complicated interplay of different cellular components that is not easy to dissect. While all of these findings should help us to understand tau pathology, one thing should be kept in mind: If tau aggregation is a seeding phenomenon, then the components that initially trigger tau aggregation (such as tau species of distinct size and a distinct phosphorylation pattern) may be underrepresented in any extract obtained from AD brains.
Chen F, David D, Ferrari A, Götz J.
Posttranslational modifications of tau--role in human tauopathies and modeling in transgenic animals.
Curr Drug Targets. 2004 Aug;5(6):503-15.
Kins S, Crameri A, Evans DR, Hemmings BA, Nitsch RM, Gotz J.
Reduced protein phosphatase 2A activity induces hyperphosphorylation and altered compartmentalization of tau in transgenic mice.
J Biol Chem. 2001 Oct 12;276(41):38193-200. Epub 2001 Jul 25
Pei JJ, Gong CX, An WL, Winblad B, Cowburn RF, Grundke-Iqbal I, Iqbal K.
Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer's disease.
Am J Pathol. 2003 Sep;163(3):845-58.
Kins S, Kurosinski P, Nitsch RM, Götz J.
Activation of the ERK and JNK signaling pathways caused by neuron-specific inhibition of PP2A in transgenic mice.
Am J Pathol. 2003 Sep;163(3):833-43.