- Research article
- Open Access
Tumor suppressor PTEN affects tau phosphorylation: deficiency in the phosphatase activity of PTEN increases aggregation of an FTDP-17 mutant Tau
© Zhang et al; licensee BioMed Central Ltd. 2006
- Received: 27 April 2006
- Accepted: 31 July 2006
- Published: 31 July 2006
Aberrant hyperphosphorylation of tau protein has been implicated in a variety of neurodegenerative disorders. Although a number of protein kinases have been shown to phosphorylate tau in vitro and in vivo, the molecular mechanisms by which tau phosphorylation is regulated pathophysiologically are largely unknown. Recently, a growing body of evidence suggests a link between tau phosphorylation and PI3K signaling. In this study, phosphorylation, aggregation and binding to the microtubule of a mutant frontal temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) tau in the presence of tumor suppressor PTEN, a major regulatory component in PI3K signaling, were investigated.
Phosphorylation of the human mutant FTDP-17 tau, T40RW, was evaluated using different phospho-tau specific antibodies in the presence of human wild-type or phosphatase activity null mutant PTEN. Among the evaluated phosphorylation sites, the levels of Ser214 and Thr212 phospho-tau proteins were significantly decreased in the presence of wild-type PTEN, and significantly increased when the phosphatase activity null mutant PTEN was ectopically expressed. Fractionation of the mutant tau transfected cells revealed a significantly increased level of soluble tau in cytosol when wild-type PTEN was expressed, and an elevated level of SDS-soluble tau aggregates in the presence of the mutant PTEN. In addition, the filter/trap assays detected more SDS-insoluble mutant tau aggregates in the cells overexpressing the mutant PTEN compared to those in the cells overexpressing wild-type PTEN and control DNA. This notion was confirmed by the immunocytochemical experiment which demonstrated that the overexpression of the phosphatase activity null mutant PTEN caused the mutant tau to form aggregates in the COS-7 cells.
Tumor suppressor PTEN can alleviate the phosporylation of the mutant FTDP-17 tau at specific sites, and the phosphatase activity null PTEN increases the mutant tau phosphorylation at these sites. The changes of the tau phosphorylation status by ectopic expression of PTEN correlate to the alteration of the mutant tau's cellular distribution. In addition, the overexpression of the mutant PTEN can increase the level of the mutant tau aggregates and lead to the formation of visible aggregates in the cells.
- PI3K Signaling
- Mutant PTEN
- Tumor Suppressor PTEN
- Paired Helical Filament
Tauopathies, including Alzheimer's disease (AD), Pick's disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), argyrophilic grain disease and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), are a group of neurodegenerative disorders that are pathologically featured by intracellular neurofibrillary tangles (NFTs) [1, 2]. Although the causal role of NFTs in neurodegeneration of tauopathies is still questionable, for example, the neurons with NFTs can live for years , and the mutations of amyloid precursor protein (APP)  and presenilins  are accused of the pathogenesis of AD, the neuronal toxicity of NFTs have been implicated by a number of studies in cellular and animal tauopathy models .
The major component of NFTs is bundles of paired helical filaments (PHF) of abnormally hyperphosphorylated tau proteins . Tau is a class of microtubule-associated protein (MAP). The tau proteins are normally expressed in neuronal and glial cytoplasm including cell bodies, neurites and axons, where they bind to and stabilize microtubules [7–9]. Under normal physiological conditions, tau is phosphorylated at 2–3 serine and threonine sites before proline. In vitro studies have identified several proline-directed kinases that can phosphorylate tau at different sites, including cyclin-dependent kinase 5 (CDK5) , glycogen synthase kinase-3 (GSK-3) , mitogen-activated protein kinase (MAPK) [12, 13], protein kinase A , protein kinase (PKC) [15, 16] and Akt/protein kinase B (PKB) . In tauopathies, tau is aberrantly hyperphosphorylated, carrying 3–4 times more phosphates [18, 19]. The hyperphosphorylation of tau has been accused of causing tau dysfunction, aggregation, and likely NFT formation [20, 21]. The evidence for a causal role of abnormal tau phosphorylation and aggregation in neurodegenerative disorders was supported by the genetic analyses of the inherited FTDP-17, which led to identification of tau FTDP-17 mutations that cause the disease [22–24]. However, the molecular mechanisms by which phosphorylation of tau protein is regulated pathophysiologically are largely unknown.
Recent studies have revealed aberrant upregulation of neuronal markers for mitogenic signaling pathways in the brains of tauopathy animals and AD patients. They include Akt and the target of rapamycin (TOR) that are downstream effectors of the tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN)-regulated phosphoinositide-3 kinase (PI3K) signaling pathway, implying a link between PI3K signaling pathway and pathogenesis of AD and tauopathies [25–28]. In the PI3K signaling pathway, tumor suppressor PTEN antagonizes PI3K by dephosphorylating phosphatidylinositol (3,4,5)-triphosphate (PIP3) to regulate a variety of crucial cellular functions, including cell proliferation, migration and apoptosis [29, 30].
The tumor suppressor gene Pten, also known as MMAC1 and TEP1, has been found to be mutated in many human sporadic and hereditary cancers [31–34]. Although PTEN exhibits both protein and lipid phosphatase activity in vitro , only PIP3 has been identified as a major lipid substrate for PTEN in vivo [35, 36], leaving PTEN's protein substrate(s) unknown. Multiple lines of evidence from PTEN-null animal models have shown that PTEN is required for normal embryonic development [37–40] and that conditional inactivation of PTEN in the brain led to abnormal development of neurons [41, 42]. Recently Griffin et al. showed decreased levels and altered distribution of PTEN along with elevated PI3K signaling in the brain of AD patients . We also showed that overexpression of PTEN can affect phosphorylation of wild-type human tau at multiple sites, decrease tau aggregation and improve tau binding to microtubules in cells . Given that tau phosphorylation is harmful to neurons, these results suggest that PTEN regulates tau phosphorylation through PI3K signaling and that the loss of PTEN functions may contribute to neurodegeneration in AD.
In the present study, in order to investigate whether PTEN can affect the phosphorylation, aggregation and microtubule binding ability of mutant tau associated with tauopathy, we used an FTDP-17 missense mutant tau, R406W, which has been shown to be less soluble and less capable of binding to microtubules than wild-type tau [44, 45]. Here we demonstrate that PTEN inhibits tau phosphorylation at Akt sites, hence reducing the aggregation and promoting the binding to microtubules of an FTDP-17 mutant tau.
Overexpression of PTEN affects the FTDP-17 mutant tau phosphorylation
Dramatic changes in the levels of phospho-tau were observed when the FTDP-17 mutant tau was cotransfected with the catalyst activity null mutant PTEN. The levels of Thr212 and Ser214 phospho-tau were significantly increased by approximately 30% and 60%, respectively (Fig. 1B). Although Thr212 and Ser214 can also be phosphorylated by other kinases, including MAPK and PKC, besides Akt, the observation that the mutant tau phosphorylation at MAPK and PKC sites, such as Ser199, Ser202 and Ser262, did not exhibit any significant change in the presence of either wild-type or the mutant PTEN. This suggests that Akt, rather than MAPK and PKC, plays an important role in the mutant tau phosphorylation, and this effect can be regulated by PTEN activity.
Overexpression of PTEN affects the FTDP-17 mutant tau aggregation and cellular distribution
Overexpression of the mutant PTEN caused formation of aggregates of the mutant tau in cells
In a previous study, we found tumor suppressor PTEN regulates tau phosphorylation at multiple sites and affects tau aggregation and binding to microtubules. To further explore the role of PTEN in the pathogenesis of tauopathies, we examined phosphorylation of an FTDP-17 mutant tau in the presence of wild-type or the catalyst activity null mutant PTEN. Similar to what happened to wild-type tau , overexpression of PTEN (wild-type and the mutant) caused changes in tau phosphorylation most significantly at Akt sites, Thr212 and Ser214, suggesting that PTEN-regulated PI3K signaling also plays a role in phosphorylation of pathological tau mutants. It has been known that Ser214 is one of the major tau phosphorylation sites in NFTs whose phosphorylation interferes with the tau-microtubule interaction in vitro . Together with the previous observation that tau is heavily phosphorylated at Ser214 in NFTs concomitant with decreased levels of PTEN in AD brains [25, 43], our current results support the notion that Ser214 phosphorylation may be a crucial factor contributing to tauopathies, which can be affected by PTEN through the PI3K signaling pathway. However, since PTEN-modulated PI3K signaling also regulates other tau kinases besides Akt, the possibility that PTEN can affect tau phosphorylation at other sites through different mechanisms requires further investigation. In addition, since PTEN may exert its cellular functions independent of the PIP3 signaling pathway, e.g., inhibiting phosphorylation of transcription factor ETS-2 through MAPK , it remains possible that PTEN may affect the pathogenesis of tauopathy by a mechanism other than regulating the phosphorylation status of tau, such as by affecting tau ubiquitination and degradation.
We have previously shown that PTEN affects phosphorylation of wild-type tau at multiple sites. Here we demonstrate that PTEN affects the mutant tau most significantly at the Akt sites. This difference is likely due to the changes in the biochemical properties of tau caused by the missense FTDP-17 mutation, which may reflect the conformational/structural changes of the mutant tau, which could alter the accessibility of the mutant tau to the tau kinases and accelerate pathogenesis of tauopathy.
It has been shown that the FTDP-17 mutant tau proteins form filaments in transgenic mouse brains [52–54], and the tau filaments are stained by the AT100 antibody that detects phospho-tau at Ser214 and Thr212 [53, 55], suggesting the mutant tau is hyperphosphorylated at the Akt sites. However, it has not been clarified why FTDP-17 mutant tau proteins fail to form aggregates and exhibit less phosphorylation at certain sites compared to wild-type tau in cultured cells [44, 45, 56–58]. In this study, we were able to detect tau aggregates in the cells coexpressing the mutant tau and the phosphatase activity null PTEN, resembling the in vivo observations. Our data suggested that abnormally upregulated PI3K signaling can forcefully increase tau phosphorylation at the two Akt sites that may play a key role in the pathogenesis of tauopathies, a notion that is supported by the observation that a higher Akt activity and loss of PTEN are indeed found in postmortem AD brains [25, 43].
In this study, we demonstrate that ectopic expression of wild-type or the phosphatase activity null mutant tumor suppressor PTEN can affect the FTDP-17 tau phosphorylation at important PHF sites to regulate tau's microtubule-binding function and aggregation. Our data suggest that mutations in Pten or deficiency in its phosphatase activity may lead to pathogenesis of tauopathies. In addition, our findings provide additional support for the link between the PI3K pro-survival signaling pathway and tauopathy in neurodegeneration, and potentially assign PTEN as a potential therapeutic target for AD.
Human wild-type and mutant Pten cDNAs were subcloned into pIRES-EGFP (Invitrogen, Carlsbad, CA) to generate pIRES-Pten expression vectors. Specifically, the 1.2 kb Pten cDNA fragments were cut and collected from pEF-PtenWT and pEF-PtenCG (gifts from Dr. Hong Wu, UCLA) using EcoRI/BamHI sites. The fragments were then ligated to EcoRI/BamHI digested pIRES-EGFP to produce pIRES-EGFP-PtenWT and pIRES-EGFP-PtenCG.
Cell cultures and transfection
COS-7 cells were maintained in DMEM medium supplemented with 10% FBS and antibiotics. Cells were first transfected with the mutant tau (T40RW) and equally split, followed by a second transfection with either wild-type PTEN or the lipid phosphatase null mutant PTEN (PTEN CG), using lipofectamine (Invitrogen). In some experiments, COS-7 cells stably expressing the FTDP-17 mutant tau (T40RW) were cultured on coverslips, and then transfected with pIRES-EGFP-PtenWT or pIRES-EGFP-PtenCG.
To analyze phospho-tau, cells were homogenized in a lysis buffer containing 10 mM Tris/Cl, pH 7.4, 150 mM NaCl, 5 mM EDTA, 5 mM EGTA, 50 mM NaF, 1 mM Na3VOF3, 5 mM DTT, 1% NP-40 and a cocktail of protease inhibitors. Cell lysates were collected after brief sonication and centrifugation at 18,000 × g. Equal amounts of lysate samples were then subjected to SDS-PAGE. Proteins were transferred to PVDF membranes and probed with anti-tau antibodies: H150 (1:1000; Santa Cruz Biotechnology, Santa Cruz, CA), pS214 (1:1000; Biosource, Carlsbad, CA), pS199 (1:1000; Biosource), pT212 (1:1000; Biosource), pS396 (1:1000; Biosource), pS202 (1:1000; Biosource), pS262 (1:1000; Biosource) and pT205 (1:500; Biosource). PTEN proteins were detected using mouse anti-PTEN antibody (1:1000; Cell signaling, Danvers, MA). Tubulin was detected using anti-α-tubulin antibody (1:10000; Sigma, St. Louis, MO). The membranes were incubated with peroxidase-labeled secondary antibodies, and signals were visualized using ECL. In some experiments, Western blots were scanned and protein bands were quantified using Scion Image software.
Fractionation of transfected COS-7 Cells
COS-7 cells were cotransfected with the mutant human tau and either wild-type, the mutant human Pten, or pcDNA control. Cells were fractioned as previously described with modifications [43, 59]. Specifically, cells were harvested 48 h after transfection and homogenized in breaking buffer (0.25 M sucrose/10 mM Hepes, pH 7.2/1 mM MgOAc2/protease inhibitors mixture) by using a stainless steel ball-bearing homogenizer (18-μm clearance). Cytosol was prepared from postnuclear supernatant by ultracentrifugation for 1 h at 190,000 × g. The resulting membrane pellet was resuspended and incubated on ice for 30 min with 5 μM nocodazole, followed by ultracentrifugation for 1 h at 190,000 × g to produce post-nocodazole supernatants containing microtubule-associated tau. The generated pellets containing both membrane-associated and aggregated tau were further extracted using 100 mM sodium carbonate buffer (pH 11.5) at 4°C for 30 min. The post-Na2CO3 pellets were prepared by ultracentrifugation at 190,000 × g for 1 h and washed with 1% SDS to produce a fraction containing tau aggregates. Aliquots containing equal amounts of protein were analyzed by SDS/PAGE-Western blotting for tau using H150. Western blotting results were quantified by densitometry to determine the tau level in each fraction.
Filter/trap assays for tau aggregates
The filter/trap assays were performed as described previously with minor modification [43, 59]. Specifically, COS-7 cells expressing the FTDP-17 mutant human tau were transfected with human wild-type Pten, the mutant Pten or pcDNA control. Cells were lysed in a buffer containing 0.5% Nonidet P-40/1 mM EDTA/50 mM Tris HCl, pH 8.0/120 mM NaCl/protease inhibitors mixture. After brief sonication, cell lysates were passed through a cellulose acetate membrane (0.2 μm; Bio-Rad, Hercules, CA) using Bio-Dot Microfiltration Apparatus (Bio-Rad) and washed three times with 1% SDS followed by immunoblotting using H150 antibody. Quantitative Western blot analyses were used to determine the level of tau aggregates in each sample.
To stain tau and tubulin in pIRES-EGFP-Pten transfected COS-7 cells that stably express the mutant human tau (T40RW), cells on coverslips were fixed in 4% paraformadelhyde (PFA)/PBS for 15 min followed by washing with PBS 5 times at 5 min each. Cells were then permeabilized with 0.1% Triton X-100 in PBS for 10 min before blocking with 5% BSA/PBS for 30 min. After washing with PBS, cells were incubated with anti-tau antibody, H150 (1:200; Santa Cruz Biotechnology) and anti-α-tubulin antibody (1:2000; Sigma) in 5% BSA/PBS for 2 hrs. Cells were then washed and incubated with 7-amino-4-methylcoumarin-3-acetic acid (AMCA)-conjugated anti-mouse IgG (1:300; Invitrogen) and Alexa Fluor 594-conjugated anti-rabbit IgG (Invitrogen; 1:300) for 1 h. The coverslips were then washed and mounted on slides. All procedures were performed at room temperature. Images were visualized and taken using deconvolution microscopy (Zeiss Axiovert 100 M).
We thank Dr. Chengxin Gong for technical assistance. This work was supported in part by National Institutes of Health grants (R01 NS046673 to H.X., R01 AG024895 to H.X., R01 NS054880 to F.F.L., R01 DC006497 to Z.Z., AG05131 and K12-AG00975 to G.T.), and by grants from the Alzheimer's Association (to H.X., and Z.Z.) and American Health Assistance Foundation (to H.X.). Y.Z. is the recipient of National Institutes of Health training grant F32 AG024895.
- Trojanowski JQ, Lee VM: "Fatal attractions" of proteins. A comprehensive hypothetical mechanism underlying Alzheimer's disease and other neurodegenerative disorders. Ann N Y Acad Sci. 2000, 924: 62-67.View ArticlePubMedGoogle Scholar
- Lee VM, Goedert M, Trojanowski JQ: Neurodegenerative tauopathies. Annu Rev Neurosci. 2001, 24: 1121-1159. 10.1146/annurev.neuro.24.1.1121.View ArticlePubMedGoogle Scholar
- Morsch R, Simon W, Coleman PD: Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol. 1999, 58: 188-197.View ArticlePubMedGoogle Scholar
- Zheng H, Koo EH: The amyloid precursor protein: beyond amyloid. Mol Neurodegeneration. 2006, 1:Google Scholar
- Vetrivel KS, Zhang Y, Xu H, Thinakaran G: Pathological and physiological functions of presenilins. Mol Neurodegeneration. 2006, 1:Google Scholar
- Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI: Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986, 83: 4913-4917. 10.1073/pnas.83.13.4913.PubMed CentralView ArticlePubMedGoogle Scholar
- Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW: A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A. 1975, 72: 1858-1862. 10.1073/pnas.72.5.1858.PubMed CentralView ArticlePubMedGoogle Scholar
- Cleveland DW, Hwo SY, Kirschner MW: Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J Mol Biol. 1977, 116: 207-225. 10.1016/0022-2836(77)90213-3.View ArticlePubMedGoogle Scholar
- Cleveland DW, Hwo SY, Kirschner MW: Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. J Mol Biol. 1977, 116: 227-247. 10.1016/0022-2836(77)90214-5.View ArticlePubMedGoogle Scholar
- Baumann K, Mandelkow EM, Biernat J, Piwnica-Worms H, Mandelkow E: Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett. 1993, 336: 417-424. 10.1016/0014-5793(93)80849-P.View ArticlePubMedGoogle Scholar
- Hanger DP, Hughes K, Woodgett JR, Brion JP, Anderton BH: Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci Lett. 1992, 147: 58-62. 10.1016/0304-3940(92)90774-2.View ArticlePubMedGoogle Scholar
- Roder HM, Ingram VM: Two novel kinases phosphorylate tau and the KSP site of heavy neurofilament subunits in high stoichiometric ratios. J Neurosci. 1991, 11: 3325-3343.PubMedGoogle Scholar
- Roder HM, Eden PA, Ingram VM: Brain protein kinase PK40erk converts TAU into a PHF-like form as found in Alzheimer's disease. Biochem Biophys Res Commun. 1993, 193: 639-647. 10.1006/bbrc.1993.1672.View ArticlePubMedGoogle Scholar
- Robertson J, Loviny TL, Goedert M, Jakes R, Murray KJ, Anderton BH, Hanger DP: Phosphorylation of tau by cyclic-AMP-dependent protein kinase. Dementia. 1993, 4: 256-263.PubMedGoogle Scholar
- Baudier J, Cole RD: Phosphorylation of tau proteins to a state like that in Alzheimer's brain is catalyzed by a calcium/calmodulin-dependent kinase and modulated by phospholipids. J Biol Chem. 1987, 262: 17577-17583.PubMedGoogle Scholar
- Baudier J, Lee SH, Cole RD: Separation of the different microtubule-associated tau protein species from bovine brain and their mode II phosphorylation by Ca2+/phospholipid-dependent protein kinase C. J Biol Chem. 1987, 262: 17584-17590.PubMedGoogle Scholar
- Ksiezak-Reding H, Pyo HK, Feinstein B, Pasinetti GM: Akt/PKB kinase phosphorylates separately Thr212 and Ser214 of tau protein in vitro. Biochim Biophys Acta. 2003, 1639: 159-168.View ArticlePubMedGoogle Scholar
- Kopke E, Tung YC, Shaikh S, Alonso AC, Iqbal K, Grundke-Iqbal I: Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem. 1993, 268: 24374-24384.PubMedGoogle Scholar
- Kenessey A, Yen SH: The extent of phosphorylation of fetal tau is comparable to that of PHF-tau from Alzheimer paired helical filaments. Brain Res. 1993, 629: 40-46. 10.1016/0006-8993(93)90478-6.View ArticlePubMedGoogle Scholar
- Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K: Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci U S A. 1994, 91: 5562-5566. 10.1073/pnas.91.12.5562.PubMed CentralView ArticlePubMedGoogle Scholar
- Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K: Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A. 2001, 98: 6923-6928. 10.1073/pnas.121119298.PubMed CentralView ArticlePubMedGoogle Scholar
- Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P: Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998, 393: 702-705. 10.1038/31508.View ArticlePubMedGoogle Scholar
- Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD: Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998, 43: 815-825. 10.1002/ana.410430617.View ArticlePubMedGoogle Scholar
- Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B: Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A. 1998, 95: 7737-7741. 10.1073/pnas.95.13.7737.PubMed CentralView ArticlePubMedGoogle Scholar
- Griffin RJ, Moloney A, Kelliher M, Johnston JA, Ravid R, Dockery P, O'Connor R, O'Neill C: Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology. J Neurochem. 2005, 93: 105-117. 10.1111/j.1471-4159.2004.02949.x.View ArticlePubMedGoogle Scholar
- Li X, An WL, Alafuzoff I, Soininen H, Winblad B, Pei JJ: Phosphorylated eukaryotic translation factor 4E is elevated in Alzheimer brain. Neuroreport. 2004, 15: 2237-2240. 10.1097/00001756-200410050-00019.View ArticlePubMedGoogle Scholar
- An WL, Cowburn RF, Li L, Braak H, Alafuzoff I, Iqbal K, Iqbal IG, Winblad B, Pei JJ: Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease. Am J Pathol. 2003, 163: 591-607.PubMed CentralView ArticlePubMedGoogle Scholar
- Khurana V, Lu Y, Steinhilb ML, Oldham S, Shulman JM, Feany MB: TOR-Mediated Cell-Cycle Activation Causes Neurodegeneration in a Drosophila Tauopathy Model. Curr Biol. 2006, 16: 230-241. 10.1016/j.cub.2005.12.042.View ArticlePubMedGoogle Scholar
- Stiles B, Groszer M, Wang S, Jiao J, Wu H: PTENless means more. Dev Biol. 2004, 273: 175-184. 10.1016/j.ydbio.2004.06.008.View ArticlePubMedGoogle Scholar
- Sulis ML, Parsons R: PTEN: from pathology to biology. Trends Cell Biol. 2003, 13: 478-483. 10.1016/S0962-8924(03)00175-2.View ArticlePubMedGoogle Scholar
- Stokoe D: Pten. Curr Biol. 2001, 11: R502-10.1016/S0960-9822(01)00303-7.View ArticlePubMedGoogle Scholar
- Li DM, Sun H: TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res. 1997, 57: 2124-2129.PubMedGoogle Scholar
- Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997, 275: 1943-1947. 10.1126/science.275.5308.1943.View ArticlePubMedGoogle Scholar
- Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV: Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997, 15: 356-362. 10.1038/ng0497-356.View ArticlePubMedGoogle Scholar
- Maehama T, Dixon JE: The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998, 273: 13375-13378. 10.1074/jbc.273.22.13375.View ArticlePubMedGoogle Scholar
- Cantley LC, Neel BG: New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A. 1999, 96: 4240-4245. 10.1073/pnas.96.8.4240.PubMed CentralView ArticlePubMedGoogle Scholar
- Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP: Pten is essential for embryonic development and tumour suppression. Nat Genet. 1998, 19: 348-355. 10.1038/1235.View ArticlePubMedGoogle Scholar
- Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, Cordon-Cardo C, Catoretti G, Fisher PE, Parsons R: Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A. 1999, 96: 1563-1568. 10.1073/pnas.96.4.1563.PubMed CentralView ArticlePubMedGoogle Scholar
- Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW: Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998, 95: 29-39. 10.1016/S0092-8674(00)81780-8.View ArticlePubMedGoogle Scholar
- Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I, Ho A, Wakeham A, Itie A, Khoo W, Fukumoto M, Mak TW: High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol. 1998, 8: 1169-1178. 10.1016/S0960-9822(07)00488-5.View ArticlePubMedGoogle Scholar
- Kwon CH, Zhu X, Zhang J, Knoop LL, Tharp R, Smeyne RJ, Eberhart CG, Burger PC, Baker SJ: Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Nat Genet. 2001, 29: 404-411. 10.1038/ng781.View ArticlePubMedGoogle Scholar
- Fraser MM, Zhu X, Kwon CH, Uhlmann EJ, Gutmann DH, Baker SJ: Pten loss causes hypertrophy and increased proliferation of astrocytes in vivo. Cancer Res. 2004, 64: 7773-7779. 10.1158/0008-5472.CAN-04-2487.View ArticlePubMedGoogle Scholar
- Zhang X, Li F, Bulloj A, Zhang Y, Tong G, Zhang Z, Liao F, Xu H: Tumor suppressor PTEN affects tau phosphorylation, aggregation and binding to microtubules. FASEB J. 2006, In Press:Google Scholar
- Perez M, Lim F, Arrasate M, Avila J: The FTDP-17-linked mutation R406W abolishes the interaction of phosphorylated tau with microtubules. J Neurochem. 2000, 74: 2583-2589. 10.1046/j.1471-4159.2000.0742583.x.View ArticlePubMedGoogle Scholar
- Vogelsberg-Ragaglia V, Bruce J, Richter-Landsberg C, Zhang B, Hong M, Trojanowski JQ, Lee VM: Distinct FTDP-17 missense mutations in tau produce tau aggregates and other pathological phenotypes in transfected CHO cells. Mol Biol Cell. 2000, 11: 4093-4104.PubMed CentralView ArticlePubMedGoogle Scholar
- Reed LA, Grabowski TJ, Schmidt ML, Morris JC, Goate A, Solodkin A, Van Hoesen GW, Schelper RL, Talbot CJ, Wragg MA, Trojanowski JQ: Autosomal dominant dementia with widespread neurofibrillary tangles. Ann Neurol. 1997, 42: 564-572. 10.1002/ana.410420406.View ArticlePubMedGoogle Scholar
- Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP, Tonks NK: The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A. 1998, 95: 13513-13518. 10.1073/pnas.95.23.13513.PubMed CentralView ArticlePubMedGoogle Scholar
- Wang X, Gjorloff-Wingren A, Saxena M, Pathan N, Reed JC, Mustelin T: The tumor suppressor PTEN regulates T cell survival and antigen receptor signaling by acting as a phosphatidylinositol 3-phosphatase. J Immunol. 2000, 164: 1934-1939.View ArticlePubMedGoogle Scholar
- Liu F, Grundke-Iqbal I, Iqbal K, Gong CX: Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci. 2005, 22: 1942-1950. 10.1111/j.1460-9568.2005.04391.x.View ArticlePubMedGoogle Scholar
- Illenberger S, Zheng-Fischhofer Q, Preuss U, Stamer K, Baumann K, Trinczek B, Biernat J, Godemann R, Mandelkow EM, Mandelkow E: The endogenous and cell cycle-dependent phosphorylation of tau protein in living cells: implications for Alzheimer's disease. Mol Biol Cell. 1998, 9: 1495-1512.PubMed CentralView ArticlePubMedGoogle Scholar
- Weng LP, Brown JL, Baker KM, Ostrowski MC, Eng C: PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway. Hum Mol Genet. 2002, 11: 1687-1696. 10.1093/hmg/11.15.1687.View ArticlePubMedGoogle Scholar
- Tatebayashi Y, Miyasaka T, Chui DH, Akagi T, Mishima K, Iwasaki K, Fujiwara M, Tanemura K, Murayama M, Ishiguro K, Planel E, Sato S, Hashikawa T, Takashima A: Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau. Proc Natl Acad Sci U S A. 2002, 99: 13896-13901. 10.1073/pnas.202205599.PubMed CentralView ArticlePubMedGoogle Scholar
- Gotz J, Chen F, Barmettler R, Nitsch RM: Tau filament formation in transgenic mice expressing P301L tau. J Biol Chem. 2001, 276: 529-534. 10.1074/jbc.M006531200.View ArticlePubMedGoogle Scholar
- Lim F, Hernandez F, Lucas JJ, Gomez-Ramos P, Moran MA, Avila J: FTDP-17 mutations in tau transgenic mice provoke lysosomal abnormalities and Tau filaments in forebrain. Mol Cell Neurosci. 2001, 18: 702-714. 10.1006/mcne.2001.1051.View ArticlePubMedGoogle Scholar
- Gotz J, Tolnay M, Barmettler R, Chen F, Probst A, Nitsch RM: Oligodendroglial tau filament formation in transgenic mice expressing G272V tau. Eur J Neurosci. 2001, 13: 2131-2140. 10.1046/j.0953-816x.2001.01604.x.View ArticlePubMedGoogle Scholar
- Matsumura N, Yamazaki T, Ihara Y: Stable expression in Chinese hamster ovary cells of mutated tau genes causing frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Am J Pathol. 1999, 154: 1649-1656.PubMed CentralView ArticlePubMedGoogle Scholar
- Mack TG, Dayanandan R, Van Slegtenhorst M, Whone A, Hutton M, Lovestone S, Anderton BH: Tau proteins with frontotemporal dementia-17 mutations have both altered expression levels and phosphorylation profiles in differentiated neuroblastoma cells. Neuroscience. 2001, 108: 701-712. 10.1016/S0306-4522(01)00434-1.View ArticlePubMedGoogle Scholar
- DeTure M, Ko LW, Easson C, Yen SH: Tau assembly in inducible transfectants expressing wild-type or FTDP-17 tau. Am J Pathol. 2002, 161: 1711-1722.PubMed CentralView ArticlePubMedGoogle Scholar
- Dou F, Netzer WJ, Tanemura K, Li F, Hartl FU, Takashima A, Gouras GK, Greengard P, Xu H: Chaperones increase association of tau protein with microtubules. Proc Natl Acad Sci U S A. 2003, 100: 721-726. 10.1073/pnas.242720499.PubMed CentralView ArticlePubMedGoogle Scholar
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