- Research article
- Open Access
NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration
© Kwak et al; licensee BioMed Central Ltd. 2010
Received: 2 October 2010
Accepted: 10 November 2010
Published: 10 November 2010
The phosphatase PTEN governs the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway which is arguably the most important pro-survival pathway in neurons. Recently, PTEN has also been implicated in multiple important CNS functions such as neuronal differentiation, plasticity, injury and drug addiction. It has been reported that loss of PTEN protein, accompanied by Akt activation, occurs under excitotoxic conditions (stroke) as well as in Alzheimer's (AD) brains. However the molecular signals and mechanism underlying PTEN loss are unknown.
In this study, we investigated redox regulation of PTEN, namely S-nitrosylation, a covalent modification of cysteine residues by nitric oxide (NO), and H2O2-mediated oxidation. We found that S-nitrosylation of PTEN was markedly elevated in brains in the early stages of AD (MCI). Surprisingly, there was no increase in the H2O2-mediated oxidation of PTEN, a modification common in cancer cell types, in the MCI/AD brains as compared to normal aged control. Using several cultured neuronal models, we further demonstrate that S-nitrosylation, in conjunction with NO-mediated enhanced ubiquitination, regulates both the lipid phosphatase activity and protein stability of PTEN. S-nitrosylation and oxidation occur on overlapping and distinct Cys residues of PTEN. The NO signal induces PTEN protein degradation via the ubiquitin-proteasome system (UPS) through NEDD4-1-mediated ubiquitination.
This study demonstrates for the first time that NO-mediated redox regulation is the mechanism of PTEN protein degradation, which is distinguished from the H2O2-mediated PTEN oxidation, known to only inactivate the enzyme. This novel regulatory mechanism likely accounts for the PTEN loss observed in neurodegeneration such as in AD, in which NO plays a critical pathophysiological role.
PTEN, the phosphatase and tensin homologue deleted on chromosome 10, is one of the most frequently mutated tumor suppressors in human cancers. The major, and best characterized, function of PTEN is its lipid phosphatase activity which dephosphorylates PIP3 to generate PIP2, and thus antagonizes the PI3K activity in the activation of Akt [1, 2]. PTEN is expressed in almost all types of neurons  and is critical in multiple CNS functions such as neuronal differentiation and synaptogenesis [3–5], neuronal plasticity , neuronal injury (e.g., axonal branching/regeneration) [7, 8] myelin thickness of periphery nerves , and in drug addiction . Our research has focused on elucidating novel roles for PTEN in neuronal death and neurodegeneration. We and others have reported that PTEN protein levels are reduced in AD brains, accompanied by elevated Akt phosphorylation [11–13]. We hypothesize that loss of PTEN protein is a key event regulating the PI3-K/Akt signaling, arguably the most important pro-survival pathway in neurons. In this study, we aimed to investigate the underlying molecular mechanism of PTEN loss.
Studies conducted in experimental models for cancer and diabetes have shown that PTEN regulation is rather complex. Multiple mechanisms might be involved in a decrease or loss of PTEN function, in addition to gene mutation and deletion. These mechanisms may include transcription and post-translational modifications (PTMs) which include phosphorylation, acetylation, oxidation and ubiquitination . PTEN is a relatively stable protein but its stability can be reduced in certain conditions, such as zinc treatment in neurons . Phosphorylation at the S/T380-385 and T366/S370 sites influences PTEN stability as well as negatively regulating its enzymatic activity [16, 17]. Besides phosphorylation, the ubiquitin-mediated proteasomal pathway is also an important mechanism regulating PTEN protein stability. We recently identified NEDD4-1 as the first ubiquitin ligase (E3) for PTEN that regulates PTEN degradation in multiple cancer types and in neurons [15, 18].
PTEN can be acutely regulated by oxidative stress and by endogenously produced reactive oxygen species (ROS) . Oxidation of the active site cysteine residue(s) by ROS has long been recognized as a common mechanism regulating several key members of the protein tyrosine phosphatases (PTPs) including PTEN. A number of ROS species, including hydrogen peroxide (H2O2), superoxide, peroxynitrite and nitrosothiol, modify PTEN on the critical cysteine residue (C124) and inactivate its lipid phosphatase activity in multiple cancer cell lines [20–24]. To investigate the molecular mechanism(s) underlying PTEN loss in the brains of AD patients, we examined these oxidative events with a special focus on H2O2 and NO-mediated S-nitrosylation; the later, a process of reversible addition of NO to Cys-sulfur in proteins, has emerged as a major regulatory mechanism in fine-tuning many critical molecules in the neuronal death pathway and neurodegeneration . To our surprise, only NO-mediated events lead to PTEN protein degradation, though both modifications inactivate PTEN's lipid phosphatase activity in neurons. To our knowledge, this is the first report of NO being the upstream signal that leads to a series of PTMs regulating PTEN protein degradation.
S-nitrosylated PTEN levels are increased in MCI/AD brains, correlating with reduced PTEN and elevated P-Akt
Initially, we sought to investigate whether S-nitrosylated PTEN (SNO-PTEN) is produced in neurodegenerative disorders associated with high levels of nitrosative stress such as stroke, AD and Parkinson's disease (PD). We included in our tests those specimens taken from autopsy patients diagnosed at an early stage of AD, called mild cognitive impairment (MCI), and compared them to aged matched control brain specimens (i.e., patients died from disorders not related to CNS). The patient cohort and information are summarized in the table [Additional file 1].
PTEN can be S-nitrosylated in cultured neuronal cells by exogenously and endogenously generated NO
NO signal induces subsequent enhanced ubiquitination of PTEN, leading to protein degradation via UPS
SNO-PTEN likely occurs at multiple Cys residues in the phosphatase domain of PTEN, inactivating its lipid phosphatase activity
Downregulation of PTEN and elevated P-Akt levels protect neurons against Aβ-induced toxicity
PI3K/Akt is arguably the most important cell-survival signaling pathway for neurons. As the key negative regulator of the PI3K/Akt pathway, PTEN is an important target of study for neuroprotection during neurodegeneration. In this work, we are the first to demonstrate NO-mediated redox regulation as the mechanism of PTEN protein degradation. We also demonstrate that NO rapidly induces S-nitrosylation of PTEN, thereby inactivating it. Moreover, NO, but not H2O2, induces PTEN protein degradation. Loss of PTEN protein is reportedly associated with myocardial and brain ischemia [27–29], presumably as a cellular adaptive stress response to activate the pro-survival PI3K/Akt signaling. Herein, we show that PTEN loss also occurs in neurons in response to a variety of neurotoxins (e.g., glutamate and Aβ peptides) as well as in chronic neurodegenerative conditions such as AD and PD brains. Hence, our findings on NO-mediated PTEN protein degradation may represent a common mechanism underlying PTEN loss in these acute and chronic degenerative conditions, in which NO plays a critical pathophysiological role.
It is widely accepted that oxidative stress is one of the earliest changes that occurs in the pathogenesis of AD, arising from the imbalance between increased production of reactive oxygen and nitrogen species and impaired antioxidant defenses, as reflected in the accumulation of oxidative damage to macromolecules detected in MCI, the clinical precursor of AD, and AD brains [30, 31]. H2O2-induced modification and S-nitrosylation represent the two dominant oxidative events through targeted modifications of critical Cys residues in proteins. H2O2-induced PTEN oxidation was reported to cause the formation of an intra-chain disulfide bond between C71-124 , and is reflected in faster mobility species by band-shift assay on non-reducing gels (Figure 2D). SNOC did not induce a band shift of PTEN on non-denaturing gels and thus unlikely induced a major conformational change due to intra-chain disulfide bond formation. However, our mutagenesis data suggest the involvement of overlapping residues on C71 and C124. It is, therefore, reasonable to predict that these two oxidative modifications can compete with each other when both oxygen and NO species are present. Moreover, our data indicate that NO-mediated oxidation is the predominant form of PTEN in aging brains and in MCI/AD brains (Figure 1D), which may generalize to other neurodegenerative diseases such as PD.
Although our mutagenesis studies (Figure 6B) cannot determine the nitrosylated sites unambiguously, the results strongly suggest that C83 is likely the most significant physiological site of S-nitrosylation on PTEN. It is possible that multiple Cys residues are involved depending on the spatial and temporal concentrations of NO. It is well known that the C124 residue is critical for the enzymatic activity of PTEN ; mutation of this residue results in inactivation of both the protein and phospholipid lipase activities of PTEN. Our data [see additional file 3] also indicate its importance in PTEN protein stability; mutation on this Cys residue renders PTEN resistance to SNOC-induced protein degradation. It warrants further investigation of the underlying mechanisms. Structural analysis based on the solved crystal structure of PTEN  indicates that Cys83 is not in close vicinity to C124, which is located face-to-face to C71 (Figure 6D). It is therefore not yet clear mechanistically how C83, in conjunction with C71 and C124, affects the lipid phosphatase activity of PTEN.
Our results demonstrate NO-mediated PTEN protein degradation via UPS, as evidenced by enhanced ubiquitination. There are several precedents showing that protein S-nitrosylation can be functionally coupled to its ubiquitination and modulate protein degradation [34–38]. It is possible that S-nitrosylation of PTEN plays a direct causative role in its degradation, as evidenced by enhanced ubiquitination upon SNOC treatment (Figure 4A). Given the role of phosphorylation in modulating PTEN protein stability and activity previously revealed by cancer cell models [14, 38], it is also possible that NO signal induces alteration on PTEN phosphorylation status which is the cause of enhanced ubiquitination and protein degradation. Interestingly, the two putative kinases identified as responsible for phosphorylation of the two major clusters on PTEN (Ser/Thr cluster 380/382/383 and Thr366/Ser370), namely glycogen synthase kinase GSK3β and casein kinase CK2, are both implicated in neurodegeneration [39, 40]. Moreover, our unpublished data show that OA can prevent PTEN dephosphorylation to a significant extent following exposure to SNOC, suggesting that PP2A, PP1 and perhaps PP2B, all major protein phosphatases implicated in AD , may play a role in modulating PTEN stability. Thus, the detailed interplay between kinases and phosphatases warrants further investigation.
Although we made our initial observation in MCI/AD brain samples, the loss of PTEN is also reported to occur in both myocardial  and cerebral ischemia/reperfusion [28, 29]. Therefore, we believe that PTEN inhibition in these acute conditions mediates subsequent activation of PI3K/Akt signaling, which is known to be key to the endogenous protective effect, similar to the neuronal adaptive response. Paradoxically, we found that loss of PTEN occurs in human brains with AD, accompanied by elevated P-Akt in AD-affected regions. Moreover, the elevated P-Akt has often been detected in the same neuron bearing neurofibrillary tangles, which is a major pathological hallmark of AD consisting of hyperphosphorylated tau protein . Although a reduction of P-Akt was also reported by previous studies ; we repeatedly found elevated P-Akt levels in degenerating neurons in AD brains by immunohistochemistry (unpublished data), which is consistent with several other reports [11, 43]. Taken with our earlier finding that downregulated PTEN resulted in tau hyperphosphorylation and aggregation, we speculate that the loss of PTEN may be a contributing factor to neurodegeneration over the course of the disease due to chronically or excessively activated Akt signaling, which we speculate to be detrimental, as has been reported in several other chronic diseases [44, 45]. Akt is activated in samples from patients with chronic heart failure; biochemical analyses demonstrated that chronic Akt activation induces feedback inhibition . This nascent theory appears to be supported by a finding that conditional PTEN ablation in the forebrain region which caused impaired synaptic structure and function with concomitant constitutive activation of Akt and mTOR signaling . An alternative view would be that the increase in Akt signaling occurs in response to damage, as an adaptive response, but fails to reach significantly protective levels under these chronic conditions. Only future experiments will be able to distinguish between these alternatives.
In summary, our studies have demonstrated that S-nitrosylation of PTEN plays a major role in PTEN regulation in neuronal systems and that NO signaling induces S-nitrosylation and ubiquitination to modulate both PTEN protein degradation and enzymatic activity, which may represent the underlying regulatory mechanism of the PI3K/Akt signaling pathway in both acute and chronic neurodegeneration. A fuller understanding of the molecular mechanisms underlying the cascade of events leading to PTEN inhibition in both acute and chronic settings will advance our knowledge of PTEN regulation in the CNS. It may also be instrumental in future therapeutic design of novel target-based intervention in treating neurodegenerative diseases and perhaps other age-related conditions such as cancers, diabetes, cardiovascular ischemia and stroke.
Cell culture, treatment of neurotoxic reagents and transfection
Primary cultured cortical neurons (PRCN) and neuroblastoma N2a cells were prepared as described . For the majority of experiments, freshly prepared SNOC (Sigma-Aldrich, St. Louis, MO) was added at 200 μM to 2-week-old cultured neurons for 30 min. SNOC was freshly prepared as described . In brief, to prepare a 100 mM stock solution, 0.0069 g sodium nitrite and 0.0121 g l-cysteine were added to 950 μl H2O. Then, 50 μl of 10 N HCl is added to adjust pH to be 7.4. For glutamate (Sigma-Aldrich), Aβ25-35 peptides (Bachem, Torrance, CA), and staurosporine/STS (Sigma-Aldrich), neurons were treated for 4 hours before cell lysates were prepared. For suppression of NOS activity, l-NMMA (Sigma-Aldrich, 1 mM) was applied to neurons before exposure to neurotoxic reagents.
Transient transfections were performed with plasmid constructs for pEF-PTEN-WT (kindly provided by Dr. Hong Wu, UCLA, CA) and its site-directed mutagenized constructs (Cysteine to Alanine substitution).
Human patient brains
Human brain samples were provided by UCSD, San Diego, CA and were analyzed with institutional permission under California and National Institutes of Health guidelines. Informed consent was obtained following the procedures of the Institutional Review Boards of the Sanford-Burnham Institute for Medical Research.
Biotin-switch assay for detection of PTEN S-nitrosylation
A biotin switch assay for detection of SNO-PTEN was performed as previously described with minor modification . PRCN cultures were exposed to various concentrations (10, 50, 100, 200 and 300 μM) of SNOC and old SNOC for 30 min, glutamate, STS, or Aβ25-35 for 4 h.
Fluorometric measurement of S-nitrosylation of PTEN
S-nitrosylation of PTEN was measured as previously described .
Detection of H2O2-mediated oxidation-band shift assay
PTEN phosphatase assay-Malachite green assay
Recombinant PTEN, which was expressed in baculovirus, was assessed for the phosphatase activity as previously described . Enzymatic activity of PTEN was quantified as activity measured relative to the control.
Immunoprecipitation and Western blot analysis
IP-Western experiments were performed as described . The following antibodies (Abs) were used: rabbit anti-PTEN Ab (Cell Signaling, Danvers, MA, USA); goat anti-PTEN (Santa Cruz, Santa Cruz, CA); mouse anti-α-tubulin Ab (Sigma, St. Louis, MO, USA); rabbit anti-P-Akt Ab (Cell Signaling, Danvers, MA, USA); rabbit Akt 1/2/3 (Santa Cruz, Santa Cruz, CA); mouse anti-mono-poly-Ub Ab (Enzo, Plymouth Meeting, PA); rabbit anti-NEDD4 Ab (Upstate, Charlottesville. VA, USA); mouse anti-β-actin Ab (Sigma); anti-mouse IgG and anti-rabbit IgG horseradish peroxidase-conjugated Abs (Chemicon, Temecula, CA, USA).
Cycloheximide chase assay
PRCN cells were incubated with 50 μg/ml cycloheximide (Sigma, St. Louis, MO, USA) for the indicated times in the presence or absence of glutamate (200 μM). Cells were simultaneously treated with glutamate and cycloheximide. To examine whether the UPS is involved in nitrosative stress induced PTEN reduction, cells were co-treated with glutamate and 25 μM MG132. Cells lysates were then prepared for Western blot analysis.
Sindbis virus-delivered RNA interference mediated silencing of PTEN in PRCN
Three different sets of siRNAs were designed by Ambion for rat PTEN (RefSeq NM_031606, Ambion). The annealed oligonucleotides encoding siRNAs were cloned into the pIRES-enhanced RFP (Invitrogen) using EcoRI/BamHI sites and the resulting siRNA-IRES-RFP fragment was further cloned into pSin-Rep5 (Invitrogen). The efficiency and specificity of PTEN-siRNAs were then assessed by RT-PCR and western blot analysis. Virus particles were generated and infection performed in primary neurons according to the manufacturer's protocol as described previously .
Site-directed mutagenesis of PTEN
PTEN mutants were created by site-directed mutagenesis (QuikChange® II Site-Directed Mutagenesis Kits, Stratagene, La Jolla USA) at C71, C83, C105, C124, C136, C211, C218, C250, C296, C304, and its double/triple mutants with various combinations. The primers for C71A forward 5'-TTTAAAGCATAAAAACCATTACAAGATATACAA-3' and reverse 5'-GTCATAATGTCTAGCAGCAAGATTGTATAT-3'; C83A forward 5'-GACACCGCCAAATTTAATGCCAGAGTTGCACAA-3' and reverse 5'-GATATTGTGCAACTCTGGCATTAATGGCGG-3'; C105A forward 5'-GAACTTATCAAACCCTTTGCTGAAGATCTTGAC-3' and reverse 5'-CCATTGGTCAAGATCTTCAGCAAAGGGTTTGAT-3'; C124A forward 5'-CATGTTGCAATTCACGCTAAAGCTGGAAAG-3' and reverse 5'-GTCCCTTTCCAGCTTTGCGTGAATTGCTGGAATTGCTGCAA-3'; C136A forward 5'-GACGAACTGGTGTAATGATAGCCGCATATTTAT-3' and reverse 5'-CCCGATGATATAAATATGCGGCTATCATTACAC-3'; C211A forward 5'-GTTCAGTGGCGGAACTGCCAATCCTCAGTTTG-3' and reverse 5'-CACAAACTGAGGATTGGCAGTTCCGCCACTGAA-3'; C218A forward 5'-CCTCAGTTTGTGGTCGCCCAGCTAAAGGTGAA-3' and reverse 5'-CTTCACCTTTAGCTGGGCGACCACAAACTGAGC-3'; C250A forward 5'-CAGCCGTTACCTGTGGCTGGTGATATCAAAG-3' and reverse 5'-CTTTGATATCACCAGCCACAGGTAACGGCTG-3'; C296A forward 5'-TCAGAAAAAGTAGAAAATGGAAGTCTAGCTGAT-3' and reverse 5'-CAAATGCTATGGATTTCTTGATCAGCTAGACTT-3'; C304A forward 5'- CAAGAAATCAGCATTGCCAGTATAGAGCGT-3' and reverse 5'-CTGCACGCTCTATACTGGCAATGCTATCGATTT-3' were utilized for PCR amplification, respectively. PCR amplification was performed according to the company's protocol. Once single mutants were constructed, we used these mutants as a template for further construction of double/triple mutants.
Immunocytochemistry for neuronal morphology/dendritic structure and cell death (TUNEL) assays
IHC on PTEN (1:500) and MAP-2/NeuN (1:500/each) and apoptotic staining were performed as described  on two week-cultured neurons seeded on glass cover slips. In PTEN heterozygous mice were genotyped as described .
All quantitative data were presented as means ± SDV. Comparison between groups were analyzed with unpaired ANOVA using Graphpad PRIZM software (La Jolla, CA, USA) and values of p < 0.05 were considered to be significant.
We thank Dr. Dong-Hyung Cho for helpful discussion and Robert C. Thompson for excellent technical support. We also thank Drs. Xuejun Jiang and Wei Pan for providing recombinant PTEN protein. This work was partially supported by the NIH grants (R01 NS054880, AG031893 to F-F. L.; R01 AG021173, R01 NS046673 and R01 AG030197 to H.X., AG18440, AG5131, AG022074 to E. M., P01 ES016738 to S.A.L.), the grants from the Alzheimer's Association (to H.X. and F.-F.L.), and the American Health Assistance Foundation (to H.X.). Y-D K was the recipient of 2008 Young Scholar Award from Alzheimer's association San Diego/Imperial Chapter.
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