Phosphoprotein Phosphatase 2A: A Novel Druggable Target for Alzheimer’s Disease

• Kidd PM . Alzheimer’s disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention.Altern. Med. Rev.13(2), 85–115 (2008).
   PubMedGoogle Scholar
• Stewart AJ , FoxA, MorimotoBH, GozesI. Looking for novel ways to treat the hallmarks of Alzheimer’s disease.Expert Opin. Investig. Drugs16(8), 1183–1196 (2007).
   PubMed Web of Science ®Google Scholar
• Seabrook GR , RayWJ, ShearmanM, HuttonM. Beyond amyloid: the next generation of Alzheimer’s disease therapeutics.Mol. Interv.7(5), 261–270 (2007).
   PubMedGoogle Scholar
• Small SA , DuffK. Linking Aβ and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis.Neuron60(4), 534–542 (2008).
   PubMed Web of Science ®Google Scholar
• Dickey CA , PetrucelliL. Current strategies for the treatment of Alzheimer’s disease and other tauopathies.Expert Opin. Ther. Targets10(5), 665–676 (2006).
   PubMed Web of Science ®Google Scholar
• Roder HM , HuttonML. Microtubule-associated protein tau as a therapeutic target in neurodegenerative disease.Expert Opin. Ther. Targets11(4), 435–442 (2007).
   PubMed Web of Science ®Google Scholar
• Schneider A , MandelkowE. Tau-based treatment strategies in neurodegenerative diseases.Neurotherapeutics5(3), 443–457 (2008).
   PubMed Web of Science ®Google Scholar
• Billingsley ML , KincaidRL. Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration.Biochem. J.323(Pt 3), 577–591 (1997).
   PubMedGoogle Scholar
• Alonso AC , ZaidiT, Grundke-IqbalI, IqbalK. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease.Proc. Natl Acad. Sci. USA91(12), 5562–5566 (1994).
   PubMed Web of Science ®Google Scholar
• Li B , ChohanMO, Grundke-IqbalI, IqbalK. Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau.Acta Neuropathol.113(5), 501–511 (2007).
   PubMed Web of Science ®Google Scholar
• Grundke-Iqbal I , IqbalK, TungYC, QuinlanM, WisniewskiHM, BinderLI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology.Proc. Natl Acad. Sci. USA83(13), 4913–4917 (1986).
   PubMed Web of Science ®Google Scholar
• Alonso A , ZaidiT, NovakM, Grundke-IqbalI, IqbalK. Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments.Proc. Natl Acad. Sci. USA98(12), 6923–6928 (2001).
   PubMed Web of Science ®Google Scholar
• Alonso AD , Di ClericoJ, LiBet al. Phosphorylation of tau at Thr212, Thr231, and Ser262 combined causes neurodegeneration. J. Biol. Chem.285(40), 30851–30860 (2010).
   PubMed Web of Science ®Google Scholar
• Mazanetz MP , FischerPM. Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases.Nat. Rev. Drug Discov.6(6), 464–479 (2007).
   PubMed Web of Science ®Google Scholar
• Bulic B , PickhardtM, KhlistunovaIet al. Rhodanine-based tau aggregation inhibitors in cell models of tauopathy. Angew Chem. Int. Ed. Engl. 46(48), 9215–9219 (2007).
   PubMed Web of Science ®Google Scholar
• Chang E , CongdonEE, HonsonNS, DuffKE, KuretJ. Structure–activity relationship of cyanine tau aggregation inhibitors.J. Med. Chem.52(11), 3539–3547 (2009).
   PubMed Web of Science ®Google Scholar
• Bulic B , PickhardtM, SchmidtB, MandelkowEM, WaldmannH, MandelkowE. Development of tau aggregation inhibitors for Alzheimer’s disease.Angew Chem. Int. Ed. Engl.48(10), 1740–1752 (2009).
   PubMed Web of Science ®Google Scholar
• Ballatore C , BrundenKR, PiscitelliFet al. Discovery of brain-penetrant, orally bioavailable aminothienopyridazine inhibitors of tau aggregation. J. Med. Chem. 53(9), 3739–3747 (2010).
   PubMed Web of Science ®Google Scholar
• Trojanowski JQ , LeeVM. Pathological tau: a loss of normal function or a gain in toxicity?Nat. Neurosci.8(9), 1136–1137 (2005).
   PubMed Web of Science ®Google Scholar
• Trojanowski JQ , SmithAB, HurynD, LeeVM. Microtubule-stabilising drugs for therapy of Alzheimer’s disease and other neurodegenerative disorders with axonal transport impairments.Expert Opin. Pharmacother.6(5), 683–686 (2005).
   PubMed Web of Science ®Google Scholar
• Wang JZ , Grundke-IqbalI, IqbalK. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration.Eur. J. Neurosci.25(1), 59–68 (2007).
   PubMed Web of Science ®Google Scholar
• Iqbal K , Grundke-IqbalI. Pharmacological approaches of neurofibrillary degeneration.Curr. Alzheimer Res.2(3), 335–341 (2005).
   PubMedGoogle Scholar
• Drewes G . MARKing tau for tangles and toxicity.Trends Biochem. Sci.29(10), 548–555 (2004).
   PubMed Web of Science ®Google Scholar
• Haddad JJ . Mitogen-activated protein kinases and the evolution of Alzheimer‘s: a revolutionary neurogenetic axis for therapeutic intervention?Prog. Neurobiol.73(5), 359–377 (2004).
   PubMed Web of Science ®Google Scholar
• Ferrer I , Gomez-IslaT, PuigBet al. Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer’s disease and tauopathies. Curr. Alzheimer Res. 2(1), 3–18 (2005).
   PubMedGoogle Scholar
• Liu F , Grundke-IqbalI, IqbalK, GongCX. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation.Eur. J. Neurosci.22(8), 1942–1950 (2005).
   PubMed Web of Science ®Google Scholar
• Tian Q , WangJ. Role of serine/threonine protein phosphatase in Alzheimer’s disease.Neurosignals11(5), 262–269 (2002).
   PubMedGoogle Scholar
• Mccluskey A , SimAT, SakoffJA. Serine-threonine protein phosphatase inhibitors: development of potential therapeutic strategies.J. Med. Chem.45(6), 1151–1175 (2002).
   PubMed Web of Science ®Google Scholar
• Combs AP . Structure-based drug design of new leads for phosphatase research.IDrugs10(2), 112–115 (2007).
   PubMedGoogle Scholar
• Lavecchia A , ColucciaA, Di Giovanni C, Novellino E. Cdc25B phosphatase inhibitors in cancer therapy: latest developments, trends and medicinal chemistry perspective. Anticancer Agents Med. Chem.8(8), 843–856 (2008).
   PubMed Web of Science ®Google Scholar
• Vogelsberg-Ragaglia V , SchuckT, TrojanowskiJQ, LeeVM. PP2A mRNA expression is quantitatively decreased in Alzheimer’s disease hippocampus.Exp. Neurol.168(2), 402–412 (2001).
   PubMed Web of Science ®Google Scholar
• Sontag E , LuangpiromA, HladikCet al. Altered expression levels of the protein phosphatase 2A ABaC enzyme are associated with Alzheimer disease pathology. J. Neuropathol. Exp. Neurol. 63(4), 287–301 (2004).
   PubMed Web of Science ®Google Scholar
• Gong CX , ShaikhS, WangJZ, ZaidiT, Grundke-IqbalI, IqbalK. Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain.J. Neurochem.65(2), 732–738 (1995).
   PubMed Web of Science ®Google Scholar
• Gong CX , SinghTJ, Grundke-IqbalI, IqbalK. Phosphoprotein phosphatase activities in Alzheimer disease brain.J. Neurochem.61(3), 921–927 (1993).
   PubMed Web of Science ®Google Scholar
• Tanimukai H , Grundke-IqbalI, IqbalK. Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer’s disease.Am. J. Pathol.166(6), 1761–1771 (2005).
   PubMed Web of Science ®Google Scholar
• Wang X , BlanchardJ, KohlbrennerEet al. The carboxy-terminal fragment of inhibitor-2 of protein phosphatase-2A induces Alzheimer disease pathology and cognitive impairment. FASEB J. 24(11), 4420–4432 (2010).
   PubMed Web of Science ®Google Scholar
• Sontag E , HladikC, MontgomeryLet al. Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis. J. Neuropathol. Exp. Neurol. 63(10), 1080–1091 (2004).
   PubMed Web of Science ®Google Scholar
• Zhou XW , GustafssonJA, TanilaHet al. Tau hyperphosphorylation correlates with reduced methylation of protein phosphatase 2A. Neurobiol. Dis. 31(3), 386–394 (2008).
   PubMed Web of Science ®Google Scholar
• Arendt T , HolzerM, FruthR, BrucknerMK, GartnerU. Paired helical filament-like phosphorylation of tau, deposition of β/A4-amyloid and memory impairment in rat induced by chronic inhibition of phosphatase 1 and 2A.Neuroscience69(3), 691–698 (1995).
   PubMed Web of Science ®Google Scholar
• Sun L , LiuSY, ZhouXWet al. Inhibition of protein phosphatase 2A- and protein phosphatase 1-induced tau hyperphosphorylation and impairment of spatial memory retention in rats. Neuroscience 118(4), 1175–1182 (2003).
   PubMed Web of Science ®Google Scholar
• Millward TA , ZolnierowiczS, HemmingsBA. Regulation of protein kinase cascades by protein phosphatase 2A.Trends Biochem. Sci.24(5), 186–191 (1999).
   PubMed Web of Science ®Google Scholar
• Lee MS , KaoSC, LemereCAet al. APP processing is regulated by cytoplasmic phosphorylation. J. Cell Biol. 163(1), 83–95 (2003).
   PubMed Web of Science ®Google Scholar
• Colombo A , BastoneA, PloiaCet al. JNK regulates APP cleavage and degradation in a model of Alzheimer’s disease. Neurobiol. Dis. 33(3), 518–525 (2009).
   PubMed Web of Science ®Google Scholar
• Braithwaite SP , SchmidRS, HeDNet al. Inhibition of c-Jun kinase provides neuroprotection in a model of Alzheimer’s disease. Neurobiol. Dis. 39(3), 311–317 (2010).
   PubMed Web of Science ®Google Scholar
• Ruvolo PP , DengX, ItoT, CarrBK, MayWS. Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A.J. Biol. Chem.274(29), 20296–20300 (1999).
   PubMed Web of Science ®Google Scholar
• Trinkle-Mulcahy L , LamondAI. Mitotic phosphatases: no longer silent partners.Curr. Opin. Cell Biol.18(6), 623–631 (2006).
   PubMed Web of Science ®Google Scholar
• Park KH , HallowsJL, ChakrabartyP, DaviesP, VincentI. Conditional neuronal simian virus 40 T antigen expression induces Alzheimer-like tau and amyloid pathology in mice.J. Neurosci.27(11), 2969–2978 (2007).
   PubMed Web of Science ®Google Scholar
• Chen Y , XuY, BaoQet al. Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40. Nat. Struct. Mol. Biol. 14(6), 527–534 (2007).
   PubMed Web of Science ®Google Scholar
• Pallas DC , ShahrikLK, MartinBLet al. Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A. Cell 60(1), 167–176 (1990).
   PubMed Web of Science ®Google Scholar
• Janssens V , GorisJ. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling.Biochem. J.353(Pt 3), 417–439 (2001).
   PubMedGoogle Scholar
• Lechward K , AwotundeOS, SwiatekW, MuszynskaG. Protein phosphatase 2A: variety of forms and diversity of functions.Acta Biochim. Pol.48(4), 921–933 (2001).
   PubMed Web of Science ®Google Scholar
• Tsujio I , ZaidiT, XuJ, KotulaL, Grundke-IqbalI, IqbalK. Inhibitors of protein phosphatase-2A from human brain structures, immunocytological localization and activities towards dephosphorylation of the Alzheimer type hyperphosphorylated tau.FEBS Lett.579(2), 363–372 (2005).
   PubMed Web of Science ®Google Scholar
• Chen J , MartinBL, BrautiganDL. Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation.Science257(5074), 1261–1264 (1992).
   PubMed Web of Science ®Google Scholar
• Lee J , StockJ. Protein phosphatase 2A catalytic subunit is methyl-esterified at its carboxyl terminus by a novel methyltransferase.J. Biol. Chem.268(26), 19192–19195 (1993).
   PubMed Web of Science ®Google Scholar
• Lee J , ChenY, TolstykhT, StockJ. A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain.Proc. Natl Acad. Sci. USA93(12), 6043–6047 (1996).
   PubMed Web of Science ®Google Scholar
• Xing Y , LiZ, ChenY, StockJB, JeffreyPD, ShiY. Structural mechanism of demethylation and inactivation of protein phosphatase 2A.Cell133(1), 154–163 (2008).
   PubMed Web of Science ®Google Scholar
• Tolstykh T , LeeJ, VafaiS, StockJB. Carboxyl methylation regulates phosphoprotein phosphatase 2A by controlling the association of regulatory B subunits.EMBO J.19(21), 5682–5691 (2000).
   PubMed Web of Science ®Google Scholar
• Wu J , TolstykhT, LeeJ, BoydK, StockJB, BroachJR. Carboxyl methylation of the phosphoprotein phosphatase 2A catalytic subunit promotes its functional association with regulatory subunits in vivo. Embo J.19(21), 5672–5681 (2000).
   PubMed Web of Science ®Google Scholar
• Cutler RG , KellyJ, StorieKet al. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc. Natl Acad. Sci. USA 101(7), 2070–2075 (2004).
   PubMed Web of Science ®Google Scholar
• Pelech S , CohenP. The protein phosphatases involved in cellular regulation. 1. Modulation of protein phosphatases-1 and 2A by histone H1, protamine, polylysine and heparin.Eur. J. Biochem.148(2), 245–251 (1985).
   PubMedGoogle Scholar
• Dobrowsky RT , KamibayashiC, MumbyMC, HannunYA. Ceramide activates heterotrimeric protein phosphatase 2A.J. Biol. Chem.268(21), 15523–15530 (1993).
   PubMed Web of Science ®Google Scholar
• Ruvolo PP , ClarkW, MumbyM, GaoF, MayWS. A functional role for the B56 α-subunit of protein phosphatase 2A in ceramide-mediated regulation of Bcl2 phosphorylation status and function.J. Biol. Chem.277(25), 22847–22852 (2002).
   PubMed Web of Science ®Google Scholar
• Chen CL , LinCF, ChiangCW, JanMS, LinYS. Lithium inhibits ceramide- and etoposide-induced protein phosphatase 2A methylation, Bcl-2 dephosphorylation, caspase-2 activation, and apoptosis.Mol. Pharmacol.70(2), 510–517 (2006).
   PubMed Web of Science ®Google Scholar
• Mukhopadhyay A , SaddoughiSA, SongPet al. Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2A activity and signaling. FASEB J. 23(3), 751–763 (2009).
   PubMed Web of Science ®Google Scholar
• Chalfant CE , SzulcZ, RoddyP, BielawskaA, HannunYA. The structural requirements for ceramide activation of serine-threonine protein phosphatases.J. Lipid Res.45(3), 496–506 (2004).
   PubMed Web of Science ®Google Scholar
• Chalfant CE , KishikawaK, MumbyMC, KamibayashiC, BielawskaA, HannunYA. Long chain ceramides activate protein phosphatase-1 and protein phosphatase-2A. Activation is stereospecific and regulated by phosphatidic acid.J. Biol. Chem.274(29), 20313–20317 (1999).
   PubMed Web of Science ®Google Scholar
• Kamibayashi C , EstesR, SlaughterC, MumbyMC. Subunit interactions control protein phosphatase 2A. Effects of limited proteolysis, N-ethylmaleimide, and heparin on the interaction of the B subunit.J. Biol. Chem.266(20), 13251–13260 (1991).
   PubMed Web of Science ®Google Scholar
• Cheng Q , EricksonAK, WangZX, KillileaSD. Stimulation of phosphorylase phosphatase activity of protein phosphatase 2A1 by protamine is ionic strength dependent and involves interaction of protamine with both substrate and enzyme.Biochemistry35(48), 15593–15600 (1996).
   PubMed Web of Science ®Google Scholar
• Matsuoka Y , NagaharaY, IkekitaM, ShinomiyaT. A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells.Br. J. Pharmacol.138(7), 1303–1312 (2003).
   PubMed Web of Science ®Google Scholar
• Liu Q , ZhaoX, FrissoraFet al. FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma. Blood 111(1), 275–284 (2008).
   PubMed Web of Science ®Google Scholar
• Habrukowich C , HanDK, LeAet al. Sphingosine interaction with acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) regulates PP2A activity and cyclooxygenase (COX)-2 expression in human endothelial cells. J. Biol. Chem. 285(35), 26825–26831 (2010).
   PubMed Web of Science ®Google Scholar
• Yoon CH , KimMJ, ParkMTet al. Activation of p38 mitogen-activated protein kinase is required for death receptor-independent caspase-8 activation and cell death in response to sphingosine. Mol. Cancer Res. 7(3), 361–370 (2009).
   PubMed Web of Science ®Google Scholar
• Leoni LM , ShihHC, DengLet al. Modulation of ceramide-activated protein phosphatase 2A activity by low molecular weight aromatic compounds. Biochem. Pharmacol. 55(7), 1105–1111 (1998).
   PubMed Web of Science ®Google Scholar
• Bauer PI , KirstenE, KunE. Mechanisms of antitumor action of methyl-3,5-diiodo-4-(4´-methoxyphenoxy)benzoate: drug-induced protein dephosphorylations and inhibition of the permissive action of ceramide on growth factor induced cell proliferation.Oncol. Rep.13(3), 465–468 (2005).
   PubMed Web of Science ®Google Scholar
• Guichard C , PedruzziE, FayMet al. Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A and promotes the endoplasmic reticulum stress response in human colon carcinoma cells. Carcinogenesis 27(9), 1812–1827 (2006).
   PubMed Web of Science ®Google Scholar
• Ricciarelli R , TasinatoA, ClementS, OzerNK, BoscoboinikD, AzziA. α-tocopherol specifically inactivates cellular protein kinase C α by changing its phosphorylation state.Biochem. J.334(Pt 1), 243–249 (1998).
   PubMedGoogle Scholar
• Kang-Woo Lee WC , JunnE, GrossoHet al. Enhanced phosphatase activity attenuates α-synucleinopathy in a mouse model. J. Neurosci. 31(19), 6963–6971 (2011).
   PubMed Web of Science ®Google Scholar
• Li Z , SemmelhackV, BraithwaiteSP, StockJB. Competition between α-tocopherol and ceramide determines protein phosphatase 2A catalytic activity. Presented AT: Society for Neuroscience Annual Meeting. San Diego, CA, USA, 13–17 November 2010.
   Google Scholar
• Usoro OB , MousaSA. Vitamin E forms in Alzheimer’s disease: a review of controversial and clinical experiences.Crit. Rev. Food Sci. Nutr.50(5), 414–419 (2010).
   PubMed Web of Science ®Google Scholar
• Chohan MO , KhatoonS, IqbalIG, IqbalK. Involvement of I2PP2A in the abnormal hyperphosphorylation of tau and its reversal by Memantine.FEBS Lett.580(16), 3973–3979 (2006).
   PubMed Web of Science ®Google Scholar
• Nishimura M , UyedaK. Purification and characterization of a novel xylulose 5-phosphate-activated protein phosphatase catalyzing dephosphorylation of fructose-6-phosphate,2-kinase:fructose-2,6-bisphosphatase.J. Biol. Chem.270(44), 26341–26346 (1995).
   PubMed Web of Science ®Google Scholar
• Van Eersel J , KeYD, LiuXet al. Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer’s disease models. Proc. Natl Acad. Sci. USA 107(31), 13888–13893 (2010).
   PubMed Web of Science ®Google Scholar
• Corcoran NM , HovensCM, MichaelM, RosenthalMA, CostelloAJ. Open-label, Phase I dose-escalation study of sodium selenate, a novel activator of PP2A, in patients with castration-resistant prostate cancer.Br. J. Cancer103(4), 462–468 (2010).
   PubMed Web of Science ®Google Scholar
• Benton D . Selenium intake, mood and other aspects of psychological functioning.Nutr. Neurosci.5(6), 363–374 (2002).
   PubMed Web of Science ®Google Scholar
• Akbaraly TN , Hininger-FavierI, CarriereIet al. Plasma selenium over time and cognitive decline in the elderly. Epidemiology 18(1), 52–58 (2007).
   PubMed Web of Science ®Google Scholar
• Cardoso BR , OngTP, Jacob-FilhoW, JaluulO, FreitasMI, CozzolinoSM. Nutritional status of selenium in Alzheimer’s disease patients.Br. J. Nutr.103(6), 803–806 (2009).
   PubMed Web of Science ®Google Scholar
• Wu Y , SongP, XuJ, ZhangM, ZouMH. Activation of protein phosphatase 2A by palmitate inhibits AMP-activated protein kinase.J. Biol. Chem.282(13), 9777–9788 (2007).
   PubMed Web of Science ®Google Scholar
• Yang X , YangY, FuZet al. Melatonin ameliorates alzheimer-like pathological changes and spatial memory retention impairment induced by calyculin A. J. Psychopharmacol. DOI: 10.1177/0269881110367723 (2010) (Epub ahead of print).
   Web of Science ®Google Scholar
• Cho DH , ChoiYJ, JoSAet al. Troglitazone acutely inhibits protein synthesis in endothelial cells via a novel mechanism involving protein phosphatase 2A-dependent p70 S6 kinase inhibition. Am. J. Physiol. Cell Physiol. 291(2), C317–C326 (2006).
   PubMed Web of Science ®Google Scholar
• Liu B , ArbogastLA. Progesterone decreases tyrosine hydroxylase phosphorylation state and increases protein phosphatase 2A activity in the stalk-median eminence on proestrous afternoon.J. Endocrinol.204(2), 209–219 (2010).
   PubMed Web of Science ®Google Scholar
• Switzer CH , RidnourLA, ChengRYet al. Dithiolethione compounds inhibit Akt signaling in human breast and lung cancer cells by increasing PP2A activity. Oncogene 28(43), 3837–3846 (2009).
   PubMed Web of Science ®Google Scholar
• Aceto N , BertinoP, BarboneDet al. Taurolidine and oxidative stress: a rationale for local treatment of mesothelioma. Eur. Respir. J. 34(6), 1399–1407 (2009).
   PubMed Web of Science ®Google Scholar
• Neviani P , SanthanamR, TrottaRet al. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell 8(5), 355–368 (2005).
   PubMed Web of Science ®Google Scholar
• Perrotti D , NevianiP. Protein phosphatase 2A (PP2A), a drugable tumor suppressor in Ph1(+) leukemias.Cancer Metastasis Rev.27(2), 159–168 (2008).
   PubMed Web of Science ®Google Scholar
• Nakashima I , LiuW, AkhandAAet al. 4-Hydroxynonenal triggers multistep signal transduction cascades for suppression of cellular functions. Mol. Aspects Med. 24(4–5), 231–238 (2003).
   PubMedGoogle Scholar
• Liu W , AkhandAA, TakedaKet al. Protein phosphatase 2A-linked and -unlinked caspase-dependent pathways for downregulation of Akt kinase triggered by 4-hydroxynonenal. Cell Death Differ. 10(7), 772–781 (2003).
   PubMed Web of Science ®Google Scholar
• Kowluru A , SeaveySE, RabagliaME, NesherR, MetzSA. Carboxylmethylation of the catalytic subunit of protein phosphatase 2A in insulin-secreting cells: evidence for functional consequences on enzyme activity and insulin secretion.Endocrinology137(6), 2315–2323 (1996).
   PubMed Web of Science ®Google Scholar
• Kitano K , NamKY, KimuraS, FujikiH, ImanishiY. Sealing effects of (-)-epigallocatechin gallate on protein kinase C and protein phosphatase 2A.Biophys. Chem.65(2–3), 157–164 (1997).
   PubMed Web of Science ®Google Scholar
• De Los Rios C , EgeaJ, Marco-ContellesJet al. Synthesis, inhibitory activity of cholinesterases, and neuroprotective profile of novel 1,8-naphthyridine derivatives. J. Med. Chem. 53(14), 5129–5143 (2010).
   PubMed Web of Science ®Google Scholar
• Altiok S , XuM, SpiegelmanBM. PPARγ induces cell cycle withdrawal: inhibition of E2F/DP DNA-binding activity via down-regulation of PP2A.Genes Dev.11(15), 1987–1998 (1997).
   PubMed Web of Science ®Google Scholar
• Norinder U , HaeberleinM. Computational approaches to the prediction of the blood-brain distribution.Adv. Drug Deliv. Rev.54(3), 291–313 (2002).
   PubMed Web of Science ®Google Scholar

Patent

• Vitek MPC, Dale J, Oddo J: US0144627 (2010).
   Google Scholar