PP2A的調(diào)控,阿茲海默的致病性和細胞信號轉(zhuǎn)導(dǎo)(精)

1、Phosphoprotein phosphatase 2A: a noveldruggable target for Alzheimers diseasePP2A structure & endogenous regulationPP2A and AD Hypothesis of PP2A in AD PP2A in cell metabolism regulationPP2A holoenzymeProtein phosphatase 2A is the most important serine/threoninephosphatases in in eukaryotic cell

2、sRegulation of PP2A B subunitsPP2/(a or卩Phosphorylati onMethylationMetal cationsRegulatory BsubuniCeramidesInhibitory peptidesPolyamines013Regulation of PP2AlPP2Al and lPP2A2 are two inhibitor proteins (subunit)PP2A1 and lPP2A2 inhibits dephosphorylation on tauRegulation of PP2A Posttranslational mo

3、dification of PP2ALeu309 carboxyl methylationPP2A methyltransferase (PPMT);PP2A methylesterase (PME)Tyr-307 phosphorylation10080604020$戈Q.dHPP2A(nM)011,0022I2PP2A (nM)1008060402000012工Regula廿on of PP2A small molecules that regulate PP2Ametal cationsMg+or Mn+ceramides Loss of PP2A function in AD brai

4、nReduced PP2A mRNA in AD brainCA3 regi on1PR55丫(weoJo Loss of PP2A function in AD brainReduced PP2A activity in AD cerebrum015 Loss of PP2A function in AD brainReduced PP2A protein in level AD cerebrum015*D CONTROL1 2 3 45 67 8AD_ CONTROL12 3 45 67 8120 jTEMPORALCONTROL ARNO AD Ve4dCONTROLARND120 -1

5、TEMPORALCONTROLARNDAD(O1U8JO Loss of PP2A function in AD brainDecreases in PP2A carboxyl methylation(PPMT) havealso been observed and may contribute to AD Loss of PP2A functionin AD brainDecreases in PP2A carboxyl methylation have also beenobserved and may contribute to AD“Anti-PHF-1Anti-PPMTAntj.PP

6、MT/PHF-l6DuoasFRONTAL*NORMAL ARND016IADFRONTAL*NORMAL ARNDAD(oco。JOADTEMPORALNORMAL ARND(OZUO3 JO %)6(otoo40 %)soAe-uogE-AeuJlenqns 0NORMAL ARNDAD Loss of PP2A function in AD brainIncreased levels of endogenous inhibitors If卩才卩in AD(b)Entorhinal cortexCAD Loss of PP2A function in AD brainPP2Atranslo

7、cate from the nucleus to the cytoplasm in ADCAD(a) Temporal cortexCADFC*宀辺：017(d)Temp:*IIP2A-#A ( (017Ausuac-叟二soo:MsuecaME-ay(e)Entorhinal cortex莎pnu0.七sod、莎pnu0l1uMaN vzddqTCHip Loss of PP2A function in AD brainl2PP2Atranslocate from the nucleus to the cytoplasm in ADtemporal cortex and hippocampu

8、snLoss of PP2A function in AD brainReduced PP2A mRNA,protein and phosphataseactivity have been observed in postmortem brains from ADpatients Increased levels of endogenous inhibitors of PP2A,along with their cleavage(l2) and redistributionDecreases in PP2A carboxyl methylation level andcorrelation w

9、ith the progression of AD pathogenesis18Anti-GFPGFPl?CTF w 于、S422 Inhibition of PP2A result in cardinal features of ADOverexpressed 12 an in vivo model result in cardinal featuresof ADTCMV H PoMinkf |flRSHpOyA R AAV4TR卜T UVJTlQI CMV H -CTF IRES HKOZHEGFP H皿八H從皿 卜01： Inhibition of PP2A result in card

10、inal features of ADOverexpressed 12 result in increased tau phosphorylationOAnti-GFP pS199 Mergedwi”rzasTT2S2I4TX3171Overexpressed 12 in vivo result in enhanced expression ofintraneuronal AB八卩一Ap*OliOverexpressed 12 in vivo result in neurodegenerationA9 weeks8 months5-nhibitionofPP2Aresu-tincardina-

11、featuresofADOkadaicAcidfoArecognizedasPP2Ainhibitivechemica-)Chronicinfusionoforecapitu-arekeyfeaturesofADT1UCTsktofc &3?LdJlyOverexpressed.2invivoresu-rtS-Total distance covered (cm)Total distance covered (cm)3550Bay,3Total distance covered (cm)Relative Intensity02468 若CREBxf S53CpnREBRelative

12、Intensity Inhibition of PP2A result in cardinal features of ADcalyculin A(PP2A specific inhibitive chemical)calyculin A injection induced tau hyperphosphophorylationInhibition of PP2A result in cardinal features of AD okadaic acidorcalyculin A treatmentandI2PP2AOverexpressionin vivo model result in

13、cardinal features ofAD, including amyloid3deposition, tauhyperphosphorylation, neurodegenera廿on and cognitivedeficits PP2A activity towards pTau1OOO I iPP1 PP2A PP2B PP5PP2A contribute to cell signaling transduction PP2A downregulate the ERK/MAP kinase pathwayPP2A can dephosphorylate and inactivate

14、MEK1 andERK-family kinasesConstitutive activation of the pathway is sufficient tocause oncogenic transformation of some cellsExpression of SV 40 small-t antigen (which inhibitsPP2A) activates MEKl and ERK, which may explain howsmall-t antigen promotes transformationProtein phosphatase 2A is a target

15、 for viruses andtoxinsto date, PP2A is the only known molecular target ofSV40 small t-antigen.U.25BJJO0:;ninn-0.801(ran%cn|nPP2A contribute to cell signaling transduction PP2A is involved in Caspase 3 dependent apoptosisPR65/A was found to be a substrate for caspase-3The induction of apoptosis activ

16、ates caspase-3, thencauses up-regulation of PP2A activity.the activated free catalytic subunit of PP2A de phosp ho ry I a tes MAP kinase; reverse active pBcl201(PP2A contribute to cell signalingj:ransduction PFprotcawomc:D0|Viitrnint ri/ylcdPP2A contribute to cell signaling transductionPP2A is requi

17、red to maintain MPF in its inactive formcAMP-dependentkinase1625582001( PP2A contribute to protein kinase regulationTable Lin vitro protein kinase substrates of protein phosphatase 2A (PP2A|Protein kinaseCommentsRef.Kinases inactivated by PP2AThe major PKA phosphatase activity in cell extracts is PP

18、2A-like 57PKB is activated/nwvo by OAPKC is dephosphorylated tjy membranessociated PP2Ap70 S6 kinase forms a stable complex with PP2ADownregulation of CaM-KII is printed by OA in vivo CaMKIV forms a stable complex vith PP2A in vivo The physiologicalAMPK phosphatase is probably PP2C RAF-1 forms a sta

19、ble complex with PP2A MEK is xtivated /nv/vo by OA and byexpression of small t antigenERK is activated in vivo by OA and by expression of small t antigenKinases activated by PP2ACasein kinaseI74GSK 3. GSK 375MST176WEE1WEE1 from mitotic extracts is phosphorylated on inhibitory sites 77Thanks for your attentionPP2A contribute to APP processing regulationGeneration of amyloid B(A0) is modulated byphosphorylation at APP-Thr-668 Th re onine 668 (T668) in the cytoplasmic domai n of APP is a