Ser396
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Home > Phosphorylation Site Page: > Ser396  -  Tau iso8 (human)

Site Information
GAEIVyKsPVVsGDt   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 449081

In vivo Characterization
Methods used to characterize site in vivo:
2D analysis ( 65 , 67 ) , electrophoretic mobility shift ( 45 ) , immunoassay ( 2 ) , mass spectrometry ( 17 , 31 , 36 , 49 , 65 ) , microscopy-colocalization with upstream kinase ( 58 ) , mutation of modification site ( 3 , 22 , 23 , 25 , 30 , 43 , 45 , 70 ) , peptide sequencing ( 57 ) , phospho-antibody ( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 18 , 23 , 24 , 26 , 27 , 28 , 29 , 31 , 32 , 33 , 34 , 37 , 38 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 51 , 53 , 54 , 55 , 56 , 58 , 60 , 61 , 63 , 66 , 69 , 70 ) , western blotting ( 1 , 2 , 3 , 4 , 5 , 6 , 10 , 12 , 13 , 14 , 15 , 16 , 18 , 23 , 24 , 25 , 27 , 28 , 29 , 32 , 34 , 37 , 38 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 48 , 51 , 55 , 57 , 58 , 63 , 65 , 66 , 69 , 70 )
Disease tissue studied:
Alzheimer's disease ( 7 , 11 , 16 , 17 , 23 , 24 , 26 , 27 , 28 , 36 , 44 , 58 , 60 , 65 ) , adrenal cancer ( 22 , 53 ) , pheochromocytoma ( 22 , 53 ) , brain cancer ( 58 ) , glioma ( 58 ) , neuroblastoma ( 1 , 38 , 40 , 45 , 63 , 66 , 67 ) , melanoma skin cancer ( 18 ) , diabetes mellitus ( 27 ) , type 2 diabetes ( 27 ) , PSP ( 31 , 48 )
Relevant cell line - cell type - tissue:
'brain, brainstem' ( 32 , 55 ) , 'brain, caudate-putamen' ( 48 ) , 'brain, cerebellum' ( 28 ) , 'brain, cerebral cortex' ( 3 , 44 , 48 , 49 , 55 ) , 'brain, embryonic' ( 69 ) , 'brain, hippocampus' ( 3 , 32 , 61 ) , 'brain, hippocampus, dentate gyrus' ( 4 ) , 'brain, striatum' ( 48 ) , 'neuron, cortical' ( 34 ) , 'neuron, cortical'-brain ( 14 ) , 'neuron, striatal'-brain ( 14 ) , 293 (epithelial) ( 3 , 5 , 12 , 13 , 16 , 25 , 29 , 43 , 54 ) , astrocyte ( 2 ) , brain ( 5 , 7 , 10 , 15 , 17 , 27 , 31 , 36 , 51 , 65 , 69 , 70 ) , brain [Tau iso8 (human)] ( 37 , 42 ) , cerebrospinal fluid ( 60 ) , CHO (fibroblast) [Tau (human), transfection] ( 67 ) , CHO (fibroblast) [Tau iso8 (human)] ( 41 ) , CHO (fibroblast) ( 22 , 24 , 38 , 46 , 57 , 70 ) , COS (fibroblast) ( 44 , 45 ) , E.coli (bacterial) ( 30 ) , H4 (glial) ( 58 ) , HEK293T (epithelial) ( 6 ) , HeLa (cervical) ( 18 , 33 ) , LAN-5 (neural crest) ( 66 , 67 ) , microglia ( 2 ) , Neuro-2a (neuron) ( 66 ) , neuron ( 2 ) , neuron-'brain, cerebral cortex' ( 11 ) , neuron-'brain, hippocampus' ( 3 , 18 , 23 , 26 , 45 ) , NPC (neural crest) ( 2 ) , PC-12 (chromaffin) ( 22 , 53 ) , SH-SY5Y (neural crest) ( 1 , 38 , 40 , 45 , 47 , 63 ) , spinal cord ( 4 )

Upstream Regulation
Regulatory protein:
APP (human) ( 32 ) , CDC37 (human) ( 18 ) , CDK5R1 (mouse) ( 55 ) , ERK5 (human) ( 63 ) , JNK1 (human) ( 45 , 57 ) , MEK5 (human) ( 63 ) , P38G (human) ( 63 ) , PTPRA (human) ( 13 ) , RASD1 (human) ( 29 ) , RXRA (mouse) ( 41 ) , SET (mouse) ( 3 ) , SPAG5 (human) ( 33 ) , Tau iso8 (human) ( 23 , 38 , 42 ) , TEBP (human) ( 18 )
Putative in vivo kinases:
CDK5 (mouse) ( 55 ) , CK1D (human) ( 54 ) , DYRK1A (human) ( 6 ) , GSK3A (human) ( 25 ) , GSK3B (human) ( 24 , 25 , 33 , 45 ) , JNK1 (human) ( 45 )
Kinases, in vitro:
AMPKA1 (human) ( 20 ) , CAMK2A (rat) ( 68 ) , CDK5 (human) ( 39 , 59 , 62 ) , CK1D (human) ( 54 ) , DYRK1A (human) ( 6 ) , DYRK1A (rat) ( 35 ) , ERK1 (human) ( 67 ) , ERK2 (human) ( 67 ) , GSK3A (cow) ( 68 ) , GSK3B (human) ( 21 , 35 , 39 , 50 , 59 , 64 ) , MARK1 (human) ( 20 ) , P38D (human) ( 63 ) , P38G (human) ( 63 ) , PKCA (rat) ( 68 )
Phosphatases, in vitro:
PPP2CA (human) ( 24 )
Treatments:
anisomycin ( 63 ) , arsenite ( 57 ) , chloroquine ( 46 ) , colforsin ( 16 ) , development ( 37 ) , doxycycline ( 58 ) , FK506 ( 37 ) , GW_9662 ( 41 ) , IC261 ( 54 ) , JNK_inhibitor_I ( 41 ) , kenpaullone ( 57 ) , lithium ( 33 , 34 , 40 , 45 , 47 , 57 ) , low_glucose ( 53 ) , LY294002 ( 41 ) , MG132 ( 46 ) , MK-591 ( 15 ) , mutation ( 52 ) , nocodazole ( 45 ) , okadaic_acid ( 13 , 16 , 34 , 53 , 57 ) , olomoucine ( 57 ) , PD98059 ( 47 ) , pioglitazone ( 41 ) , PUGNAc ( 53 ) , rolipram ( 5 ) , SB202190 ( 63 ) , SB203580 ( 45 , 57 ) , SB216763 ( 40 ) , seliciclib ( 45 , 57 ) , siRNA ( 29 ) , sorbitol ( 63 ) , SP600125 ( 45 ) , staurosporine ( 63 ) , streptozotocin ( 53 ) , T0070907 ( 41 ) , tanespimycin ( 46 ) , taxol ( 45 ) , triciribine ( 41 ) , troglitazone ( 41 ) , tungstate ( 47 ) , U0126 ( 57 ) , wortmannin ( 41 )

Downstream Regulation
Effects of modification on Tau iso8:
intracellular localization ( 58 ) , molecular association, regulation ( 43 , 52 , 54 , 61 , 62 , 70 ) , O-GlcNAc glycosylation ( 28 ) , phosphorylation ( 43 ) , protein conformation ( 16 , 30 ) , protein processing ( 50 )
Effects of modification on biological processes:
cytoskeletal reorganization ( 30 , 35 , 43 , 58 , 61 , 62 , 70 )
Induce interaction with:
Tau iso8 (human) ( 43 , 52 )
Inhibit interaction with:
TUBA1A (cow) ( 62 ) , TUBA4A (human) ( 43 ) , TUBB (cow) ( 62 ) , TUBB (human) ( 70 )

Disease / Diagnostics Relevance
Relevant diseases:
Alzheimer's disease ( 2 , 4 , 9 , 14 , 17 , 26 , 27 , 28 , 30 , 60 , 61 , 65 , 70 ) , ALS ( 69 ) , DLB ( 14 ) , type 2 diabetes ( 27 ) , Down syndrome ( 9 ) , Parkinson's disease ( 14 , 69 ) , PSP ( 31 )

References 

1

Li J, Chen W, Yi Y, Tong Q (2018) miR-219-5p inhibits tau phosphorylation by targeting TTBK1 and GSK-3β in Alzheimer's disease. J Cell Biochem
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2

Park J, et al. (2018) A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer's disease. Nat Neurosci 21, 941-951
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3

Zhang Q, et al. (2018) CK2 Phosphorylating I/SET Mediates Tau Pathology and Cognitive Impairment. Front Mol Neurosci 11, 146
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4

Le Pichon CE, et al. (2017) Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease. Sci Transl Med 9
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5

Myeku N, et al. (2016) Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat Med 22, 46-53
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6

Jin N, et al. (2015) Truncation and Activation of Dual Specificity Tyrosine Phosphorylation-regulated Kinase 1A by Calpain I: A MOLECULAR MECHANISM LINKED TO TAU PATHOLOGY IN ALZHEIMER DISEASE. J Biol Chem 290, 15219-37
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7

Day RJ, et al. (2015) Caspase-Cleaved Tau Co-Localizes with Early Tangle Markers in the Human Vascular Dementia Brain. PLoS One 10, e0132637
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8

Luo HB, et al. (2014) SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination. Proc Natl Acad Sci U S A 111, 16586-91
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9

Mondragón-Rodríguez S, et al. (2014) Phosphorylation of tau protein at sites Ser(396-404) is one of the earliest events in Alzheimer's disease and Down syndrome. Neuropathol Appl Neurobiol 40, 121-35
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10

Bailey RM, et al. (2013) LRRK2 phosphorylates novel tau epitopes and promotes tauopathy. Acta Neuropathol 126, 809-27
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11

Yanamandra K, et al. (2013) Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 80, 402-14
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12

Yu G, et al. (2013) Ser9 phosphorylation causes cytoplasmic detention of I2PP2A/SET in Alzheimer disease. Neurobiol Aging 34, 1748-58
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13

Luo Y, et al. (2013) PTPA activates protein phosphatase-2A through reducing its phosphorylation at tyrosine-307 with upregulation of protein tyrosine phosphatase 1B. Biochim Biophys Acta 1833, 1235-43
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14

Duka V, et al. (2013) Identification of the sites of tau hyperphosphorylation and activation of tau kinases in synucleinopathies and Alzheimer's diseases. PLoS One 8, e75025
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15

Chu J, Lauretti E, Di Meco A, Praticò D (2013) FLAP pharmacological blockade modulates metabolism of endogenous tau in vivo . Transl Psychiatry 3, e333
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16

Tak H, et al. (2013) Bimolecular fluorescence complementation; lighting-up tau-tau interaction in living cells. PLoS One 8, e81682
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17

Rudrabhatla P, Jaffe H, Pant HC (2011) Direct evidence of phosphorylated neuronal intermediate filament proteins in neurofibrillary tangles (NFTs): phosphoproteomics of Alzheimer's NFTs. FASEB J 25, 3896-905
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18

Jinwal UK, et al. (2011) The Hsp90 kinase co-chaperone Cdc37 regulates tau stability and phosphorylation dynamics. J Biol Chem 286, 16976-83
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19

Yuzwa SA, et al. (2011) Mapping O-GlcNAc modification sites on tau and generation of a site-specific O-GlcNAc tau antibody. Amino Acids 40, 857-68
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20

Thornton C, et al. (2011) AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid β-peptide exposure. Biochem J 434, 503-12
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21

Leroy A, et al. (2010) Spectroscopic studies of GSK3{beta} phosphorylation of the neuronal tau protein and its interaction with the N-terminal domain of apolipoprotein E. J Biol Chem 285, 33435-44
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22

Alonso AD, et al. (2010) Phosphorylation of tau at Thr212, Thr231, and Ser262 combined causes neurodegeneration. J Biol Chem 285, 30851-60
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23

Bertrand J, Plouffe V, Sénéchal P, Leclerc N (2010) The pattern of human tau phosphorylation is the result of priming and feedback events in primary hippocampal neurons. Neuroscience 168, 323-34
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24

Qian W, et al. (2010) PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3beta. J Alzheimers Dis 19, 1221-9
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25

Buescher JL, Phiel CJ (2010) A noncatalytic domain of glycogen synthase kinase-3 (GSK-3) is essential for activity. J Biol Chem 285, 7957-63
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26

Tremblay MA, Acker CM, Davies P (2010) Tau phosphorylated at tyrosine 394 is found in Alzheimer's disease tangles and can be a product of the Abl-related kinase, Arg. J Alzheimers Dis 19, 721-33
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27

Liu Y, et al. (2009) Brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer's disease. J Neurochem 111, 242-9
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28

Liu F, et al. (2009) Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain 132, 1820-32
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29

Lau KF, et al. (2008) Dexras1 interacts with FE65 to regulate FE65-amyloid precursor protein-dependent transcription. J Biol Chem 283, 34728-37
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30

Jeganathan S, et al. (2008) Proline-directed pseudo-phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of Tau and generates a pathological (MC-1) conformation. J Biol Chem 283, 32066-76
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31

Wray S, Saxton M, Anderton BH, Hanger DP (2008) Direct analysis of tau from PSP brain identifies new phosphorylation sites and a major fragment of N-terminally cleaved tau containing four microtubule-binding repeats. J Neurochem 105, 2343-52
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32

Terwel D, et al. (2008) Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice. Am J Pathol 172, 786-98
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33

Cheng TS, et al. (2008) Glycogen Synthase Kinase 3 Interacts with and Phosphorylates the Spindle-associated Protein Astrin. J Biol Chem 283, 2454-2464
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34

Meske V, Albert F, Ohm TG (2008) Coupling of mammalian target of rapamycin with phosphoinositide 3-kinase signaling pathway regulates protein phosphatase 2A- and glycogen synthase kinase-3 -dependent phosphorylation of Tau. J Biol Chem 283, 100-9
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35

Liu F, et al. (2007) Site-specific effects of tau phosphorylation on its microtubule assembly activity and self-aggregation. Eur J Neurosci 26, 3429-36
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36

Hanger DP, et al. (2007) Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J Biol Chem 282, 23645-54
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37

Yoshiyama Y, et al. (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337-51
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38

Iliev AI, Ganesan S, Bunt G, Wouters FS (2006) Removal of pattern-breaking sequences in microtubule binding repeats produces instantaneous tau aggregation and toxicity. J Biol Chem 281, 37195-204
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39

Liu F, et al. (2006) PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners. FEBS Lett 580, 6269-74
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40

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41

d'Abramo C, Ricciarelli R, Pronzato MA, Davies P (2006) Troglitazone, a peroxisome proliferator-activated receptor-gamma agonist, decreases tau phosphorylation in CHOtau4R cells. J Neurochem 98, 1068-77
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42

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43

Ding H, Matthews TA, Johnson GV (2006) Site-specific phosphorylation and caspase cleavage differentially impact tau-microtubule interactions and tau aggregation. J Biol Chem 281, 19107-14
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44

Zhang X, et al. (2006) Tumor-suppressor PTEN affects tau phosphorylation, aggregation, and binding to microtubules. FASEB J 20, 1272-4
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45

Tatebayashi Y, et al. (2006) c-jun N-terminal kinase hyperphosphorylates R406W tau at the PHF-1 site during mitosis. FASEB J 20, 762-4
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46

Dickey CA, et al. (2006) HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites. FASEB J 20, 753-5
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47

Gómez-Ramos A, et al. (2006) Sodium tungstate decreases the phosphorylation of tau through GSK3 inactivation. J Neurosci Res 83, 264-73
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48

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49

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50

Arai T, Guo JP, McGeer PL (2005) Proteolysis of non-phosphorylated and phosphorylated tau by thrombin. J Biol Chem 280, 5145-53
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51

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52

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53

Liu F, et al. (2004) O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. Proc Natl Acad Sci U S A 101, 10804-9
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54

Li G, Yin H, Kuret J (2004) Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules. J Biol Chem 279, 15938-45
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55

Noble W, et al. (2003) Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38, 555-65
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56

Grace EA, Busciglio J (2003) Aberrant activation of focal adhesion proteins mediates fibrillar amyloid beta-induced neuronal dystrophy. J Neurosci 23, 493-502
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57

Giasson BI, et al. (2002) The environmental toxin arsenite induces tau hyperphosphorylation. Biochemistry 41, 15376-87
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58

DeTure M, Ko LW, Easson C, Yen SH (2002) Tau assembly in inducible transfectants expressing wild-type or FTDP-17 tau. Am J Pathol 161, 1711-22
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59

Liu F, Iqbal K, Grundke-Iqbal I, Gong CX (2002) Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK-3beta. FEBS Lett 530, 209-14
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60

Hu YY, et al. (2002) Levels of nonphosphorylated and phosphorylated tau in cerebrospinal fluid of Alzheimer's disease patients : an ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay. Am J Pathol 160, 1269-78
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61

Abraha A, et al. (2000) C-terminal inhibition of tau assembly in vitro and in Alzheimer's disease. J Cell Sci 113 Pt 21, 3737-45
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62

Evans DB, et al. (2000) Tau phosphorylation at serine 396 and serine 404 by human recombinant tau protein kinase II inhibits tau's ability to promote microtubule assembly. J Biol Chem 275, 24977-83
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63

Jenkins SM, Zinnerman M, Garner C, Johnson GV (2000) Modulation of tau phosphorylation and intracellular localization by cellular stress. Biochem J 345 Pt 2, 263-70
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64

Schneider A, et al. (1999) Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry 38, 3549-58
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65

Hanger DP, et al. (1998) New phosphorylation sites identified in hyperphosphorylated tau (paired helical filament-tau) from Alzheimer's disease brain using nanoelectrospray mass spectrometry. J Neurochem 71, 2465-76
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66

Preuss U, Mandelkow EM (1998) Mitotic phosphorylation of tau protein in neuronal cell lines resembles phosphorylation in Alzheimer's disease. Eur J Cell Biol 76, 176-84
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67

Illenberger S, et al. (1998) The endogenous and cell cycle-dependent phosphorylation of tau protein in living cells: implications for Alzheimer's disease. Mol Biol Cell 9, 1495-512
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68

Singh TJ, et al. (1997) Protein kinase C and calcium/calmodulin-dependent protein kinase II phosphorylate three-repeat and four-repeat tau isoforms at different rates. Mol Cell Biochem 168, 141-8
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69

Mawal-Dewan M, et al. (1996) Identification of phosphorylation sites in PHF-TAU from patients with Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex. J Neuropathol Exp Neurol 55, 1051-9
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70

Bramblett GT, et al. (1993) Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding. Neuron 10, 1089-99
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