Ser202
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Phosphorylation Site Page:
Ser202 - Tau iso8 (human)

Site Information
SGYSSPGsPGTPGSR    SwissProt Entrez-Gene
Predicted information: Scansite
Orthologous residues: Tau (rat): S513, Tau (human): S519, Tau iso3 (human): S108, Tau (mouse): S494, Tau (cow): S209, Tau iso5 (human): S202, Tau iso6 (human): S144, Tau iso7 (human): S173, Tau iso7 (mouse): S151, Tau iso3 (mouse): S191, Tau iso2 (human): S144
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 447928

In vivo Characterization
Methods used to characterize site in vivo: 2D analysis (39, 55, 57), electrophoretic mobility shift (30), mass spectrometry (22, 26, 30, 41, 55), microscopy-colocalization with upstream kinase (51), mutation of modification site (15, 39, 53), peptide sequencing (49), phospho-antibody (4, 7, 8, 11, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 25, 27, 28, 30, 31, 32, 33, 34, 35, 36, 38, 39, 40, 42, 45, 46, 47, 48, 51, 53, 56, 58), western blotting (7, 8, 11, 13, 14, 15, 16, 17, 18, 19, 20, 23, 25, 27, 28, 31, 32, 33, 34, 39, 40, 42, 47, 48, 49, 51, 53, 55, 56)
Disease tissue studied: Alzheimer's disease (4, 8, 15, 17, 19, 20, 26, 33, 51, 55), adrenal cancer (45), pheochromocytoma (45), brain cancer (51), glioma (51), neuroblastoma (11, 28, 47, 53, 56, 57), diabetes mellitus (19), type 2 diabetes (19), PSP (22, 40)
Relevant cell line - cell type - tissue: 'brain, brainstem' (48), 'brain, caudate-putamen' (40), 'brain, cerebellum' (20), 'brain, cerebral cortex' (25, 33, 40, 41, 48), 'brain, hippocampus' (25, 38), 'brain, striatum' (40), 'eye, retinal pigmented epithelium' (16), 'neuron, cortical' (23), 'neuron, cortical'-brain (36, 39), 'neuron, hippocampal'-brain (36), 293 (epithelial) (8, 46), 293T (epithelial) (25), brain (7, 19, 22, 26, 42, 55), brain [Tau iso8 (human)] (27, 32), CHO (fibroblast) (17, 28, 34, 49, 53), CHO (fibroblast) [Tau (human), transfection] (57), CHO (fibroblast) [Tau iso8 (human)] (31), COS (fibroblast) (30, 33, 39), H4 (glial) (51), HCN-2 ('neuron, cortical') (18), LAN-5 (neural crest) (56, 57), N2a (neuron) (56), neuron-'brain, cerebral cortex' (4), neuron-'brain, hippocampus' (13, 15), neuron:synaptosome (47), PC-12 (chromaffin) (45), SH-SY5Y (neural crest) (28, 30, 35), SK-N-MC (neural crest) (11, 47, 53), spinal cord (58)

Controlled by
Regulatory protein: APP (human) (14), APP (mouse) (42), CDK5R1 (mouse) (48), nAChRA7 (human) (47), PKN1 (human) (53), PTEN (human) (33), Tau (mouse) (42)
Putative upstream kinases: CDK5 (human) (39, 48), CK1D (human) (46), DYRK1A (human) (25), GSK3B (human) (17), TTBK1 (human) (30)
Kinases, in vitro: CDK1 (human) (57), CDK5 (human) (29, 39, 50, 52, 57), CK1D (human) (46), DYRK1A (mouse) (25), DYRK1A (rat) (24), ERK1 (human) (47, 54), ERK2 (human) (47), GSK3B (human) (24, 29, 52), JNK1 (human) (47), JNK2 (human) (47), TTBK1 (human) (30)
Putative upstream phosphatases: PPP2CA (rat) (13)
Phosphatases, in vitro: PPP2CA (human) (17)
Treatments: 17-AAG (34), AICAR (23), alpha-BTX (47), alpha-conotoxin MI (47), arsenite (49), atropine (47), BAPTA-AM (11), beta-amyloid 42 (47), calpeptin (11), chloroquine (34), cytosine (47), doxycycline (51), epibatidine (47), FK506 (27), forskolin (8), IC261 (46), insulin (23), JNK inhibitor I (31), kenpaullone (49), lithium (11, 23, 35, 36, 49), low glucose (45), LY294002 (23, 31), mecamylamine (47), methyllycaconitine (47), MG132 (34), MSH (47), nicotine (47), NMDA (36), okadaic acid (8, 13, 23, 45, 49), olomoucine (49), PD98059 (35), pioglitazone (31), PLTP (18), PUGNAc (45), roscovitine (11, 49), Rp-cAMPS (11), SB203580 (49), SB216763 (36), SCH 23390 (11), SKF38393 (11), streptozotocin (45), troglitazone (31), tungstate (35), U0126 (49), wortmannin (31)

Downstream Regulation
Effects of modification on Tau iso8: intracellular localization (13, 51), molecular association, regulation (30, 37, 46), O-GlcNAc glycosylation (20), protein conformation (8, 21)
Effects of modification on biological processes: cytoskeletal reorganization (42, 43, 51)
Induce interaction with: Tau (human) (30)
Inhibit interaction with: Fyn (human) (37)

Disease / Diagnostics Relevance
Relevant diseases: Alzheimer's disease (19, 20, 21, 55, 58), type 2 diabetes (19), PSP (22)

References

1

Yu UY, Yoo BC, Ahn JH (2014) Regulatory B Subunits of Protein Phosphatase 2A Are Involved in Site-specific Regulation of Tau Protein Phosphorylation. Korean J Physiol Pharmacol 18, 155-61
24757378   Curated Info

2

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
24033439   Curated Info

3

Bailey RM, et al. (2013) LRRK2 phosphorylates novel tau epitopes and promotes tauopathy. Acta Neuropathol 126, 809-27
24113872   Curated Info

4

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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5

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
23428800   Curated Info

6

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
24073234   Curated Info

7

Chu J, Lauretti E, Di Meco A, Praticò D (2013) FLAP pharmacological blockade modulates metabolism of endogenous tau in vivo . Transl Psychiatry 3, e333
24301651   Curated Info

8

Tak H, et al. (2013) Bimolecular fluorescence complementation; lighting-up tau-tau interaction in living cells. PLoS One 8, e81682
24312574   Curated Info

9

Smet-Nocca C, et al. (2011) Identification of O-GlcNAc sites within peptides of the Tau protein and their impact on phosphorylation. Mol Biosyst 7, 1420-9
21327254   Curated Info

10

Jinwal UK, et al. (2011) The Hsp90 kinase co-chaperone Cdc37 regulates tau stability and phosphorylation dynamics. J Biol Chem 286, 16976-83
21367866   Curated Info

11

Lebel M, Cyr M (2011) Molecular and cellular events of dopamine D1 receptor-mediated tau phosphorylation in SK-N-MC cells. Synapse 65, 69-76
20506302   Curated Info

12

Landrieu I, et al. (2011) Molecular implication of PP2A and Pin1 in the Alzheimer's disease specific hyperphosphorylation of Tau. PLoS One 6, e21521
21731772   Curated Info

13

Bertrand J, et al. (2010) The formation of tau pathological phospho-epitopes in the axon is prevented by the dephosphorylation of selective sites in primary hippocampal neurons over-expressing human tau. J Neurochem 114, 1353-67
20550628   Curated Info

14

Iijima K, Gatt A, Iijima-Ando K (2010) Tau Ser262 phosphorylation is critical for Abeta42-induced tau toxicity in a transgenic Drosophila model of Alzheimer's disease. Hum Mol Genet 19, 2947-57
20466736   Curated Info

15

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
20394726   Curated Info

16

Iijima-Ando K, et al. (2010) A DNA damage-activated checkpoint kinase phosphorylates tau and enhances tau-induced neurodegeneration. Hum Mol Genet 19, 1930-8
20159774   Curated Info

17

Qian W, et al. (2010) PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3beta. J Alzheimers Dis 19, 1221-9
20308788   Curated Info

18

Dong W, Albers JJ, Vuletic S (2009) Phospholipid transfer protein reduces phosphorylation of tau in human neuronal cells. J Neurosci Res 87, 3176-85
19472218   Curated Info

19

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
19659459   Curated Info

20

Liu F, et al. (2009) Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain 132, 1820-32
19451179   Curated Info

21

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
18725412   Curated Info

22

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
18315566   Curated Info

23

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
17971449   Curated Info

24

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
18052981   Curated Info

25

Ryoo SR, et al. (2007) DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease. J Biol Chem 282, 34850-7
17906291   Curated Info

26

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
17562708   Curated Info

27

Yoshiyama Y, et al. (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337-51
17270732   Curated Info

28

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
17008320   Curated Info

29

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
17078951   Curated Info

30

Sato S, Cerny RL, Buescher JL, Ikezu T (2006) Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is involved in tau phosphorylation and aggregation. J Neurochem 98, 1573-84
16923168   Curated Info

31

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
16787414   Curated Info

32

Schindowski K, et al. (2006) Alzheimer's disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol 169, 599-616
16877359   Curated Info

33

Zhang X, et al. (2006) Tumor-suppressor PTEN affects tau phosphorylation, aggregation, and binding to microtubules. FASEB J 20, 1272-4
16645045   Curated Info

34

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
16464956   Curated Info

35

Gómez-Ramos A, et al. (2006) Sodium tungstate decreases the phosphorylation of tau through GSK3 inactivation. J Neurosci Res 83, 264-73
16397900   Curated Info

36

Szatmari E, et al. (2005) A positive feedback loop between glycogen synthase kinase 3beta and protein phosphatase 1 after stimulation of NR2B NMDA receptors in forebrain neurons. J Biol Chem 280, 37526-35
16155008   Curated Info

37

Bhaskar K, Yen SH, Lee G (2005) Disease-related modifications in tau affect the interaction between Fyn and Tau. J Biol Chem 280, 35119-25
16115884   Curated Info

38

Härtig W, et al. (2005) Phosphorylation of the tau protein sequence 199-205 in the hippocampal CA3 region of Syrian hamsters in adulthood and during aging. Brain Res 1056, 100-4
16095576   Curated Info

39

Sakaue F, et al. (2005) Phosphorylation of FTDP-17 mutant tau by cyclin-dependent kinase 5 complexed with p35, p25, or p39. J Biol Chem 280, 31522-9
15994305   Curated Info

40

Puig B, Rey MJ, Ferrer I (2005) Individual and regional variations of phospho-tau species in progressive supranuclear palsy. Acta Neuropathol (Berl) 110, 261-8
15973541   Curated Info

41

DeGiorgis JA, et al. (2005) Phosphoproteomic analysis of synaptosomes from human cerebral cortex. J Proteome Res 4, 306-15
15822905   Curated Info

42

Pérez M, et al. (2005) Characterization of a double (amyloid precursor protein-tau) transgenic: tau phosphorylation and aggregation. Neuroscience 130, 339-47
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43

Necula M, Kuret J (2004) Pseudophosphorylation and glycation of tau protein enhance but do not trigger fibrillization in vitro. J Biol Chem 279, 49694-703
15364924   Curated Info

44

Alonso Adel C, et al. (2004) Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem 279, 34873-81
15190058   Curated Info

45

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
15249677   Curated Info

46

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
14761950   Curated Info

47

Wang HY, Li W, Benedetti NJ, Lee DH (2003) Alpha 7 nicotinic acetylcholine receptors mediate beta-amyloid peptide-induced tau protein phosphorylation. J Biol Chem 278, 31547-53
12801934   Curated Info

48

Noble W, et al. (2003) Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38, 555-65
12765608   Curated Info

49

Giasson BI, et al. (2002) The environmental toxin arsenite induces tau hyperphosphorylation. Biochemistry 41, 15376-87
12484777   Curated Info

50

Hashiguchi M, Saito T, Hisanaga S, Hashiguchi T (2002) Truncation of CDK5 activator p35 induces intensive phosphorylation of Ser202/Thr205 of human tau. J Biol Chem 277, 44525-30
12226093   Curated Info

51

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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52

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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53

Taniguchi T, et al. (2001) Phosphorylation of tau is regulated by PKN. J Biol Chem 276, 10025-31
11104762   Curated Info

54

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
10090741   Curated Info

55

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
9832145   Curated Info

56

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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57

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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58

Goedert M, et al. (1993) The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc Natl Acad Sci U S A 90, 5066-70
8506352   Curated Info

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