Thr231
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Home > Phosphorylation Site Page: > Thr231  -  Tau iso8 (human)

Site Information
KKVAVVRtPPKsPss   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 449079

In vivo Characterization
Methods used to characterize site in vivo:
2D analysis ( 55 , 58 ) , mass spectrometry ( 1 , 7 , 15 , 28 , 31 , 42 , 55 ) , microscopy-colocalization with upstream kinase ( 51 ) , multiple reaction monitoring (MRM) ( 1 ) , mutation of modification site ( 3 , 5 , 18 , 19 , 20 , 22 , 23 , 36 , 53 , 56 ) , peptide sequencing ( 50 ) , phospho-antibody ( 2 , 3 , 7 , 9 , 10 , 11 , 13 , 14 , 16 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 32 , 35 , 36 , 37 , 38 , 41 , 44 , 46 , 47 , 48 , 51 , 53 , 57 , 60 ) , western blotting ( 2 , 3 , 7 , 9 , 10 , 11 , 12 , 13 , 15 , 16 , 20 , 21 , 22 , 23 , 24 , 26 , 27 , 32 , 35 , 36 , 46 , 47 , 48 , 49 , 50 , 51 , 53 , 55 , 57 , 60 )
Disease tissue studied:
Alexander's disease ( 46 ) , Alzheimer's disease ( 12 , 15 , 22 , 25 , 27 , 31 , 49 , 51 , 55 ) , adrenal cancer ( 19 , 23 ) , pheochromocytoma ( 19 , 23 ) , brain cancer ( 7 , 51 ) , glioma ( 7 , 51 ) , neuroblastoma ( 32 , 46 , 47 , 53 , 57 , 58 ) , melanoma skin cancer ( 16 ) , diabetes mellitus ( 27 ) , type 2 diabetes ( 27 ) , PSP ( 28 )
Relevant cell line - cell type - tissue:
'brain, brainstem' ( 48 ) , 'brain, cerebral cortex' ( 3 , 42 , 48 ) , 'brain, embryonic' ( 60 ) , 'brain, hippocampus' ( 2 , 3 , 46 ) , 'eye, retinal pigmented epithelium' ( 24 ) , 'neuron, cortical'-brain ( 11 ) , 'stem, induced pluripotent' ( 14 ) , 293 (epithelial) ( 3 , 9 , 10 , 36 ) , brain ( 1 , 13 , 15 , 27 , 28 , 31 , 55 , 60 ) , brain [Tau iso8 (human)] ( 35 ) , cerebrospinal fluid ( 1 , 12 , 25 , 38 , 41 , 44 , 49 ) , CHO (fibroblast) [Tau (human), transfection] ( 58 ) , CHO (fibroblast) ( 19 , 32 , 50 , 53 ) , E.coli (bacterial) ( 56 ) , H4 (glial) ( 7 , 51 ) , HCN-2 ('neuron, cortical') ( 26 ) , HeLa (cervical) ( 16 , 29 ) , LAN-5 (neural crest) ( 57 , 58 ) , Neuro-2a (neuron) ( 57 ) , neuron-'brain, hippocampus' ( 3 , 16 , 20 , 22 ) , neuron:synaptosome ( 47 ) , PC-12 (chromaffin) ( 19 , 23 ) , SH-SY5Y (neural crest) ( 32 , 37 ) , SK-N-MC (neural crest) ( 47 , 53 ) , SKNSH (neural crest) ( 46 ) , spinal cord ( 2 )

Upstream Regulation
Regulatory protein:
APP (human) ( 21 ) , CDC37 (human) ( 16 ) , CDK5R1 (mouse) ( 48 ) , MKK6 (human) ( 50 ) , nAChRA7 (human) ( 47 ) , PKN1 (human) ( 53 ) , SET (mouse) ( 3 ) , Tau iso8 (human) ( 22 , 32 , 35 )
Putative in vivo kinases:
CDK5 (mouse) ( 48 ) , GSK3B (human) ( 5 , 29 )
Kinases, in vitro:
AMPKA1 (human) ( 17 ) , CAMK2A (rat) ( 59 ) , CDK1 (human) ( 58 ) , CDK2 (human) ( 18 ) , CDK5 (human) ( 33 , 52 ) , DYRK1A (rat) ( 30 ) , ERK1 (human) ( 54 ) , ERK2 (human) ( 4 ) , GSK3A (cow) ( 59 ) , GSK3A (human) ( 34 , 56 ) , GSK3B (human) ( 30 , 33 , 34 , 43 , 52 , 54 ) , JNK1 (human) ( 47 ) , JNK2 (human) ( 47 ) , LRRK2 (human) ( 8 ) , MARK1 (human) ( 17 ) , PKCA (rat) ( 59 )
Putative upstream phosphatases:
PPP2CA (rat) ( 20 ) , PPP2R2A (human) ( 7 ) , PPP2R5D (human) ( 7 )
Phosphatases, in vitro:
PPP2CA (human) ( 18 )
Treatments:
alpha-BTX ( 47 ) , alpha-conotoxin_MI ( 47 ) , arsenite ( 50 ) , atropine ( 47 ) , beta-amyloid_42 ( 47 ) , cytosine ( 47 ) , doxycycline ( 51 ) , epibatidine ( 47 ) , lithium ( 37 , 50 ) , LY294002 ( 26 ) , mecamylamine ( 47 ) , methyllycaconitine ( 47 ) , MK-591 ( 13 ) , MSH ( 47 ) , mutation ( 45 ) , NGF ( 23 ) , nicotine ( 47 ) , okadaic_acid ( 7 , 20 ) , PD98059 ( 37 ) , PLTP ( 26 ) , SB203580 ( 50 ) , tungstate ( 37 ) , U0126 ( 50 )

Downstream Regulation
Effects of modification on Tau iso8:
intracellular localization ( 2 , 20 , 51 ) , molecular association, regulation ( 19 , 34 , 36 , 39 , 40 , 45 ) , phosphorylation ( 18 , 36 ) , protein conformation ( 19 ) , protein processing ( 43 )
Effects of modification on biological processes:
apoptosis, altered ( 19 ) , cytoskeletal reorganization ( 5 , 19 , 36 , 51 ) , signaling pathway regulation ( 23 )
Induce interaction with:
PIN1 (human) ( 40 ) , TUBA1A (cow) ( 19 ) , Tau iso8 (human) ( 45 )
Inhibit interaction with:
Fyn (human) ( 39 ) , TUBA4A (human) ( 36 ) , TUBA4A (rat) ( 34 )

Disease / Diagnostics Relevance
Relevant diseases:
Alzheimer's disease ( 1 , 7 , 11 , 12 , 14 , 15 , 25 , 41 , 44 , 46 , 49 , 55 ) , ALS ( 2 , 60 ) , CTE ( 2 ) , DLB ( 11 ) , Parkinson's disease ( 60 ) , PSP ( 28 )

References 

1

Barthélemy NR, et al. (2019) Tau Phosphorylation Rates Measured by Mass Spectrometry Differ in the Intracellular Brain vs. Extracellular Cerebrospinal Fluid Compartments and Are Differentially Affected by Alzheimer's Disease. Front Aging Neurosci 11, 121
31178717   Curated Info

2

Moszczynski AJ, et al. (2018) Pathologic Thrtau phosphorylation in CTE and CTE with ALS. Neurology 90, e380-e387
29298849   Curated Info

3

Zhang Q, et al. (2018) CK2 Phosphorylating I/SET Mediates Tau Pathology and Cognitive Impairment. Front Mol Neurosci 11, 146
29760653   Curated Info

4

Qi H, et al. (2016) Characterization of Neuronal Tau Protein as a Target of Extracellular Signal-regulated Kinase. J Biol Chem 291, 7742-53
26858248   Curated Info

5

Moszczynski AJ, et al. (2015) Thr(175)-phosphorylated tau induces pathologic fibril formation via GSK3β-mediated phosphorylation of Thr(231) in vitro. Neurobiol Aging 36, 1590-9
25573097   Curated Info

6

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
25378699   Curated Info

7

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

8

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

9

Yu G, et al. (2013) Ser9 phosphorylation causes cytoplasmic detention of I2PP2A/SET in Alzheimer disease. Neurobiol Aging 34, 1748-58
23374587   Curated Info

10

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

11

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

12

Meredith JE, et al. (2013) Characterization of Novel CSF Tau and ptau Biomarkers for Alzheimer's Disease. PLoS One 8, e76523
24116116   Curated Info

13

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

14

Israel MA, et al. (2012) Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature 482, 216-20
22278060   Curated Info

15

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
21828286   Curated Info

16

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

17

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
21204788   Curated Info

18

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

19

Alonso AD, et al. (2010) Phosphorylation of tau at Thr212, Thr231, and Ser262 combined causes neurodegeneration. J Biol Chem 285, 30851-60
20663882   Curated Info

20

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

21

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

22

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

23

Leugers CJ, Lee G (2010) Tau potentiates nerve growth factor-induced mitogen-activated protein kinase signaling and neurite initiation without a requirement for microtubule binding. J Biol Chem 285, 19125-34
20375017   Curated Info

24

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

25

Singer D, Soininen H, Alafuzoff I, Hoffmann R (2009) Immuno-PCR-based quantification of multiple phosphorylated tau-epitopes linked to Alzheimer's disease. Anal Bioanal Chem 395, 2263-7
19821112   Curated Info

26

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

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
19659459   Curated Info

28

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

29

Cheng TS, et al. (2008) Glycogen Synthase Kinase 3 Interacts with and Phosphorylates the Spindle-associated Protein Astrin. J Biol Chem 283, 2454-2464
18055457   Curated Info

30

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

31

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

32

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

33

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

34

Sengupta A, Novak M, Grundke-Iqbal I, Iqbal K (2006) Regulation of phosphorylation of tau by cyclin-dependent kinase 5 and glycogen synthase kinase-3 at substrate level. FEBS Lett 580, 5925-33
17045592   Curated Info

35

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

36

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
16687396   Curated Info

37

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

38

Buerger K, et al. (2005) Increased levels of CSF phosphorylated tau in apolipoprotein E epsilon4 carriers with mild cognitive impairment. Neurosci Lett 391, 48-50
16165272   Curated Info

39

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

40

Smet C, et al. (2005) Regulation of Pin1 peptidyl-prolyl cis/trans isomerase activity by its WW binding module on a multi-phosphorylated peptide of Tau protein. FEBS Lett 579, 4159-64
16024016   Curated Info

41

Hampel H, et al. (2005) Correlation of cerebrospinal fluid levels of tau protein phosphorylated at threonine 231 with rates of hippocampal atrophy in Alzheimer disease. Arch Neurol 62, 770-3
15883264   Curated Info

42

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

43

Arai T, Guo JP, McGeer PL (2005) Proteolysis of non-phosphorylated and phosphorylated tau by thrombin. J Biol Chem 280, 5145-53
15542598   Curated Info

44

de Leon MJ, et al. (2004) MRI and CSF studies in the early diagnosis of Alzheimer's disease. J Intern Med 256, 205-23
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45

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

46

Sze CI, et al. (2004) Down-regulation of WW domain-containing oxidoreductase induces Tau phosphorylation in vitro. A potential role in Alzheimer's disease. J Biol Chem 279, 30498-506
15126504   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
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49

Mitchell A, Brindle N (2003) CSF phosphorylated tau--does it constitute an accurate biological test for Alzheimer's disease? Int J Geriatr Psychiatry 18, 407-11
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50

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

Sengupta A, et al. (1998) Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. Arch Biochem Biophys 357, 299-309
9735171   Curated Info

57

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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58

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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59

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
9062903   Curated Info

60

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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