Ser262
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Home > Phosphorylation Site Page: > Ser262  -  Tau iso8 (human)

Site Information
NVKsKIGstENLkHQ   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 447930

In vivo Characterization
Methods used to characterize site in vivo:
2D analysis ( 47 , 50 ) , [32P] bio-synthetic labeling ( 51 ) , mass spectrometry ( 4 , 13 , 27 , 47 ) , mass spectrometry (in vitro) ( 1 ) , microscopy-colocalization with upstream kinase ( 28 ) , mutation of modification site ( 16 , 17 , 18 , 19 , 28 , 32 ) , peptide sequencing ( 44 ) , phospho-antibody ( 2 , 4 , 9 , 10 , 14 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 28 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 39 , 40 , 42 , 45 , 48 , 53 ) , phosphopeptide mapping ( 51 ) , western blotting ( 2 , 4 , 9 , 10 , 13 , 14 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 28 , 31 , 32 , 33 , 34 , 37 , 39 , 40 , 44 , 45 , 47 , 53 )
Disease tissue studied:
Alzheimer's disease ( 10 , 13 , 18 , 20 , 21 , 22 , 23 , 27 , 33 , 47 ) , adrenal cancer ( 16 , 24 , 42 ) , pheochromocytoma ( 16 , 24 , 42 ) , brain cancer ( 4 , 21 ) , glioma ( 4 , 21 ) , neuroblastoma ( 2 , 24 , 45 , 50 ) , melanoma skin cancer ( 14 ) , diabetes mellitus ( 22 ) , type 2 diabetes ( 22 )
Relevant cell line - cell type - tissue:
'brain, cerebellum' ( 23 ) , 'brain, cerebral cortex' ( 2 , 33 ) , 'brain, embryonic' ( 53 ) , 'brain, hippocampus' ( 2 ) , 'eye, retinal pigmented epithelium' ( 19 ) , 'neuron, cerebellar granule'-brain ( 35 ) , 'neuron, cortical' ( 25 ) , 'neuron, cortical'-brain ( 9 , 24 , 28 ) , 'neuron, striatal'-brain ( 9 ) , 293 (epithelial) ( 10 , 32 , 37 ) , brain ( 13 , 22 , 27 , 39 , 47 , 53 ) , brain [Tau iso8 (human)] ( 31 ) , CHO (fibroblast) [Tau (human), transfection] ( 50 ) , CHO (fibroblast) ( 16 , 20 , 34 , 44 ) , COS (fibroblast) ( 33 ) , E.coli (bacterial) ( 1 ) , F11 (neuron) ( 37 ) , H4 (glial) ( 4 , 21 ) , HeLa (cervical) ( 14 ) , HPAEC (endothelial) ( 40 ) , LAN-5 (neural crest) ( 50 ) , Neuro-2a (neuron) ( 24 ) , neuron-'brain, hippocampus' ( 14 , 18 ) , PC-12 (chromaffin) ( 16 , 24 , 42 ) , SH-SY5Y (neural crest) ( 35 , 36 , 45 ) , SK-N-BE(2) (neural crest) ( 2 )

Upstream Regulation
Regulatory protein:
AKAP13 (human) ( 21 ) , APP (human) ( 17 ) , APP (mouse) ( 39 ) , CDC37 (human) ( 14 ) , DYRK1A (human) ( 21 ) , GSK3B (human) ( 24 ) , MARK2 (human) ( 24 ) , Tau (mouse) ( 39 ) , Tau iso8 (human) ( 18 , 31 )
Putative in vivo kinases:
CAMK2A (rat) ( 48 ) , Chk2 (human) ( 19 ) , GSK3B (human) ( 20 ) , MARK1 (human) ( 24 ) , MARK2 (rat) ( 11 , 21 , 37 ) , NuaK1 (human) ( 2 ) , PKR (human) ( 21 )
Kinases, in vitro:
AMPKA1 (human) ( 15 ) , CAMK2A (human) ( 30 ) , CAMK2A (rat) ( 48 ) , CDK5 (human) ( 29 ) , Chk1 (human) ( 19 ) , Chk2 (human) ( 19 ) , GSK3A (human) ( 30 ) , GSK3B (human) ( 29 , 38 ) , MARK1 (human) ( 15 , 46 , 50 , 54 ) , MARK1 (rat) ( 51 ) , MARK2 (rat) ( 51 ) , NuaK1 (human) ( 2 ) , p70S6K (human) ( 36 ) , PHKG1 (rabbit) ( 48 , 52 ) , PKACA (human) ( 1 , 26 , 29 , 30 , 46 ) , PKACA (rat) ( 48 )
Putative upstream phosphatases:
PPP2R2A (human) ( 4 )
Phosphatases, in vitro:
PPP2CA (human) ( 20 )
Treatments:
acadesine ( 25 ) , arsenite ( 44 ) , BDNF ( 6 ) , bradykinin ( 48 ) , C3_toxin ( 40 ) , colforsin ( 10 ) , insulin ( 25 ) , KN-62 ( 48 ) , lithium ( 25 , 37 ) , LY294002 ( 25 ) , mutation ( 41 ) , okadaic_acid ( 4 , 10 , 25 , 35 , 42 ) , PUGNAc ( 42 ) , retinoic_acid ( 6 ) , salicylate ( 35 ) , sorbitol ( 45 ) , staurosporine ( 11 ) , streptozotocin ( 42 ) , tanespimycin ( 34 ) , taxol ( 40 ) , thrombin ( 40 ) , Y27632 ( 40 )

Downstream Regulation
Effects of modification on Tau iso8:
molecular association, regulation ( 15 , 16 , 30 , 41 , 54 ) , O-GlcNAc glycosylation ( 23 ) , phosphorylation ( 24 ) , protein conformation ( 16 ) , protein stabilization ( 38 )
Effects of modification on biological processes:
apoptosis, altered ( 16 , 19 ) , apoptosis, induced ( 17 ) , cytoskeletal reorganization ( 16 , 24 , 38 , 39 , 46 , 54 )
Induce interaction with:
TUBA1A (cow) ( 16 ) , Tau iso8 (human) ( 41 )
Inhibit interaction with:
TUBA1A (cow) ( 54 ) , TUBA4A (rat) ( 30 ) , TUBB (cow) ( 54 )

Disease / Diagnostics Relevance
Relevant diseases:
Alzheimer's disease ( 4 , 5 , 9 , 13 , 22 , 23 , 38 , 47 ) , ALS ( 53 ) , type 2 diabetes ( 22 ) , Down syndrome ( 5 ) , Parkinson's disease ( 9 , 53 )

References 

1

Tugaeva KV, Tsvetkov PO, Sluchanko NN (2017) Bacterial co-expression of human Tau protein with protein kinase A and 14-3-3 for studies of 14-3-3/phospho-Tau interaction. PLoS One 12, e0178933
28575131   Curated Info

2

Lasagna-Reeves CA, et al. (2016) Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model. Neuron 92, 407-418
27720485   Curated Info

3

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

4

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

5

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

6

Chen Q, et al. (2014) The cellular distribution and ser262 phosphorylation of tau protein are regulated by BDNF in vitro. PLoS One 9, e91793
24618580   Curated Info

7

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

8

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

9

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

10

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

11

Gu GJ, et al. (2013) Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease. J Alzheimers Dis 33, 699-713
23001711   Curated Info

12

Thomas SN, et al. (2012) Dual modification of Alzheimer's disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach. Acta Neuropathol 123, 105-17
22033876   Curated Info

13

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

14

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

15

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

16

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

17

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

18

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

19

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

20

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

21

Azorsa DO, et al. (2010) High-content siRNA screening of the kinome identifies kinases involved in Alzheimer's disease-related tau hyperphosphorylation. BMC Genomics 11, 25
20067632   Curated Info

22

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

23

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

24

Timm T, et al. (2008) Glycogen synthase kinase (GSK) 3beta directly phosphorylates Serine 212 in the regulatory loop and inhibits microtubule affinity-regulating kinase (MARK) 2. J Biol Chem 283, 18873-82
18424437   Curated Info

25

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

26

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

27

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

28

Barnes AP, et al. (2007) LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons. Cell 129, 549-63
17482548   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

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

31

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

32

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

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

Tortosa E, Avila J, Pérez M (2006) Acetylsalicylic acid decreases tau phosphorylation at serine 422. Neurosci Lett 396, 77-80
16386371   Curated Info

36

Pei JJ, et al. (2006) P70 S6 kinase mediates tau phosphorylation and synthesis. FEBS Lett 580, 107-14
16364302   Curated Info

37

Kosuga S, et al. (2005) GSK-3beta directly phosphorylates and activates MARK2/PAR-1. J Biol Chem 280, 42715-22
16257959   Curated Info

38

Mendieta J, et al. (2005) Phosphorylation modulates the alpha-helical structure and polymerization of a peptide from the third tau microtubule-binding repeat. Biochim Biophys Acta 1721, 16-26
15652175   Curated Info

39

Pérez M, et al. (2005) Characterization of a double (amyloid precursor protein-tau) transgenic: tau phosphorylation and aggregation. Neuroscience 130, 339-47
15664690   Curated Info

40

Birukova AA, et al. (2004) Novel role of microtubules in thrombin-induced endothelial barrier dysfunction. FASEB J 18, 1879-90
15576491   Curated Info

41

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

42

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

43

Timm T, et al. (2003) MARKK, a Ste20-like kinase, activates the polarity-inducing kinase MARK/PAR-1. EMBO J 22, 5090-101
14517247   Curated Info

44

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

45

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
10620503   Curated Info

46

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

47

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

48

Sironi JJ, et al. (1998) Ser-262 in human recombinant tau protein is a markedly more favorable site for phosphorylation by CaMKII than PKA or PhK. FEBS Lett 436, 471-5
9801171   Curated Info

49

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

50

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
9614189   Curated Info

51

Drewes G, et al. (1997) MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89, 297-308
9108484   Curated Info

52

Paudel HK (1997) The regulatory Ser262 of microtubule-associated protein tau is phosphorylated by phosphorylase kinase. J Biol Chem 272, 1777-85
8999860   Curated Info

53

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
8858002   Curated Info

54

Drewes G, et al. (1995) Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262. J Biol Chem 270, 7679-88
7706316   Curated Info