Ser199
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Home > Phosphorylation Site Page: > Ser199  -  Tau iso8 (human)

Site Information
GDRsGyssPGsPGtP   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 447927

In vivo Characterization
Methods used to characterize site in vivo:
2D analysis ( 39 , 40 ) , electrophoretic mobility shift ( 26 ) , mass spectrometry ( 4 , 24 , 26 , 39 ) , microscopy-colocalization with upstream kinase ( 36 ) , mutation of modification site ( 1 , 14 , 16 , 27 ) , phospho-antibody ( 1 , 2 , 4 , 9 , 10 , 12 , 15 , 16 , 17 , 18 , 19 , 20 , 22 , 26 , 27 , 28 , 29 , 30 , 32 , 35 ) , western blotting ( 1 , 2 , 4 , 9 , 10 , 12 , 15 , 16 , 17 , 18 , 19 , 20 , 22 , 27 , 28 , 30 , 37 , 39 )
Disease tissue studied:
Alzheimer's disease ( 9 , 16 , 17 , 19 , 20 , 24 , 28 , 37 , 39 ) , adrenal cancer ( 14 , 35 ) , pheochromocytoma ( 14 , 35 ) , brain cancer ( 4 ) , glioma ( 4 ) , neuroblastoma ( 12 , 40 ) , melanoma skin cancer ( 10 ) , diabetes mellitus ( 19 ) , type 2 diabetes ( 19 )
Relevant cell line - cell type - tissue:
'brain, cerebellum' ( 20 ) , 'brain, cerebral cortex' ( 1 , 28 ) , 'brain, hippocampus' ( 1 , 32 ) , 'neuron, cortical' ( 22 ) , 293 (epithelial) ( 1 , 9 , 27 , 30 ) , 293T (epithelial) ( 2 ) , brain ( 19 , 24 , 39 ) , cerebrospinal fluid ( 37 ) , CHO (fibroblast) ( 14 , 17 ) , CHO (fibroblast) [Tau (human), transfection] ( 40 ) , COS (fibroblast) ( 26 , 28 ) , F11 (neuron) ( 30 ) , H4 (glial) ( 4 ) , HCN-2 ('neuron, cortical') ( 18 ) , HeLa (cervical) ( 10 ) , LAN-5 (neural crest) ( 40 ) , neuron-'brain, hippocampus' ( 1 , 10 , 15 , 16 ) , neuron-brain ( 36 ) , PC-12 (chromaffin) ( 14 , 35 ) , SH-SY5Y (neural crest) ( 26 , 29 ) , SK-N-MC (neural crest) ( 12 )

Upstream Regulation
Regulatory protein:
CDC37 (human) ( 10 ) , PTEN (human) ( 28 ) , SET (mouse) ( 1 ) , Tau iso8 (human) ( 16 ) , WWOX (human) ( 36 )
Putative in vivo kinases:
DYRK1A (human) ( 2 ) , GSK3B (human) ( 17 ) , TTBK1 (human) ( 26 )
Kinases, in vitro:
CDK5 (human) ( 25 , 38 ) , DYRK1A (human) ( 2 ) , DYRK1A (rat) ( 23 ) , ERK1 (human) ( 40 ) , ERK2 (human) ( 40 ) , GSK3B (human) ( 13 , 23 , 25 , 30 , 38 ) , TTBK1 (human) ( 26 )
Putative upstream phosphatases:
PPP2CA (rat) ( 15 ) , PPP2R2A (human) ( 4 )
Phosphatases, in vitro:
PPP2CA (human) ( 17 )
Treatments:
BAPTA-AM ( 12 ) , calpeptin ( 12 ) , colforsin ( 9 ) , lithium ( 12 , 22 , 29 , 30 ) , low_glucose ( 35 ) , mutation ( 34 ) , okadaic_acid ( 4 , 9 , 15 , 22 , 35 ) , PD98059 ( 29 ) , PLTP ( 18 ) , PUGNAc ( 35 ) , Rp-cAMPS ( 12 ) , SCH_23390 ( 12 ) , seliciclib ( 12 ) , SKF38393 ( 12 ) , SP600125 ( 36 ) , streptozotocin ( 35 ) , tungstate ( 29 )

Downstream Regulation
Effects of modification on Tau iso8:
intracellular localization ( 15 ) , molecular association, regulation ( 26 , 31 , 34 , 36 ) , O-GlcNAc glycosylation ( 20 ) , protein conformation ( 9 , 21 )
Effects of modification on biological processes:
cytoskeletal reorganization ( 33 )
Induce interaction with:
Tau (human) ( 26 ) , Tau iso8 (human) ( 34 ) , WWOX (human) ( 36 )
Inhibit interaction with:
Fyn (human) ( 31 )

Disease / Diagnostics Relevance
Relevant diseases:
Alzheimer's disease ( 4 , 19 , 20 , 21 , 36 , 37 , 39 ) , type 2 diabetes ( 19 )

References 

1

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

2

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
25918155   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

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

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

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

12

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

13

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
20679343   Curated Info

14

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

15

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

16

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

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

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

23

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

24

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

25

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

26

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

27

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

28

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

29

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

30

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

31

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

32

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

33

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

34

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

35

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

36

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

37

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
12766916   Curated Info

38

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
12387894   Curated Info

39

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

40

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

41

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