Ser40
Javascript is not enabled on this browser. This site will not work properly without Javascript.
PhosphoSitePlus Homepage PhosphoSitePlus® v6.6.0.4
Powered by Cell Signaling Technology
Home > Phosphorylation Site Page: > Ser40  -  TH (rat)

Site Information
RFIGRRQsLIEDARK   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 448545

In vivo Characterization
Methods used to characterize site in vivo:
[32P] bio-synthetic labeling ( 25 , 26 , 27 ) , immunoprecipitation ( 22 , 24 ) , peptide sequencing ( 26 , 27 ) , phospho-antibody ( 3 , 4 , 6 , 7 , 8 , 9 , 13 , 14 , 15 , 16 , 18 , 20 , 21 , 22 , 23 , 24 ) , phosphoamino acid analysis ( 26 , 27 ) , phosphopeptide mapping ( 25 , 26 , 27 ) , western blotting ( 3 , 4 , 6 , 7 , 8 , 13 , 20 , 23 , 24 )
Disease tissue studied:
adrenal cancer ( 20 , 23 , 27 ) , pheochromocytoma ( 20 , 23 , 27 ) , pituitary cancer ( 23 ) , prostate cancer ( 7 )
Relevant cell line - cell type - tissue:
'brain, caudate-putamen' ( 3 , 8 , 18 ) , 'brain, hypothalamus' ( 13 , 15 ) , 'brain, nucleus accumbens' ( 8 , 18 ) , 'brain, striatum' ( 3 , 21 , 23 ) , 'brain, substantia nigra' ( 3 ) , 'brain, ventral tegmental area' ( 3 ) , 'neuron, cortical'-brain ( 14 , 22 ) , 'neuron, substantia nigra'-brain ( 6 , 14 ) , 'neuron, ventral tegmental'-brain ( 9 ) , A126-1B2 (chromaffin) ( 20 ) , adrenal gland ( 4 , 7 ) , AtT20 (pituitary cell) ( 23 , 24 ) , brain ( 4 ) , N27 (neuron) ( 6 ) , PC-12 (chromaffin) ( 6 , 16 , 20 , 23 , 24 , 27 ) , PC3 (prostate cell) ( 7 )

Upstream Regulation
Regulatory protein:
GFRA1 (rat) ( 14 )
Putative in vivo kinases:
PKACA (rat) ( 20 , 26 )
Kinases, in vitro:
CAMK1A (human) ( 28 ) , CAMK2A (rat) ( 19 ) , PKACA (human) ( 10 , 11 , 28 ) , PKACA (rat) ( 16 , 19 ) , PKCA (human) ( 28 )
Putative upstream phosphatases:
PPP2CA (mouse) ( 6 ) , PPP2CB (rat) ( 7 )
Phosphatases, in vitro:
PPP2CA (rat) ( 17 ) , PPP2CB (rat) ( 7 ) , PPPM1A (human) ( 17 )
Treatments:
angiotensin ( 15 ) , apomorphine ( 23 ) , ATP ( 25 ) , bradykinin ( 25 ) , butyrolactone ( 23 ) , caffeine ( 25 ) , cAMP_analog ( 21 , 22 , 25 , 27 ) , cocaine ( 18 ) , colforsin ( 20 , 21 , 22 , 26 , 27 ) , depolarization ( 20 , 24 , 26 ) , EGF ( 27 ) , electrical_stimulation ( 26 ) , eticlopride ( 21 ) , food deprivation ( 8 ) , GDNF ( 14 ) , genistein ( 25 ) , hypoxia ( 16 ) , insulin ( 4 ) , KN-62 ( 16 ) , leptin ( 9 ) , levamfetamine ( 8 ) , LPS ( 3 ) , muscarine ( 25 ) , nerve_damage ( 23 ) , neurotensin ( 27 ) , NGF ( 25 , 27 ) , NMDA ( 22 ) , NSD-1015 ( 23 ) , okadaic_acid ( 6 , 7 , 21 , 22 , 27 ) , PD98059 ( 16 , 20 ) , phorbol_ester ( 26 , 27 ) , PKI ( 16 ) , PRL ( 13 ) , quinpirole ( 21 ) , Ro-20-1724 ( 21 ) , rottlerin ( 6 ) , secretin human ( 27 ) , somatostatin ( 27 ) , substance_P ( 27 ) , t-Bu2BHQ ( 25 ) , thapsigargin ( 25 ) , Theophylline ( 25 ) , Time ( 3 ) , VIP ( 27 )

Downstream Regulation
Effects of modification on TH:
enzymatic activity, induced ( 6 , 15 , 16 , 18 , 22 , 24 , 25 ) , molecular association, regulation ( 12 ) , protein conformation ( 5 , 19 ) , protein stabilization ( 12 )

References 

1

Bittencourt A, et al. (2022) High fat diet-induced obesity causes a reduction in brain tyrosine hydroxylase levels and non-motor features in rats through metabolic dysfunction, neuroinflammation and oxidative stress. Nutr Neurosci 25, 1026-1040
33078695   Curated Info

2

González-Sepúlveda M, et al. (2022) Spontaneous changes in brain striatal dopamine synthesis and storage dynamics ex vivo reveal end-product feedback-inhibition of tyrosine hydroxylase. Neuropharmacology 212, 109058
35429504   Curated Info

3

Ong LK, et al. (2021) Peripheral inflammation induces long-term changes in tyrosine hydroxylase activation in the substantia nigra. Neurochem Int 146, 105022
33746005   Curated Info

4

Senthilkumaran M, Johnson ME, Bobrovskaya L (2016) The Effects of Insulin-Induced Hypoglycaemia on Tyrosine Hydroxylase Phosphorylation in Rat Brain and Adrenal Gland. Neurochem Res 41, 1612-24
26935743   Curated Info

5

Wang S, et al. (2011) Fluorescence spectroscopy as a probe of the effect of phosphorylation at serine 40 of tyrosine hydroxylase on the conformation of its regulatory domain. Biochemistry 50, 2364-70
21302933   Curated Info

6

Zhang D, et al. (2007) Protein kinase C delta negatively regulates tyrosine hydroxylase activity and dopamine synthesis by enhancing protein phosphatase-2A activity in dopaminergic neurons. J Neurosci 27, 5349-62
17507557   Curated Info

7

Saraf A, Virshup DM, Strack S (2007) Differential expression of the B'beta regulatory subunit of protein phosphatase 2A modulates tyrosine hydroxylase phosphorylation and catecholamine synthesis. J Biol Chem 282, 573-80
17085438   Curated Info

8

Pan Y, et al. (2006) Synthesis, protein levels, activity, and phosphorylation state of tyrosine hydroxylase in mesoaccumbens and nigrostriatal dopamine pathways of chronically food-restricted rats. Brain Res 1122, 135-42
17010321   Curated Info

9

Hommel JD, et al. (2006) Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 51, 801-10
16982424   Curated Info

10

Lehmann IT, et al. (2006) Differential regulation of the human tyrosine hydroxylase isoforms via hierarchical phosphorylation. J Biol Chem 281, 17644-51
16644734   Curated Info

11

Royo M, Colette Daubner S (2006) Kinetics of regulatory serine variants of tyrosine hydroxylase with cyclic AMP-dependent protein kinase and extracellular signal-regulated protein kinase 2. Biochim Biophys Acta 1764, 786-92
16503426   Curated Info

12

Royo M, Fitzpatrick PF, Daubner SC (2005) Mutation of regulatory serines of rat tyrosine hydroxylase to glutamate: effects on enzyme stability and activity. Arch Biochem Biophys 434, 266-74
15639226   Curated Info

13

Ma FY, Grattan DR, Goffin V, Bunn SJ (2005) Prolactin-regulated tyrosine hydroxylase activity and messenger ribonucleic acid expression in mediobasal hypothalamic cultures: the differential role of specific protein kinases. Endocrinology 146, 93-102
15388649   Curated Info

14

Salvatore MF, et al. (2004) Striatal GDNF administration increases tyrosine hydroxylase phosphorylation in the rat striatum and substantia nigra. J Neurochem 90, 245-54
15198683   Curated Info

15

Ma FY, et al. (2004) Angiotensin II regulates tyrosine hydroxylase activity and mRNA expression in rat mediobasal hypothalamic cultures: the role of specific protein kinases. J Neurochem 90, 431-41
15228599   Curated Info

16

Kumar GK, et al. (2003) Activation of tyrosine hydroxylase by intermittent hypoxia: involvement of serine phosphorylation. J Appl Physiol 95, 536-44
12692140   Curated Info

17

Bevilaqua LR, et al. (2003) Role of protein phosphatase 2C from bovine adrenal chromaffin cells in the dephosphorylation of phospho-serine 40 tyrosine hydroxylase. J Neurochem 85, 1368-73
12787056   Curated Info

18

Jedynak JP, Ali SF, Haycock JW, Hope BT (2002) Acute administration of cocaine regulates the phosphorylation of serine-19, -31 and -40 in tyrosine hydroxylase. J Neurochem 82, 382-8
12124439   Curated Info

19

Bevilaqua LR, et al. (2001) Phosphorylation of Ser(19) alters the conformation of tyrosine hydroxylase to increase the rate of phosphorylation of Ser(40). J Biol Chem 276, 40411-6
11502746   Curated Info

20

Salvatore MF, Waymire JC, Haycock JW (2001) Depolarization-stimulated catecholamine biosynthesis: involvement of protein kinases and tyrosine hydroxylase phosphorylation sites in situ. J Neurochem 79, 349-60
11677263   Curated Info

21

Lindgren N, et al. (2001) Dopamine D(2) receptors regulate tyrosine hydroxylase activity and phosphorylation at Ser40 in rat striatum. Eur J Neurosci 13, 773-80
11207812   Curated Info

22

Lindgren N, et al. (2000) Regulation of tyrosine hydroxylase activity and phosphorylation at Ser(19) and Ser(40) via activation of glutamate NMDA receptors in rat striatum. J Neurochem 74, 2470-7
10820208   Curated Info

23

Lew JY, et al. (1999) Increased site-specific phosphorylation of tyrosine hydroxylase accompanies stimulation of enzymatic activity induced by cessation of dopamine neuronal activity. Mol Pharmacol 55, 202-9
9927609   Curated Info

24

Haycock JW, et al. (1998) Role of serine-19 phosphorylation in regulating tyrosine hydroxylase studied with site- and phosphospecific antibodies and site-directed mutagenesis. J Neurochem 71, 1670-5
9751201   Curated Info

25

Haycock JW, Ahn NG, Cobb MH, Krebs EG (1992) ERK1 and ERK2, two microtubule-associated protein 2 kinases, mediate the phosphorylation of tyrosine hydroxylase at serine-31 in situ. Proc Natl Acad Sci U S A 89, 2365-9
1347949   Curated Info

26

Haycock JW, Haycock DA (1991) Tyrosine hydroxylase in rat brain dopaminergic nerve terminals. Multiple-site phosphorylation in vivo and in synaptosomes. J Biol Chem 266, 5650-7
1672315   Curated Info

27

Haycock JW (1990) Phosphorylation of tyrosine hydroxylase in situ at serine 8, 19, 31, and 40. J Biol Chem 265, 11682-91
1973163   Curated Info

28

Campbell DG, Hardie DG, Vulliet PR (1986) Identification of four phosphorylation sites in the N-terminal region of tyrosine hydroxylase. J Biol Chem 261, 10489-92
2874140   Curated Info