Ser40

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 ( 26 , 27 , 28 ) , immunoassay ( 2 ) , immunoprecipitation ( 3 , 23 , 25 ) , mass spectrometry ( 3 ) , peptide sequencing ( 27 , 28 ) , phospho-antibody ( 1 , 2 , 3 , 4 , 5 , 7 , 8 , 9 , 10 , 14 , 15 , 16 , 17 , 19 , 21 , 22 , 23 , 24 , 25 ) , phosphoamino acid analysis ( 27 , 28 ) , phosphopeptide mapping ( 26 , 27 , 28 ) , western blotting ( 1 , 3 , 4 , 5 , 7 , 8 , 9 , 14 , 21 , 24 , 25 )
Disease tissue studied:	adrenal cancer ( 21 , 24 , 28 ) , pheochromocytoma ( 21 , 24 , 28 ) , pituitary cancer ( 24 ) , prostate cancer ( 8 )
Relevant cell line - cell type - tissue:	'brain, caudate-putamen' ( 4 , 9 , 19 ) , 'brain, hypothalamus' ( 14 , 16 ) , 'brain, nucleus accumbens' ( 9 , 19 ) , 'brain, striatum' ( 3 , 4 , 22 , 24 ) , 'brain, substantia nigra' ( 2 , 4 ) , 'brain, ventral tegmental area' ( 2 , 4 ) , 'neuron, cortical'-brain ( 15 , 23 ) , 'neuron, substantia nigra'-brain ( 7 , 15 ) , 'neuron, ventral tegmental'-brain ( 10 ) , A126-1B2 (chromaffin) ( 21 ) , adrenal gland ( 5 , 8 ) , AtT20 (pituitary cell) ( 24 , 25 ) , brain ( 5 ) , muscle ( 1 ) , N27 (neuron) ( 7 ) , PC-12 (chromaffin) ( 7 , 17 , 21 , 24 , 25 , 28 ) , PC3 (prostate cell) ( 8 )

Upstream Regulation
Regulatory protein:	GFRA1 (rat) ( 15 )
Putative in vivo kinases:	PKACA (rat) ( 21 , 27 )
Kinases, in vitro:	CAMK1A (human) ( 29 ) , CAMK2A (rat) ( 20 ) , PKACA (human) ( 11 , 12 , 29 ) , PKACA (rat) ( 17 , 20 ) , PKCA (human) ( 29 )
Putative upstream phosphatases:	PPP2CA (mouse) ( 7 ) , PPP2CB (rat) ( 8 )
Phosphatases, in vitro:	PPP2CA (rat) ( 18 ) , PPP2CB (rat) ( 8 ) , PPPM1A (human) ( 18 )
Treatments:	angiotensin ( 16 ) , apomorphine ( 24 ) , ATP ( 26 ) , bradykinin ( 26 ) , butyrolactone ( 24 ) , caffeine ( 26 ) , cAMP_analog ( 22 , 23 , 26 , 28 ) , CHIR99021 ( 1 ) , cocaine ( 19 ) , colforsin ( 21 , 22 , 23 , 27 , 28 ) , depolarization ( 21 , 25 , 27 ) , EGF ( 28 ) , electrical_stimulation ( 27 ) , eticlopride ( 22 ) , food deprivation ( 9 ) , GDNF ( 15 ) , genistein ( 26 ) , high-fat diet ( 2 ) , hypoxia ( 17 ) , insulin ( 5 ) , KN-62 ( 17 ) , leptin ( 10 ) , levamfetamine ( 9 ) , lithium ( 1 ) , LPS ( 4 ) , muscarine ( 26 ) , nerve_damage ( 24 ) , neurotensin ( 28 ) , NGF ( 26 , 28 ) , NMDA ( 23 ) , NSD-1015 ( 24 ) , okadaic_acid ( 3 , 7 , 8 , 22 , 23 , 28 ) , PD98059 ( 17 , 21 ) , phorbol_ester ( 27 , 28 ) , PKI ( 17 ) , PRL ( 14 ) , quinpirole ( 22 ) , Ro-20-1724 ( 22 ) , rottlerin ( 7 ) , secretin human ( 28 ) , somatostatin ( 28 ) , substance_P ( 28 ) , t-Bu2BHQ ( 26 ) , thapsigargin ( 26 ) , Theophylline ( 26 ) , Time ( 4 ) , VIP ( 28 )

Downstream Regulation
Effects of modification on TH:	enzymatic activity, induced ( 2 , 7 , 16 , 17 , 19 , 23 , 25 , 26 ) , molecular association, regulation ( 13 ) , protein conformation ( 6 , 20 ) , protein stabilization ( 13 )

References
1	Hamdon S, et al. (2023) CHIR99021 causes inactivation of Tyrosine Hydroxylase and depletion of dopamine in rat brain striatum. Neuropharmacology 242, 109759 37844866 Curated Info
2	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
3	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
4	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
5	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
6	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
7	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
8	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
9	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
10	Hommel JD, et al. (2006) Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 51, 801-10 16982424 Curated Info
11	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
12	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
13	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
14	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
15	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
16	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
17	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
18	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
19	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
20	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
21	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
22	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
23	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
24	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
25	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
26	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
27	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
28	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
29	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