Ser16

Site Information
RSAIRRAstIEMPQQ SwissProt Entrez-Gene
Blast this site against: NCBI SwissProt PDB
Site Group ID: 448114

In vivo Characterization
Methods used to characterize site in vivo:	[32P] bio-synthetic labeling ( 28 ) , immunoprecipitation ( 14 ) , mass spectrometry ( 12 ) , mutation of modification site ( 14 , 23 ) , phospho-antibody ( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 13 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ) , western blotting ( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 13 , 14 , 15 , 16 , 17 , 18 , 24 , 26 , 27 )
Disease tissue studied:	type 2 diabetes ( 6 )
Relevant cell line - cell type - tissue:	'heart, ventricle' ( 1 , 2 , 6 , 7 ) , CHO-K1 (fibroblast) ( 14 ) , heart ( 5 , 8 , 9 , 10 , 11 , 12 , 13 , 18 , 20 , 24 , 28 ) , HeLa (cervical) ( 14 ) , intestine ( 12 ) , lung ( 12 ) , muscle ( 12 ) , myocardium ( 8 ) , myocyte ( 2 , 7 ) , myocyte-heart ( 1 , 3 , 4 , 6 , 13 , 14 , 15 , 16 , 17 , 19 , 22 , 23 , 25 , 26 , 27 ) , stomach ( 12 )

Upstream Regulation
Regulatory protein:	ADCY6 (mouse) ( 16 ) , Akt1 (human) ( 16 ) , PMCA4 iso2 (human) ( 15 ) , PRKD1 (mouse) ( 17 )
Putative in vivo kinases:	Akt1 (rat) ( 16 ) , PKACA (rat) ( 19 )
Kinases, in vitro:	Akt1 (human) ( 16 )
Putative upstream phosphatases:	PPP1CA (human) ( 13 )
Treatments:	5-Methoxytryptophan ( 3 ) , 8-Rp-cAMP ( 16 ) , acidosis ( 24 ) , Akt-I-1 ( 16 ) , Akt-I-1,2 ( 16 ) , aortic banding ( 8 ) , azaserine ( 14 ) , Bay 60-7550 ( 7 ) , bradykinin ( 21 ) , Ca(2+) ( 24 , 28 ) , cariporide ( 4 ) , ciclosporin ( 13 , 19 ) , cigarette smoke extract ( 1 ) , colforsin ( 16 ) , CPA ( 16 ) , electrical_stimulation ( 20 , 26 ) , empagliflozin ( 4 ) , endothelin ( 17 ) , exercise ( 18 ) , exercise training ( 10 ) , FK506 ( 13 ) , Go_6976 ( 13 ) , H-89 ( 16 , 19 , 24 ) , high_glucose ( 14 ) , hypertension ( 25 ) , ibrutinib ( 3 ) , ICI-118,551 ( 16 ) , inhibitor-1 ( 11 ) , ischemia ( 13 , 23 ) , ischemia/reperfusion ( 23 ) , isoproterenol ( 7 , 15 , 16 , 17 , 19 , 20 , 24 , 28 ) , ketogenic diet ( 2 ) , liothyronine ( 27 ) , low_pH ( 28 ) , nifedipine ( 24 ) , norepinephrine ( 22 , 26 ) , obesity ( 9 ) , okadaic_acid ( 19 , 24 ) , PKI ( 16 ) , prazosin ( 22 , 26 ) , pressure ( 10 ) , propranolol ( 23 ) , PUGNAc ( 14 ) , resistance training ( 9 ) , serum ( 16 ) , SMLT ( 15 ) , streptozotocin ( 14 )

Downstream Regulation
Effects of modification on PLB:	activity, induced ( 13 ) , enzymatic activity, induced ( 7 , 8 )

Disease / Diagnostics Relevance
Relevant diseases:	hypertrophic cardiomyopathy ( 8 ) , diabetes mellitus ( 2 ) , type 2 diabetes ( 6 )

References
1	Matsumura S, et al. (2024) Direct toxicity of cigarette smoke extract on cardiac function mediated by mitochondrial dysfunction in Sprague-Dawley rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes. PLoS One 19, e0295737 38165883 Curated Info
2	Lee TI, et al. (2023) Ketogenic Diet Regulates Cardiac Remodeling and Calcium Homeostasis in Diabetic Rat Cardiomyopathy. Int J Mol Sci 24 38003332 Curated Info
3	Shuai W, et al. (2023) 5-Methoxytryptophan alleviates atrial structural remodeling in ibrutinib-associated atrial fibrillation. Heliyon 9, e19501 37810107 Curated Info
4	Silva Dos Santos D, et al. (2023) Empagliflozin reduces arrhythmogenic effects in rat neonatal and human iPSC-derived cardiomyocytes and improves cytosolic calcium handling at least partially independent of NHE1. Sci Rep 13, 8689 37248416 Curated Info
5	Chaoul V, et al. (2023) Differential changes in cyclic adenosine 3'-5' monophosphate (cAMP) effectors and major Ca handling proteins during diabetic cardiomyopathy. J Cell Mol Med 36967707 Curated Info
6	Ng YH, et al. (2022) Sarco/endoplasmic reticulum calcium ATPase activity is unchanged despite increased myofilament calcium sensitivity in Zucker type 2 diabetic fatty rat heart. Sci Rep 12, 16904 36207382 Curated Info
7	Wang YW, et al. (2021) Bay 60-7550, a PDE2 inhibitor, exerts positive inotropic effect of rat heart by increasing PKA-mediated phosphorylation of phospholamban. Eur J Pharmacol 901, 174077 33798601 Curated Info
8	Mazeto IFS, et al. (2021) Calcium homeostasis behavior and cardiac function on left ventricular remodeling by pressure overload. Braz J Med Biol Res 54, e10138 33624728 Curated Info
9	Melo AB, et al. (2020) Resistance training promotes reduction in Visceral Adiposity without improvements in Cardiomyocyte Contractility and Calcium handling in Obese Rats. Int J Med Sci 32714085 Curated Info
10	de Souza SLB, et al. (2020) Adjustments in ¿¿-Adrenergic Signaling Contribute to the Amelioration of Cardiac Dysfunction by Exercise Training in Supravalvular Aortic Stenosis. Cell Physiol Biochem 32639114 Curated Info
11	Pritchard TJ, et al. (2013) Active inhibitor-1 maintains protein hyper-phosphorylation in aging hearts and halts remodeling in failing hearts. PLoS One 8, e80717 24312496 Curated Info
12	Lundby A, et al. (2012) Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues. Nat Commun 3, 876 22673903 Curated Info
13	Shintani-Ishida K, Yoshida K (2011) Ischemia induces phospholamban dephosphorylation via activation of calcineurin, PKC-α, and protein phosphatase 1, thereby inducing calcium overload in reperfusion. Biochim Biophys Acta 1812, 743-51 21447388 Curated Info
14	Yokoe S, et al. (2010) Inhibition of phospholamban phosphorylation by O-GlcNAcylation: implications for diabetic cardiomyopathy. Glycobiology 20, 1217-26 20484118 Curated Info
15	Mohamed TM, et al. (2009) Specific role of neuronal nitric-oxide synthase when tethered to the plasma membrane calcium pump in regulating the beta-adrenergic signal in the myocardium. J Biol Chem 284, 12091-8 19278978 Curated Info
16	Gao MH, et al. (2008) Adenylyl cyclase type VI increases Akt activity and phospholamban phosphorylation in cardiac myocytes. J Biol Chem 283, 33527-35 18838385 Curated Info
17	Cuello F, et al. (2007) Protein kinase D selectively targets cardiac troponin I and regulates myofilament Ca2+ sensitivity in ventricular myocytes. Circ Res 100, 864-73 17322173 Curated Info
18	Kolwicz SC, et al. (2007) Effects of forskolin on inotropic performance and phospholamban phosphorylation in exercise-trained hypertensive myocardium. J Appl Physiol 102, 628-33 17082376 Curated Info
19	El-Armouche A, et al. (2006) Role of calcineurin and protein phosphatase-2A in the regulation of phosphatase inhibitor-1 in cardiac myocytes. Biochem Biophys Res Commun 346, 700-6 16774736 Curated Info
20	Valverde CA, et al. (2005) Frequency-dependent acceleration of relaxation in mammalian heart: a property not relying on phospholamban and SERCA2a phosphorylation. J Physiol 562, 801-13 15528241 Curated Info
21	Tschöpe C, et al. (2004) Improvement of defective sarcoplasmic reticulum Ca2+ transport in diabetic heart of transgenic rats expressing the human kallikrein-1 gene. FASEB J 18, 1967-9 15448111 Curated Info
22	Wang W, et al. (2004) Sustained beta1-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway. Circ Res 95, 798-806 15375008 Curated Info
23	Said M, et al. (2003) Role of dual-site phospholamban phosphorylation in the stunned heart: insights from phospholamban site-specific mutants. Am J Physiol Heart Circ Physiol 285, H1198-205 12763747 Curated Info
24	Said M, Mundiña-Weilenmann C, Vittone L, Mattiazzi A (2002) The relative relevance of phosphorylation of the Thr(17) residue of phospholamban is different at different levels of beta-adrenergic stimulation. Pflugers Arch 444, 801-9 12355181 Curated Info
25	Bokník P, et al. (2001) Enhanced protein phosphorylation in hypertensive hypertrophy. Cardiovasc Res 51, 717-28 11530105 Curated Info
26	Hagemann D, et al. (2000) Frequency-encoding Thr17 phospholamban phosphorylation is independent of Ser16 phosphorylation in cardiac myocytes. J Biol Chem 275, 22532-6 10825152 Curated Info
27	Ojamaa K, Kenessey A, Klein I (2000) Thyroid hormone regulation of phospholamban phosphorylation in the rat heart. Endocrinology 141, 2139-44 10830301 Curated Info
28	Vittone L, Mundiña-Weilenmann C, Said M, Mattiazzi A (1998) Mechanisms involved in the acidosis enhancement of the isoproterenol-induced phosphorylation of phospholamban in the intact heart. J Biol Chem 273, 9804-11 9545319 Curated Info