Ser256
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Home > Phosphorylation Site Page: > Ser256  -  AQP2 (rat)

Site Information
REVRRRQsVELHsPQ   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 449854

In vivo Characterization
Methods used to characterize site in vivo:
[32P] bio-synthetic labeling ( 41 ) , immunoassay ( 20 ) , immunoprecipitation ( 4 , 25 ) , mass spectrometry ( 17 , 25 , 27 , 32 , 35 ) , mutation of modification site ( 18 , 20 , 25 , 29 , 41 , 44 ) , phospho-antibody ( 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 16 , 20 , 22 , 23 , 24 , 26 , 27 , 28 , 30 , 31 , 33 , 34 , 35 , 36 , 39 , 40 , 41 , 42 , 43 , 45 ) , western blotting ( 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 13 , 16 , 20 , 22 , 23 , 24 , 26 , 28 , 29 , 35 , 39 , 40 , 42 , 45 )
Disease tissue studied:
kidney cancer ( 24 , 31 ) , diabetes mellitus ( 30 )
Relevant cell line - cell type - tissue:
'kidney, cortex' ( 30 , 39 ) , 'kidney, inner medulla' ( 7 , 9 , 10 , 13 , 22 , 23 , 25 , 26 , 27 , 28 , 32 , 35 , 39 , 42 ) , 'kidney, outer medulla' ( 39 ) , IMCD ( 16 , 20 ) , kidney ( 12 , 17 , 22 , 24 , 31 , 33 , 34 , 42 , 43 , 45 ) , LLC-PK1 (renal) ( 3 , 5 , 8 , 18 , 29 , 44 ) , MDCK (epithelial) ( 4 , 6 , 12 , 25 ) , mIMCD-3 (epithelial) ( 36 ) , mpkCCD (renal) ( 23 ) , RC.SV3 (renal tubule cell) ( 41 )

Upstream Regulation
Regulatory protein:
ILK (rat) ( 8 )
Putative in vivo kinases:
PKACA (rat) ( 27 )
Kinases, in vitro:
PKACA (human) ( 27 ) , PKACA (rat) ( 41 )
Treatments:
4AD ( 16 ) , ANP ( 36 ) , BUO ( 20 , 26 ) , calyculin_A ( 9 , 10 , 14 ) , cAMP_analog ( 27 ) , candesartan ( 26 , 39 ) , colforsin ( 6 , 14 , 16 , 21 , 29 , 41 ) , cpd22 ( 8 ) , desmopressin ( 7 , 11 , 21 , 22 , 23 , 27 , 28 , 31 , 32 , 33 , 35 , 39 , 45 ) , FK506 ( 9 , 10 ) , GH ( 34 ) , H-89 ( 27 ) , IBMX ( 7 ) , ibuprofen ( 13 ) , meloxicam ( 13 ) , Mn(2+) ( 3 ) , NH4Cl ( 24 ) , NKH_477 ( 4 ) , okadaic_acid ( 5 ) , osmotic_stress ( 27 ) , PGE2 ( 43 ) , roflumilast N-oxide ( 7 ) , rolipram ( 42 ) , sanguinarine ( 5 ) , seliciclib ( 14 ) , streptozotocin ( 30 ) , tolvaptan ( 15 ) , V2_vasopressin_receptor_antagonist ( 45 ) , vasopressin ( 3 , 5 , 8 , 12 , 15 , 29 , 43 )

Downstream Regulation
Effects of modification on AQP2:
intracellular localization ( 16 , 21 , 25 , 29 , 40 , 41 , 43 ) , molecular association, regulation ( 25 , 44 )
Effects of modification on biological processes:
endocytosis, inhibited ( 18 )
Induce interaction with:
GRP78 (rat) ( 25 )
Inhibit interaction with:
ANXA2 (rat) ( 25 ) , GDI2 (rat) ( 25 ) , HSC70 (rat) ( 25 ) , HSP70 (rat) ( 25 ) , PPP1CA (rat) ( 25 ) , RAN (rat) ( 25 )

Disease / Diagnostics Relevance
Relevant diseases:
diabetes mellitus ( 30 )

References 

1

Cheung PW, et al. (2018) Inhibition of non-receptor tyrosine kinase Src induces phosphoserine 256-independent aquaporin-2 membrane accumulation. J Physiol
30488437   Curated Info

2

Liwang J, et al. (2018) Role of PKC and AMPK in hypertonicity-stimulated water reabsorption in rat inner medullary collecting ducts. Am J Physiol Renal Physiol
30427219   Curated Info

3

Lei L, et al. (2017) Manganese promotes intracellular accumulation of AQP2 via modulating F-actin polymerization and reduces urinary concentration in mice. Am J Physiol Renal Physiol, ajprenal003912017
29046300   Curated Info

4

Yui N, Ando F, Sasaki S, Uchida S (2017) Ser-261 phospho-regulation is involved in pS256 and pS269-mediated aquaporin-2 apical translocation. Biochem Biophys Res Commun 490, 1039-1044
28668390   Curated Info

5

Cheung PW, et al. (2017) Protein phosphatase 2C is responsible for VP-induced dephosphorylation of AQP2 serine 261. Am J Physiol Renal Physiol 313, F404-F413
28381458   Curated Info

6

Yui N, Sasaki S, Uchida S (2017) Aquaporin-2 Ser-261 phosphorylation is regulated in combination with Ser-256 and Ser-269 phosphorylation. Biochem Biophys Res Commun 482, 524-529
27889609   Curated Info

7

Umejiego EN, Wang Y, Knepper MA, Chou CL (2017) Roflumilast and aquaporin-2 regulation in rat renal inner medullary collecting duct. Physiol Rep 5
28108651   Curated Info

8

Mamuya FA, et al. (2016) ILK and cytoskeletal architecture: an important determinant of AQP2 recycling and subsequent entry into the exocytotic pathway. Am J Physiol Renal Physiol 311, F1346-F1357
27760768   Curated Info

9

Ren H, et al. (2016) Phosphatase inhibition increases AQP2 accumulation in the rat IMCD apical plasma membrane. Am J Physiol Renal Physiol 311, F1189-F1197
27488997   Curated Info

10

Al-Bataineh MM, et al. (2016) Activation of the metabolic sensor AMP-activated protein kinase inhibits aquaporin-2 function in kidney principal cells. Am J Physiol Renal Physiol 311, F890-F900
27534994   Curated Info

11

Choi HJ, Jung HJ, Kwon TH (2015) Extracellular pH affects phosphorylation and intracellular trafficking of AQP2 in inner medullary collecting duct cells. Am J Physiol Renal Physiol 308, F737-48
25651562   Curated Info

12

Rice WL, et al. (2015) Polarized Trafficking of AQP2 Revealed in Three Dimensional Epithelial Culture. PLoS One 10, e0131719
26147297   Curated Info

13

Ren H, et al. (2015) NSAIDs Alter Phosphorylated Forms of AQP2 in the Inner Medullary Tip. PLoS One 10, e0141714
26517129   Curated Info

14

Tamma G, et al. (2014) A protein kinase A-independent pathway controlling aquaporin 2 trafficking as a possible cause for the syndrome of inappropriate antidiuresis associated with polycystic kidney disease 1 haploinsufficiency. J Am Soc Nephrol 25, 2241-53
24700872   Curated Info

15

Miranda CA, Lee JW, Chou CL, Knepper MA (2014) Tolvaptan as a tool in renal physiology. Am J Physiol Renal Physiol 306, F359-66
24305472   Curated Info

16

Bogum J, et al. (2013) Small-molecule screening identifies modulators of aquaporin-2 trafficking. J Am Soc Nephrol 24, 744-58
23559583   Curated Info

17

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

18

Rice WL, et al. (2012) Differential, phosphorylation dependent trafficking of AQP2 in LLC-PK1 cells. PLoS One 7, e32843
22403603   Curated Info

19

Olesen ET, et al. (2011) Vasopressin-independent targeting of aquaporin-2 by selective E-prostanoid receptor agonists alleviates nephrogenic diabetes insipidus. Proc Natl Acad Sci U S A 108, 12949-54
21768374   Curated Info

20

St√łdkilde L, et al. (2011) Bilateral ureteral obstruction induces early downregulation and redistribution of AQP2 and phosphorylated AQP2. Am J Physiol Renal Physiol 301, F226-35
21525134   Curated Info

21

Tamma G, et al. (2011) Regulation of AQP2 localization by S256 and S261 phosphorylation and ubiquitination. Am J Physiol Cell Physiol 300, C636-46
21148409   Curated Info

22

Hwang S, et al. (2010) Vasopressin increases phosphorylation of Ser84 and Ser486 in Slc14a2 collecting duct urea transporters. Am J Physiol Renal Physiol 299, F559-67
20576681   Curated Info

23

Xie L, et al. (2010) Quantitative analysis of aquaporin-2 phosphorylation. Am J Physiol Renal Physiol 298, F1018-23
20089674   Curated Info

24

Nowik M, et al. (2010) Induction of metabolic acidosis with ammonium chloride (NH4Cl) in mice and rats--species differences and technical considerations. Cell Physiol Biochem 26, 1059-72
21220937   Curated Info

25

Zwang NA, et al. (2009) Identification of phosphorylation-dependent binding partners of aquaporin-2 using protein mass spectrometry. J Proteome Res 8, 1540-54
19209902   Curated Info

26

Jensen AM, et al. (2009) Angiotensin II regulates V2 receptor and pAQP2 during ureteral obstruction. Am J Physiol Renal Physiol 296, F127-34
18971210   Curated Info

27

Hoffert JD, et al. (2008) Vasopressin-stimulated increase in phosphorylation at Ser269 potentiates plasma membrane retention of aquaporin-2. J Biol Chem 283, 24617-27
18606813   Curated Info

28

Yu MJ, et al. (2008) Large-scale quantitative LC-MS/MS analysis of detergent-resistant membrane proteins from rat renal collecting duct. Am J Physiol Cell Physiol 295, C661-78
18596208   Curated Info

29

Lu HJ, et al. (2008) The phosphorylation state of serine 256 is dominant over that of serine 261 in the regulation of AQP2 trafficking in renal epithelial cells. Am J Physiol Renal Physiol 295, F290-4
18434387   Curated Info

30

O'Neill H, et al. (2008) Aldosterone-mediated apical targeting of ENaC subunits is blunted in rats with streptozotocin-induced diabetes mellitus. Nephrol Dial Transplant 23, 1546-55
18029369   Curated Info

31

Fenton RA, et al. (2008) Acute regulation of aquaporin-2 phosphorylation at Ser-264 by vasopressin. Proc Natl Acad Sci U S A 105, 3134-9
18287043   Curated Info

32

Hoffert JD, et al. (2007) An automated platform for analysis of phosphoproteomic datasets: application to kidney collecting duct phosphoproteins. J Proteome Res 6, 3501-8
17683130   Curated Info

33

Hoffert JD, et al. (2007) Dynamics of aquaporin-2 serine-261 phosphorylation in response to short-term vasopressin treatment in collecting duct. Am J Physiol Renal Physiol 292, F691-700
16985212   Curated Info

34

Dimke H, et al. (2007) Acute growth hormone administration induces antidiuretic and antinatriuretic effects and increases phosphorylation of NKCC2. Am J Physiol Renal Physiol 292, F723-35
17062845   Curated Info

35

Hoffert JD, et al. (2006) Quantitative phosphoproteomics of vasopressin-sensitive renal cells: regulation of aquaporin-2 phosphorylation at two sites. Proc Natl Acad Sci U S A 103, 7159-64
16641100   Curated Info

36

Wang W, et al. (2006) Biphasic effects of ANP infusion in conscious, euvolumic rats: roles of AQP2 and ENaC trafficking. Am J Physiol Renal Physiol 290, F530-41
16174867   Curated Info

37

Bouley R, et al. (2005) Stimulation of AQP2 membrane insertion in renal epithelial cells in vitro and in vivo by the cGMP phosphodiesterase inhibitor sildenafil citrate (Viagra). Am J Physiol Renal Physiol 288, F1103-12
15644488   Curated Info

38

Nejsum LN, et al. (2005) Bidirectional regulation of AQP2 trafficking and recycling: involvement of AQP2-S256 phosphorylation. Am J Physiol Renal Physiol 288, F930-8
15625084   Curated Info

39

Kwon TH, et al. (2005) Angiotensin II AT1 receptor blockade decreases vasopressin-induced water reabsorption and AQP2 levels in NaCl-restricted rats. Am J Physiol Renal Physiol 288, F673-84
15585668   Curated Info

40

Hadrup N, et al. (2004) Opioid receptor-like 1 stimulation in the collecting duct induces aquaresis through vasopressin-independent aquaporin-2 downregulation. Am J Physiol Renal Physiol 287, F160-8
15010357   Curated Info

41

Procino G, et al. (2003) Ser-256 phosphorylation dynamics of Aquaporin 2 during maturation from the ER to the vesicular compartment in renal cells. FASEB J 17, 1886-8
12897058   Curated Info

42

Wang W, et al. (2002) AQP3, p-AQP2, and AQP2 expression is reduced in polyuric rats with hypercalcemia: prevention by cAMP-PDE inhibitors. Am J Physiol Renal Physiol 283, F1313-25
12388409   Curated Info

43

Zelenina M, et al. (2000) Prostaglandin E(2) interaction with AVP: effects on AQP2 phosphorylation and distribution. Am J Physiol Renal Physiol 278, F388-94
10710543   Curated Info

44

Umenishi F, Verbavatz JM, Verkman AS (2000) cAMP regulated membrane diffusion of a green fluorescent protein-aquaporin 2 chimera. Biophys J 78, 1024-35
10653816   Curated Info

45

Christensen BM, Zelenina M, Aperia A, Nielsen S (2000) Localization and regulation of PKA-phosphorylated AQP2 in response to V(2)-receptor agonist/antagonist treatment. Am J Physiol Renal Physiol 278, F29-42
10644653   Curated Info