Phosphorylation Sites Regulated by Vasopressin in Collecting Duct
Consensus responses from two experimental models: native rat IMCD cells (Deshpande et al. ) and cultured mouse mpkCCD cells (Datta et al. ).
Green nodes indicate increased phosphorylation in response to vasopressin; red nodes indicate decreased phosphorylation. Yellow nodes represent cell-level processes regulated by vasoporessin. (Place cursor over object to reveal documentation. References given as PMID numbers.) Please cite : Park et al., 2023, PMID:36264882 .
image/svg+xml
Vasopressin inhibits AQP2 endocytosis (PMID:12676734, 8396343). Vasopressin increases the rate of exocytic insertion of AQP2 into the apical plasma membrane in collecting duct cells (PMID:18799651, 8396343, 12676734). (Note: Many studies have demonstrated vasopressin-induced redistribution of AQP2 to the apical domain in collecting duct cells but do not distinguish between effects of exo- versus endocytosis.)
Transmembrane transport
Aquaporin-2 (Aqp2) forms a water-specific channel that provides the apical plasma membranes of renal collecting duct with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient (PMID:8429910, 7532304). Plays an essential role in renal water homeostasis (PMID:11773613). Phosphorylation at S256 (EVRRRQS*VELHSP) increases with vasopressin and is necessary for channel exocytosis (PMID:9169447, 9227644).
Aqp2 S256
The apical and subapical distribution of AQP2 is dependent on microtubules (PMID: 7539496)
Microtubule cytoskeleton
CAP-Gly domain-containing linker protein 1 binds to the plus end of microtubules and regulates the dynamics of the microtubule cytoskeleton. Promotes microtubule growth and microtubule bundling. Links cytoplasmic vesicles to microtubules and thereby plays an important role in intracellular vesicle trafficking. Plays a role macropinocytosis and endosome trafficking (PMID:12433698, 17889670, 17563362_human). Vasopressin increases phosphorylation at S347 (RYARKIS*GTTALQ); effect unknown.
Clip1 S347
Regulator of microtubule dynamics protein 3 is involved in cellular calcium homeostasis regulation (Bysimilarity). May participate in differentiation and apoptosis of keratinocytes. Overexpression induces apoptosis. Vasopressin increases phosphorylation at S46 (RHGRSHS*LPNSLD); effect unknown.
Rmdn3 S46
Vasopressin stimulates intracellular Ca2+ mobilization. As a critical secondary messenger, Ca2+ oscillations in collecting duct is involved in protein trafficking to the plasma membrane and osmotic water permeability (PMID:2838523, 8342613, 10973964).
Calcium Signaling
Inositol 1,4,5-trisphosphate receptor type 1 is an intracellular channel that mediates calcium release from the endoplasmic reticulum following stimulation by inositol 1,4,5-trisphosphate. Involved in the regulation of epithelial secretion of electrolytes and fluid through the interaction with AHCYL1 (PMID:23542070). Plays a role in ER stress-induced apoptosis. Cytoplasmic calcium released from the ER triggers apoptosis by the activation of CaM kinase II, eventually leading to the activation of downstream apoptosis pathways(PMID:19752026, 20813840, 23542070, 2554142). Vasopressin increases phosphorylation at S1588 (NAARRDS*VLAASR); PKA-mediated phosphorylation of S1588 enhances Ca2+ release (PMID:15308649, 17257671, 22495310).
Itpr1 S1588
Phosphatidylinositol 4-kinase beta phosphorylates phosphatidylinositol (PI) in the first committed step in the production of the second messenger inositol-1,4,5,-trisphosphate (PIP) (PMID:8973579_rat). May regulate Golgi disintegration/reorganization during mitosis, possibly via its phosphorylation. Involved in Golgi-to-plasma membrane trafficking. (PMID:8973579_rat). Vasopressin increases phosphorylation at S511 (DIRRRLS*EQLAHT); effect unknown.
Pi4kb S511
Inositol 1,4,5-trisphosphate receptor type 3 is a receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium. (PMID:20813840, 21030605). Vasopressin increases phosphorylation at S1832 (TKGRVSS*FSMPSS); effect unknown.
Itpr3 S1832
Inositol 1,4,5-trisphosphate receptor type 2 is a receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium. This release is regulated by cAMP both dependently and independently of PKA (PMID:15632133, 19608738, 20189985). Isoform 3 has neither inositol 1,4,5-trisphosphate binding activity nor calcium releasing activity (PMID:15632133).Vasopressin increases phosphorylation at S1709 (YFKGDHS*ISVNGP); effect unknown.
Itpr2 S1709
Inositol 1,4,5-trisphosphate receptor type 1 is an intracellular channel that mediates calcium release from the endoplasmic reticulum following stimulation by inositol 1,4,5-trisphosphate. Involved in the regulation of epithelial secretion of electrolytes and fluid through the interaction with AHCYL1 (PMID:23542070). Plays a role in ER stress-induced apoptosis. Cytoplasmic calcium released from the ER triggers apoptosis by the activation of CaM kinase II, eventually leading to the activation of downstream apoptosis pathways(PMID:19752026, 20813840, 23542070, 2554142). Vasopressin increases phosphorylation at S1755 (PSGRRES*LTSFGN); PKA-mediated phosphorylation of S1755 enhances Ca2+ release (PMID:15308649, 17257671, 22495310).
Itpr1 S1755
Stromal interaction molecule 1 plays a role in mediating store-operated Ca(2+) entry (SOCE), a Ca(2+) influx following depletion of intracellular Ca(2+) stores. Acts as Ca(2+) sensor in the endoplasmic reticulum via its EF-hand domain. Upon Ca(2+) depletion, translocates from the endoplasmic reticulum to the plasma membrane where it activates the Ca(2+) release-activated Ca(2+) (CRAC) channel subunit ORAI1 (PMID:16208375, 16537481). Involved in enamel formation (PMID:24621671_human). Activated following interaction with STIMATE, leading to promote STIM1 conformational switch. (PMID:16208375, 16537481_human). Vasopressin decreases phosphorylation at S575 (VEKLPDS*PALAKK); ERK1/2 phosphorylates STIM1 at S575. Prevention of S575 phosphorylation reduced Ca2+ entry (PMID:20736304, 23687376)
Stim1 S575
Vasopressin regulates the transcription of several genes in collecting duct cells. Interaction of RNA polymerase II with promotor-proximal region (PPR) of genes accelerates transcriptional elongation (PMID: 27725713).
RNA processing
mRNA decay activator protein ZFP36L1, Zinc-finger RNA-binding protein that destabilizes several cytoplasmic AU-rich element (ARE)-containing mRNA transcripts by promoting their poly(A) tail removal or deadenylation, and hence provide a mechanism for attenuating protein synthesis (PMID:22701344, 24700863, 24733888, 27102483). Binds to 3'-UTR ARE of numerous mRNAs (PMID:22701344, 24700863, 24733888). Promotes ARE-mediated mRNA decay of mineralocorticoid receptor NR3C2 mRNA in response to hypertonic stress (PMID:24700863). Plays a role in the regulation of nuclear mRNA 3'-end processing; modulates mRNA 3'-end maturation efficiency of the DLL4 mRNA through binding with an ARE embedded in a weak noncanonical polyadenylation (poly(A)) signal in endothelial cells. Vasopressin increases phosphorylation at S54 (GFPRRHS*VTLPSS); MAPKAPK2 phosphorylates at S54, which inhibits its binding to mRNA (PMID:26280535, 27708140).
Zfp36l1 S54
Protein PRRC2A may play a role in the regulation of pre-mRNA splicing. Vasopressin increases phosphorylation at S454 (RQRRKQS*SSEISL); effect unknown.
Prrc2a S454
Protein PRRC2A may play a role in the regulation of pre-mRNA splicing. Vasopressin decreases phosphorylation at T782 (LLRERGT*PPVDPK); effect unknown.
Prrc2a T782
Protein phosphorylation plays a pivotal role in regulating vasopressin-mediated water and solute transport in collecting duct cells. Majority of protein phosphorylation is mediated by Protein kinase A (PKA), and downstream protein kinases, such as Cdk18, Camkk2, and Mylk, are involved in protein phosphorylation in vasopressin signaling (PMID: 33346914, 32245905, 28973931, 31904282).
Protein phosphorylation
Src, non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation (PMID:8672527,9442882,11964124). Role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors (PMID:9344858). Mediates IL6 signaling by activating YAP1-NOTCH pathway to induce inflammation-induced epithelial regeneration (PMID:25731159). Vasopressin increases phosphorylation at S17 (ASQRRRS*LEPSEN); In PC12 cells, both cAMP and NGF induce phosphorylation of Src at S17 and activate the small G protein Rap1 (PMID:15546918).
Src S17
Calcium/calmodulin-dependent protein kinase kinase 2, Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Phosphorylates CAMK1, CAMK4 and CAMK1D. Efficiently phosphorylates 5'-AMP-activated protein kinase (AMPK) trimer, including that consisting of PRKAA1, PRKAB1 and PRKAG1. This phosphorylation is stimulated in response to Ca(2+) signals. May play a role in neurite growth. Isoform 2 may promote neurite elongation, while isoform 1 may promoter neurite branching. May be involved in hippocampal activation of CREB1(PMID:14586002). Vasopressin increases phosphorylation at S511 (TMIRKRS*FGNPFE); effect unknown.
Camkk2 S511
Receptor tyrosine-protein kinase erbB-3. Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins. Binds to neuregulin-1 (NRG1) and is activated by it; ligand-binding increases phosphorylation on tyrosine residues and promotes its association with the p85 subunit of phosphatidylinositol 3-kinase (PMID:20682778_human). May also be activated by CSPG5 (PMID:15358134). Involved in the regulation of myeloid cell differentiation (PMID:27416908). Vasopressin increases phosphorylation at S980 (LVIKRAS*GPGIPP); effect unknown.
Erbb3 S980
Calcium/calmodulin-dependent protein kinase kinase 2, Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Phosphorylates CAMK1, CAMK4 and CAMK1D. Efficiently phosphorylates 5'-AMP-activated protein kinase (AMPK) trimer, including that consisting of PRKAA1, PRKAB1 and PRKAG1. This phosphorylation is stimulated in response to Ca(2+) signals. May play a role in neurite growth. Isoform 2 may promote neurite elongation, while isoform 1 may promoter neurite branching. May be involved in hippocampal activation of CREB1(PMID:14586002). Vasopressin increases phosphorylation at S495 (TMIRKRS*FGNPFE); effect unknown.
Camkk2 S495
Cyclin-dependent kinase 18 may play a role in signal transduction cascades in terminally differentiated cells. Vasopressin increases phosphorylation at S66 (QNQRRFS*MEDLNK); effect unknown.
Cdk18 S66
Misshapen-like kinase 1, serine/threonine kinase which acts as a negative regulator of Ras-related Rap2-mediated signal transduction to control neuronal structure and AMPA receptor trafficking. Required for normal synaptic density, dendrite complexity, as well as surface AMPA receptor expression in hippocampal neurons. Can activate the JNK and MAPK14/p38 pathways and mediates stimulation of the stress-activated protein kinase MAPK14/p38 MAPK downstream of the Raf/ERK pathway. Phosphorylates: TANC1 upon stimulation by RAP2A, MBP and SMAD1. Has an essential function in negative selection of thymocytes, perhaps by coupling NCK1 to activation of NK1. (PMID:10708748, 15608642) Vasopressin decreases phosphorylation at S746 (STKLDSS*PVLSPG); effect unknown.
Mink1 S746
Aquaporin-2 (Aqp2) forms a water-specific channel that provides the apical plasma membranes of renal collecting duct with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient (PMID:8429910, 7532304). Plays an essential role in renal water homeostasis (PMID:11773613). Phosphorylation at S261 (QSVELHS*PQSLPR) decreases with vasopressin (PMID:16985212) and its role in aquaporin-2 trafficking is uncertain (PMID:18434387, 21148409).
Aqp2 S261
Vasopressin-mediated structural changes is associated with the multiple interaction between the cytoskeleton and the plasma membrane, including focal adhesions, adherens junction, and tight junctions (PMID: 22992673, 15347643, 24085853). The formation of tight junction and cell-cell adhesions at the border of an apical and a basolateral regions are closely related to establish apicobasal polarity of renal epithelial cells.
Cell polarity
Leucine zipper protein 1. Vasopressin increases phosphorylation at S261 (ESKRKGS*LDYLKQ); effect unknown.
Luzp1 S261
Immunoglobulin superfamily member 5 provides, together with MAGI1, an adhesion machinery at tight junctions, which may regulate the permeability of kidney glomerulus and small intestinal epithelial cells. Mediates calcium-independent homophilic cell adhesion. In testis, it mayfunction as a cell adhesion molecule rather than a tight-junction protein. It may participate in the adhesion between spermatogonia-spermatogonia, spermatogonia-Sertoli cells, and Sertoli cells-Sertoli cells (PMID:12773569, 16982697). Vasopressin increases phosphorylation at S335 (PEKRSSS*LPYQEL); effect unknown.
Igsf5 S335
Na(+)/H(+) exchange regulatory cofactor NHE-RF1 is a scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family. Helps to link them to the actin cytoskeleton and to regulate their surface expression. Necessary for recycling of internalized ADRB2. Play a role in the regulation of the activity and subcellular location of SLC9A3. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. May enhance Wnt signaling. Involved in the regulation of phosphate reabsorption in the renal proximal tubules. (PMID:9560162). Vasopressin decreases phosphorylation at S275 (VEPASES*PRPALA); effect unknown.
Slc9a3r1 S275
Septin-9 a is Filament-forming cytoskeletal GTPase. May play a role in cytokinesis. Vasopressin decreases phosphorylation at T143 (EVLGHKT*PEPVPR); effect unknown.
Sept9 T143
Protein TANC1 may be a scaffold component in the postsynaptic density. Vasopressin decreases phosphorylation at S1665 (SSGSSGS*PSSSIK); effect unknown.
Tanc1 S1665
Tomosyn (Stxbp5) interacts with the t-SNAREs syntaxin4 and SNAP23 and inhibits translocation of GLUT4 from intracellular vesicles to the plasma membrane (PMID:12832401) Regulatory role in calcium-dependent exocytosis and neurotransmitter release. Inhibits membrane fusion between transport vesicles and the plasma membrane. May modulate the assembly of trans-SNARE complexes between transport vesicles and the plasma membrane. Vasopressin increases phosphoryation of S760; effect unknown.
Stxbp5 S760
Vasopressin promotes cellular water permeability mediated by stimulating exocytosis of AQP2-laden vesicles from cytoplasm to apical membrane (PMID: 7532304,15905145).
Vesicle-mediated transport
Intersectin-1 regulates endocytosis by linking to dynamin and Eps15; Itsn1-Eps15 scaffold links dynamin, epsin and other endocytic pathway components (PMID:10064583). Provides a link between the endocytic membrane traffic and the actin assembly machinery. Acts as guanine nucleotide exchange factor (GEF) for CDC42, and thereby stimulates actin nucleation mediated by WASL and the ARP2/3 complex. Plays a role in the assembly and maturation of clathrin-coated vesicles. Inhibits ARHGAP31 activity toward RAC1. (PMID:10064583, 16914641, 18676989, 23633571). Binds to C-terminal proline-rich domain of dynamin via SH3 domain (PMID:25374663). Three dynamin-binding partners (intersectin, amphiphysin and endophilin) have been shown to play important roles in the clathrin-mediated endocytosis process(PMID:25374663). Links WNK kinases to endocytosis of ROMK in kidney (PMID:17380208). Vasopressin increases phosphorylation at S315 (RRVRSGS*GMSVIS); effect unknown.
Itsn1 S315
Amphiphsin 2. Involved in the control of plasma membrane curvature, and membrane shaping and remodeling. A negative regulator of endocytosis. Involved in the regulation of intracellular vesicle sorting. May be involved in the regulation of MYC activity and the control cell proliferation (PMID:12183633, 12668730, 27179792). Vasopressin increases phosphorylation at S304 (SPPPDGS*PAATPE); effect unknown.
Bin1 S304
NSFL1 cofactor p47. Part of a ternary complex containing STX5A, NSFL1C and Valosin-containing protein (VCP). Reduces the ATPase activity of VCP. PINK1-activated PKA phosphorylates NSFL1C at a novel site (S176) to regulate dendritic complexity (PMID:30783609). Vasopressin increases phosphorylation at S176 (GERRRHS*GQDVHV). Phosphorylation induces activity.
Nsfl1c S176
BLOC-1-related complex subunit 6 (Borcs6) is part of the BORC complex composed of BLOC1S1, BLOC1S2, BORCS5, BORCS6, BORCS7, BORCS8, KXD1 and SNAPIN. Possible role in lysosome movement and localization at the cell periphery. On cytosolic face of lysosomes, the BORC complex may recruit ARL8B and couple lysosomes to microtubule plus-end-directed kinesin motor. It regulates late endosomal/lysosomal size through PIKfyve-dependent phosphatidylinositol-3,5-bisphosphate (PMID:31314175). Vasopressin increases phosphorylation at S173 (RLQDSRS*LDGLSG); effect unknown.
Borcs6 S173
Biogenesis of lysosome-related organelles complex 1 subunit 5 (Bloc1s5), a component of the BLOC-1 complex, composed of BLOC1S1, BLOC1S2, BLOC1S3, BLOC1S4, BLOC1S5, BLOC1S6, DTNBP1/BLOC1S7 and SNAPIN/BLOC1S8. Required for normal biogenesis of lysosome-related organelles (LRO), such as melanosomes. In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles. (PMID:11912185, 12019270, 16760431). Required for selective membrane protein trafficking from endosomes to primary cilia (PMID:28576874). Vasopressin increases phosphorylation at S23 (GGKKRDS*LGTPGA); effect unknown.
Bloc1s5 S23
Vesicle-trafficking protein SEC22b, a SNARE involved in targeting and fusion of ER-derived transport vesicles with the Golgi complex as well as Golgi-derived retrograde transport vesicles with the ER. Vasopressin increases phosphorlation at S137 (ARRNLGS*INTELQ); effect unknown.
Sec22b S137
Exocyst complex component 7 is part of the exocyst complex composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8. The exocyst complex is involved in the docking of exocytic vesicles with fusion sites on the plasma membrane. Plays a crucial role in targeting SLC2A4 vesicle to the plasma membrane in response to insulin (PMID:12687004). Serves to direct vesicles after the Golgi complex to specific locations on the plasma membrane and to mediate their tethering and localization to the membrane immediately before fusion (PMID:8978675). Localized to the plasma membrane, and is attached to the membrane by Rho GTPases such as CDC42. In epithelial cells, being recruited to cell-cell contacts, but then sorts out to the apex of the lateral membrane with components of tight junction and nectin complexes (PMID:14709721). Vasopressin decreases phosphorylation at S250 (SSGVPYS*PAIPNK). ERK1/2 phosphorylates Exo70 at Ser250, promoting exocyst complex assembly and exocytosis (PMID:22595671).
Exoc7 S250
Rabconnectin-3 (Wdr7). involved in vesicle mobilization and Ca2+-dependent exocytosis at synapses. Contributes to activation and deactivation of RAB3A (PMID:16473606). Vasopressin decreases phosphorylation at S935 (LSKARDS*PPPSSN); effect unknown.
Wdr7 S935
Leucine-rich repeat flightless-interacting protein 1, transcriptional repressor which preferentially binds to the GC-rich consensus sequence (5'-AGCCCCCGGCG-3') and may regulate expression of TNF, EGFR and PDGFA. May control smooth muscle cells proliferation following artery injury through PDGFA repression. May also bind double-stranded RNA. Positively regulates Toll-like receptor (TLR) signaling in response to agonist probably by competing with the negative FLII regulator for MYD88-binding. Vasopressin increases phosphorylation at S88 (TSSRRGS*GDTSIS); effect unknown.
Lrrfip1 S88
Ventricular zone-expressed PH domain-containing protein 1 interacts with TGF-beta receptor type-1 (TGFBR1) and inhibits dissociation of activated SMAD2 from TGFBR1, impeding its nuclear accumulation and resulting in impaired TGF-beta signaling. May also affect FOXO, Hippo and Wnt signaling (PMID: 26039994). Vasopressin increases phosphorylation at S430 (GSGRRYS*LDHISK); effect unknown.
Veph1 S430
Catenin beta-1 is a downstream component of the canonical Wnt signaling pathway (PMID:15132997). In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes. Binds TCF/LEF-1 family members, BCL9, BCL9L and possibly also RUVBL1 and CHD8. Involved in the regulation of cell adhesion, as component of an E-cadherin:catenin adhesion complex (PMID:16325582, 18093941). Vasopressin increases phosphorylation at T551 (QDTQRRT*SMGGTQ); effect unknown.
Ctnnb1 T551
Catenin beta-1 is a downstream component of the canonical Wnt signaling pathway (PMID:15132997). In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes. Binds TCF/LEF-1 family members, BCL9, BCL9L and possibly also RUVBL1 and CHD8. Involved in the regulation of cell adhesion, as component of an E-cadherin:catenin adhesion complex (PMID:16325582, 18093941). Vasopressin increases phosphorylation at S552 (DTQRRTS*MGGTQQ); effect unknown.
Ctnnb1 S552
Histone deacetylase 4 is responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PMID: 10523670). Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D. Deacetylates HSPA1A and HSPA1A at 'Lys-77' leading to their preferential binding to co-chaperoneSTUB1 (PMID:27708256). Vasopressin decreases phosphorylation at S245 (PLRKTAS*EPNLKL); effect unknown.
Hdac4 S245
TSC22 domain family protein 4 is a transcriptional repressor. Vasopressin decreases phosphorylation at T223 (GGSAAAT*PPLSRR); effect unknown.
Tsc22d4 T223
Vasopressin increases the intracellular level of cAMP in renal collecting duct cells through activating adenylyl cyclase 6 (AC6). Increase intracellular cAMP promotes activation of protein kinases, such as PKA and MLCK, intracellular Ca2+ oscillation and activation of Rap-GEF Epac (PMID: 1320335, 17928581).
cAMP dependent signaling
High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A hydrolyzes the second messenger cAMP, which is a keyregulator of many important physiological processes (PMID:11027622). May have a role in muscle signal transduction(PMID:11027622). Vasopressin increases phosphorylation at S58 (ETERRGS*HPYIDF); effect unknown.
Pde7a S58
A-kinase anchor protein 12, Anchoring protein that mediates the subcellular compartmentation of protein kinase A (PKA) and protein kinase C (PKC). Vasopressin decreases phosphorylation at S467 (TQLTDLS*PEEKML); effect unknown.
Akap12 S467
cAMP-dependent protein kinase type II-alpha regulatory subunit, Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Type II regulatory chains mediate membrane association by binding to anchoring proteins, including the MAP2 kinase. Vasopressin decreases phosphorylation at S96 (KFTRRVS*VCAETF); effect unknown.
Prkar2a S96
Vasopressin promotes the rearrangement of actin cytoskeleton in the apical membrane region of collecting duct cell which is a critical step in trafficking of AQP2 (PMID: 8214031, 11704560, 15347643, 24085853).
Actin cytoskeleton
Cytospin-A is involved in cytokinesis and spindle organization. May play a role in actin cytoskeleton organization and microtubule stabilization and hence required for proper cell adhesion and migration (PMID:21703590). Vasopressin increases phosphorylation at S833 (GLSRRSS*TSSEPT); effect unknown.
Specc1l S833
Cytospin-A is involved in cytokinesis and spindle organization. May play a role in actin cytoskeleton organization and microtubule stabilization and hence required for proper cell adhesion and migration (PMID:21703590). Vasopressin increases phosphorylation at S385 (ERSRKGS*SGNASE); effect unknown.
Specc1l S385
Unconventional myosin-IXb. Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. Binds actin with high affinity both in the absence and presence of ATP and its mechanochemical activity is inhibited by calcium ions. Also acts as a GTPase activator for RHOA. Plays a role in the regulation of cell migration via its role as RHOA GTPase activator. This is regulated by its interaction with the SLIT2 receptor ROBO1; interaction with ROBO1 impairs interaction with RHOA and subsequent activation of RHOA GTPase activity, and thereby leads to increased levels of active, GTP-bound RHOA. (PMID:9490638, 26529257_Human). Vasopressin increases phosphorylation at S1647 (YTGRRKS*ELGAEP); effect unknown.
Myo9b S1647
PDZ and LIM domain protein 5 may play an important role in the heart development byscaffolding PKC to the Z-disk region. Isoform 2 and isoform 3 maynegatively modulate the scaffolding activity of isoform 1. May play a role in the regulation of cardiomyocyte expansion. Overexpression promotes the development of heart hypertrophy. Contributes to the regulation of dendritic spine morphogenesis in neurons. May restrain postsynaptic growth of excitatory synapses. (PMID:20097676, 26365342). Vasopressin decreases phosphorylation at S111 (KPVPITS*PAVSKV); effect unknown.
Pdlim5 S111
Rho family (Rho, Rac, and Cdc42) of small GTP-binding proteins participate in the regulation of the F-actin cytoskeleton. Vasopressin-mediated PKA activation increases RhoA phosphorylation which attenuates RhoA activity. The decrease of RhoA GTPase activity leads to actin depolymerization, promoting AQP2 trafficking to apical plasma membrane (PMID:12640036, 11704560, 24085853).
Regulation of GTPase activity
Rho guanine nucleotide exchange factor 2 activates Rho-GTPases by promoting the exchange of GDP for GTP. May be involved in epithelial barrier permeability, cell motility and polarization, and cell cycle regulation. Binds Rac-GTPases, but does not seem to promote nucleotide exchange activity toward Rac-GTPases. May stimulate instead the cortical activity of Rac. Inactive toward CDC42, TC10, or Ras-GTPases. Acts as a signaling intermediate between NOD2 receptor and RIPK2 kinase. Contributes to the tyrosine phosphorylation of RIPK2 through Src tyrosine kinase leading to NF-kappaB activation by NOD2. Overexpression activates Rho-, but not Rac-GTPases, and increases paracellular permeability (PMID:19043560,21887730,28453519). Vasopressin increases phosphorylation at S885 (LDPRRRS*LPAGDA); Phosphorylation of S885 by PKA mediate the direct interaction with 14-3-3 proteins and inhibits its activity (PMID:19667072, 22405273, 24270516, 33740666).
Arhgef2 S885
Alsin may act as a GTPase regulator. Controls survival and growth of spinal motoneurons. Vasopressin decreases phosphorylation at S486 (GLLSQVS*PRLLRK); effect unknown.
Als2 S486
Brefeldin A-inhibited guanine nucleotide-exchange protein 1 promotes guanine-nucleotide exchange on ARF1 and ARF3. Promotes the activation of ARF1/ARF3 through replacement of GDP with GTP. Involved in vesicular trafficking. Required for the maintenance of Golgi structure; the function may be independent of its GEF activity. Required for the maturaion of integrin beta-1 in the Golgi. Involved in the establishment and persistence of cell polarity during directed cell movement in wound healing. Proposed to act as A kinase-anchoring protein (AKAP) and may mediate crosstalk between Arf and PKA pathways. Inhibits GAP activity of MYO9B probably through competitive RhoA binding. The function in the nucleus remains to be determined. Vasopressin decreases phosphorylation at S1566 (DAISQKS*VDIHDS); effect unknown.
Arfgef1 S1566
Arf-GAP domain and FG repeat-containing protein 1 is required for vesicle docking or fusion during acrosome biogenesis. May play a role in RNA trafficking or localization (PMID:11711676). Vasopressin decreases phosphorylation at S181 (KGTPSQS*PVVGRS); effect unknown.
Agfg1 S181
Ral GTPase-activating protein subunit alpha-2. Catalytic subunit of the heterodimeric RalGAP2 complex which acts as a GTPase activator for the Ras-like small GTPases RALA and RALB. Vasopressin decreases phosphorylation at S820 (LVRRSSS*PAELEL); effect unknown.
Ralgapa2 S820
Vasopressin regulates the transcription of several genes in collecting duct cells. Vasopressin-mediated transcriptional regulation is highly selective for Aqp2 (PMID: 27725713, 19244407).
Regulation of transcription
Arginine vasopressin (AVP) is the essential regulator of renal water excretion and reabsorption. AVP binds to the V2 vasopressin receptor (V2R) which triggers activation of adenylyl cyclase 6 (AC6) through heterotrimeric G-protein subunit Gsa. Subsequently, AC6 increases the intracellular level of cAMP, and causes activation of protein kinase A (PKA). PKA phosphorylates several downstream targets, AQP2, resulting in AQP2 trafficking to apical membrane (PMID: 25830425, 32245905, 23584881, 19193633).
Vasopressin signaling
Epithelial Systems Biology Laboratory, NHLBI