ArticleCells2020
Cyclin-Dependent Kinase 18 Controls Trafficking of Aquaporin-2 and Its Abundance through Ubiquitin Ligase STUB1, Which Functions as an AKAP.
Article in Cells, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 25 citations in OpenAlex.
- Bayesian mapping of protein kinases to vasopressin-regulated phosphorylation sites in renal collecting duct.American journal of physiology. Renal physiology · 2024Article
- Cyclic Adenosine Monophosphate Signaling in Chronic Kidney Disease: Molecular Targets and Therapeutic Potentials.International journal of molecular sciences · 2024Review
- Insights into the structural and functional activities of forgotten Kinases: PCTAIREs CDKs.Molecular cancer · 2024Review
- Regulation of the water channel aquaporin-2 by cullin E3 ubiquitin ligases.American journal of physiology. Renal physiology · 2024Article
- Pharmacogenetics in IBS: update and impact of GWAS studies in drug targets and metabolism.Expert opinion on drug metabolism & toxicology · 2024Review
- Collecting duct water permeability inhibition by EGF is associated with decreased cAMP, PKA activity, and AQP2 phosphorylation at SerAmerican journal of physiology. Renal physiology · 2024Article
- Data resource: vasopressin-regulated protein phosphorylation sites in the collecting duct.American journal of physiology. Renal physiology · 2023Article
- Chaperone-assisted E3 ligase CHIP: A double agent in cancer.Genes & diseases · 2022Review
- Aurora Kinase A Is Involved in Controlling the Localization of Aquaporin-2 in Renal Principal Cells.International journal of molecular sciences · 2022Article
- Aquaporin 2 regulation: implications for water balance and polycystic kidney diseases.Nature reviews. Nephrology · 2021Review
- Hepatocellular carcinoma progression mediated by hepatitis B virus-encoded circRNA HBV_circ_1 through interaction with CDK1.Molecular therapy. Nucleic acids · 2021Article
- Phosphoproteomic identification of vasopressin-regulated protein kinases in collecting duct cells.British journal of pharmacology · 2021Article
- AKAP Signaling Islands: Venues for Precision Pharmacology.Trends in pharmacological sciences · 2020Review
- Exogenous melatonin alleviates PEG-induced short-term water deficiency in maize by increasing hydraulic conductance.BMC plant biology · 2020Article
Corrections and comments
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Authors and funding
17 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Arginine-vasopressin (AVP) facilitates water reabsorption in renal collecting duct principal cells through regulation of the water channel aquaporin-2 (AQP2). The hormone binds to vasopressin V2 receptors (V2R) on the surface of the cells and stimulates cAMP synthesis. The cAMP activates protein kinase A (PKA), which initiates signaling that causes an accumulation of AQP2 in the plasma membrane of the cells facilitating water reabsorption from primary urine and fine-tuning of body water homeostasis. AVP-mediated PKA activation also causes an increase in the AQP2 protein abundance through a mechanism that involves dephosphorylation of AQP2 at serine 261 and a decrease in its poly-ubiquitination. However, the signaling downstream of PKA that controls the localization and abundance of AQP2 is incompletely understood. We carried out an siRNA screen targeting 719 kinase-related genes, representing the majority of the kinases of the human genome and analyzed the effect of the knockdown on AQP2 by high-content imaging and biochemical approaches. The screening identified 13 hits whose knockdown inhibited the AQP2 accumulation in the plasma membrane. Amongst the candidates was the so far hardly characterized cyclin-dependent kinase 18 (CDK18). Our further analysis revealed a hitherto unrecognized signalosome comprising CDK18, an E3 ubiquitin ligase, STUB1 (CHIP), PKA and AQP2 that controls the localization and abundance of AQP2. CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. STUB1 functions as an A-kinase anchoring protein (AKAP) tethering PKA to the protein complex and bridging AQP2 and CDK18. The modulation of the protein complex may lead to novel concepts for the treatment of disorders which are caused or are associated with dysregulated AQP2 and for which a satisfactory treatment is not available, e.g., hyponatremia, liver cirrhosis, diabetes insipidus, ADPKD or heart failure.
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