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Article

Cyclin-Dependent Kinase 18 Controls Trafficking of Aquaporin-2 and Its Abundance through Ubiquitin Ligase STUB1, Which Functions as an AKAP

1
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany
2
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin, Germany
3
DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Oudenarder Strasse 16, 13347 Berlin, Germany
*
Author to whom correspondence should be addressed.
Current address: University of California, San Francisco, 513 Parnassus Avenue, CA 94122, USA.
Cells 2020, 9(3), 673; https://doi.org/10.3390/cells9030673
Received: 3 February 2020 / Revised: 27 February 2020 / Accepted: 9 March 2020 / Published: 10 March 2020
(This article belongs to the Special Issue Physiopathology of Signaling Transmission in Renal Diseases)
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. View Full-Text
Keywords: CDK18; AQP2; PKA; AKAP; STUB1; CHIP CDK18; AQP2; PKA; AKAP; STUB1; CHIP
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MDPI and ACS Style

Dema, A.; Faust, D.; Lazarow, K.; Wippich, M.; Neuenschwander, M.; Zühlke, K.; Geelhaar, A.; Pallien, T.; Hallscheidt, E.; Eichhorst, J.; Wiesner, B.; Černecká, H.; Popp, O.; Mertins, P.; Dittmar, G.; von Kries, J.P.; Klussmann, E. Cyclin-Dependent Kinase 18 Controls Trafficking of Aquaporin-2 and Its Abundance through Ubiquitin Ligase STUB1, Which Functions as an AKAP. Cells 2020, 9, 673. https://doi.org/10.3390/cells9030673

AMA Style

Dema A, Faust D, Lazarow K, Wippich M, Neuenschwander M, Zühlke K, Geelhaar A, Pallien T, Hallscheidt E, Eichhorst J, Wiesner B, Černecká H, Popp O, Mertins P, Dittmar G, von Kries JP, Klussmann E. Cyclin-Dependent Kinase 18 Controls Trafficking of Aquaporin-2 and Its Abundance through Ubiquitin Ligase STUB1, Which Functions as an AKAP. Cells. 2020; 9(3):673. https://doi.org/10.3390/cells9030673

Chicago/Turabian Style

Dema, Alessandro, Dörte Faust, Katina Lazarow, Marc Wippich, Martin Neuenschwander, Kerstin Zühlke, Andrea Geelhaar, Tamara Pallien, Eileen Hallscheidt, Jenny Eichhorst, Burkhard Wiesner, Hana Černecká, Oliver Popp, Philipp Mertins, Gunnar Dittmar, Jens P. von Kries, and Enno Klussmann. 2020. "Cyclin-Dependent Kinase 18 Controls Trafficking of Aquaporin-2 and Its Abundance through Ubiquitin Ligase STUB1, Which Functions as an AKAP" Cells 9, no. 3: 673. https://doi.org/10.3390/cells9030673

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