An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells

Autor: Schrade, K, Tröger, J, Eldahshan, A, Zühlke, K, Abdul Azeez, K, Elkins, J, Neuenschwander, M, Oder, A, Elkewedi, M, Jaksch, S, Andrae, K, Li, J, Fernandes, J, Müller, P, Grunwald, S, Marino, S, Vukićević, T, Eichhorst, J, Wiesner, B, Weber, M, Kapiloff, M, Rocks, O, Daumke, O, Wieland, T, Knapp, S, von Kries, J, Klussmann, E
Přispěvatelé: Garcia-Mata, Rafael
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Cancer Research
Hydrolases
Cell Membranes
lcsh:Medicine
A Kinase Anchor Proteins
Biochemistry
Signaling Molecules
Cell Signaling
Guanine Nucleotide Exchange Factors
Post-Translational Modification
Phosphorylation
lcsh:Science
Organic Compounds
Enzymes
Chemistry
Protein Transport
ddc:540
Physical Sciences
Technology Platforms
Cellular Structures and Organelles
Oxidoreductases
Luciferase
Research Article
Signal Transduction
Biotechnology
Protein Binding
Library Screening
Research and Analysis Methods
Minor Histocompatibility Antigens
Small Molecule Libraries
Structure-Activity Relationship
Proto-Oncogene Proteins
Humans
Vesicles
Kidney Tubules
Collecting
Molecular Biology Techniques
Molecular Biology
Molecular Biology Assays and Analysis Techniques
Aquaporin 2
urogenital system
lcsh:R
Organic Chemistry
Cell Membrane
Chemical Compounds
Biology and Life Sciences
Proteins
Cell Biology
Guanosine Triphosphatase
HEK293 Cells
Cardiovascular and Metabolic Diseases
Small Molecules
Enzymology
lcsh:Q
rhoA GTP-Binding Protein
Zdroj: PLoS ONE
PLoS ONE, Vol 13, Iss 1, p e0191423 (2018)
PLOS ONE, 13(1):e0191423
ISSN: 1932-6203
Popis: Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking.
Databáze: OpenAIRE
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