Universität zu Köln

Reusch, Bjorn, Bartram, Malte P., Dafinger, Claudia, Palacio-Escat, Nicolas ORCID: 0000-0002-7022-1437, Wenzel, Andrea, Fenton, Robert A., Saez-Rodriguez, Julio ORCID: 0000-0002-8552-8976, Schermer, Bernhard, Benzing, Thomas, Altmueller, Janine, Beck, Bodo B. and Rinschen, Markus M. (2022). MAGED2 controls vasopressin-induced aquaporin-2 expression in collecting duct cells. J. Proteomics, 252. AMSTERDAM: ELSEVIER. ISSN 1876-7737

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Abstract

Mutations in the Melanoma-Associated Antigen D2 (MAGED2) cause antenatal Bartter syndrome type 5 (BARTS5). This rare disease is characterized by perinatal loss of urinary concentration capability and large urine volumes. The underlying molecular mechanisms of this disease are largely unclear. Here, we study the effect MAGED2 knockdown on kidney cell cultures using proteomic and phosphoproteomic analyses. In HEK293T cells, MAGED2 knockdown induces prominent changes protein phosphorylation rather than changes in protein abundance. MAGED2 is expressed in mouse embryonic kidneys and its expression declines during development. MAGED2 interacts with G-protein alpha subunit (GNAS), suggesting a role in G-protein coupled receptors (GPCR) signalling. In kidney collecting duct lines, Maged2 knockdown subtly modulated vasopressin type 2 receptor (V2R)-induced cAMP-generation kinetics, rewired phosphorylation-dependent signalling, and phosphorylation of CREB. Maged2 knockdown resulted in a large increase in aquaporin-2 abundance during long-term V2R activation. The increase in aquaporin2 protein was mediated transcriptionally. Taken together, we link MAGED2 function to cellular signalling as a desensitizer of V2R-induced aquaporin-2 expression. Significance: In most forms of Bartter Syndrome, the underlying cause of the disease is well understood. In contrast, the role of MAGED2 mutations in a newly discovered form of Bartter Syndrome (BARTS5) is unknown. In our manuscript we could show that MAGED2 modulates vasopressin-induced protein and phosphorylation patterns in kidney cells, providing a broad basis for further studies of MAGED2 function in development and disease.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Reusch, Bjorn UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartram, Malte P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dafinger, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Palacio-Escat, Nicolas UNSPECIFIED orcid.org/0000-0002-7022-1437 UNSPECIFIED Wenzel, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Fenton, Robert A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Saez-Rodriguez, Julio UNSPECIFIED orcid.org/0000-0002-8552-8976 UNSPECIFIED Schermer, Bernhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Benzing, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Beck, Bodo B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rinschen, Markus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-598123
DOI:	10.1016/j.jprot.2021.104424
Journal or Publication Title:	J. Proteomics
Volume:	252
Date:	2022
Publisher:	ELSEVIER
Place of Publication:	AMSTERDAM
ISSN:	1876-7737
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language THICK ASCENDING LIMB; BARTTERS-SYNDROME; MUTATIONS; RECEPTOR; GENE; PHOSPHORYLATION; IDENTIFICATION; TRANSCRIPTION; DEAFNESS; CHANNEL Multiple languages Biochemical Research Methods Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59812