title: The (pro)renin receptor ((P)RR) can act as a repressor of Wnt signalling.
abstract: The (pro)renin receptor ((P)RR) and Wnt signalling are both involved in different diseases ranging from cardiac and renal end-organ damage to cancer. (P)RR function involves signalling via the transcription factor promyelocytic leukemia zinc finger protein (PLZF) as well as the furin-mediated generation of vacuolar proton-translocating ATPase (V-ATPase)-associated and soluble (P)RR isoforms. Recently, the (P)RR was described as adaptor protein of Wnt (co)receptors. The aim of this study was to analyse the contribution of these distinct (P)RR functions to Wnt signalling. Using Tcf/Lef reporter gene systems in HEK293T and HepG2 cells and quantification of endogenous axin2 mRNA and protein levels in HEK293T cells we were able to demonstrate that full-length (P)RR acts as a repressor of Wnt signalling in a system preactivated either by Wnt3a stimulation or by constitutively active β-catenin. These repressive effects are mediated by Dvl but are independent of the mutation status of β-catenin. Furthermore, the V-ATPase complex, but not PLZF translocation or renin enzymatic activity, is necessary for the induction of Tcf/Lef-responsive genes by Wnt3a. Our data indicate interference of (P)RR and Wnt cascades, a fact that has to be considered concerning pathophysiology of cardio-renal and oncological entities as well as in drug development programs targeting (P)RR or Wnt pathways.
authors.affiliation: Center for Cardiovascular Research (CCR)/Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Bernhard
authors.forename: Kerstin
authors.initials: K
authors.lastname: Seidel
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schmitz
authors.forename: Sabrina
authors.initials: S
authors.lastname: Klare
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kirsch
authors.forename: Eva
authors.initials: E
authors.lastname: Schrezenmeier
authors.forename: Daniela
authors.initials: D
authors.lastname: Zaade
authors.forename: Heike
authors.initials: H
authors.lastname: Meyborg
authors.forename: Petra
authors.initials: P
authors.lastname: Goldin-Lang
authors.forename: Philipp
authors.initials: P
authors.lastname: Stawowy
authors.forename: Frank S
authors.initials: FS
authors.lastname: Zollmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.forename: Heiko
authors.initials: H
authors.lastname: Funke-Kaiser
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D019833:Genistein / Q000494:pharmacology; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*; D000093342:Prorenin Receptor
chemical_list: D017931:DNA Primers; D018942:Macrolides; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D051153:Wnt Proteins; C040929:bafilomycin A1; D019833:Genistein; D000093342:Prorenin Receptor