title: Nephrocystin-4 regulates Pyk2-induced tyrosine phosphorylation of nephrocystin-1 to control targeting to monocilia.
abstract: Nephronophthisis is the most common genetic cause of end-stage renal failure during childhood and adolescence. Genetic studies have identified disease-causing mutations in at least 11 different genes (NPHP1-11), but the function of the corresponding nephrocystin proteins remains poorly understood. The two evolutionarily conserved proteins nephrocystin-1 (NPHP1) and nephrocystin-4 (NPHP4) interact and localize to cilia in kidney, retina, and brain characterizing nephronophthisis and associated pathologies as result of a ciliopathy. Here we show that NPHP4, but not truncating patient mutations, negatively regulates tyrosine phosphorylation of NPHP1. NPHP4 counteracts Pyk2-mediated phosphorylation of three defined tyrosine residues of NPHP1 thereby controlling binding of NPHP1 to the trans-Golgi sorting protein PACS-1. Knockdown of NPHP4 resulted in an accumulation of NPHP1 in trans-Golgi vesicles of ciliated retinal epithelial cells. These data strongly suggest that NPHP4 acts upstream of NPHP1 in a common pathway and support the concept of a role for nephrocystin proteins in intracellular vesicular transport.
authors.affiliation: Renal Division, Department of Medicine and Center for Molecular Medicine, University of Cologne, 50937 Cologne, Germany.
authors.forename: Max C
authors.initials: MC
authors.lastname: Liebau
authors.forename: Katja
authors.initials: K
authors.lastname: Höpker
authors.forename: Roman U
authors.initials: RU
authors.lastname: Müller
authors.forename: Ingolf
authors.initials: I
authors.lastname: Schmedding
authors.forename: Sibylle
authors.initials: S
authors.lastname: Zank
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schairer
authors.forename: Francesca
authors.initials: F
authors.lastname: Fabretti
authors.forename: Martin
authors.initials: M
authors.lastname: Höhne
authors.forename: Malte P
authors.initials: MP
authors.lastname: Bartram
authors.forename: Claudia
authors.initials: C
authors.lastname: Dafinger
authors.forename: Matthias
authors.initials: M
authors.lastname: Hackl
authors.forename: Volker
authors.initials: V
authors.lastname: Burst
authors.forename: Sandra
authors.initials: S
authors.lastname: Habbig
authors.forename: Hanswalter
authors.initials: H
authors.lastname: Zentgraf
authors.forename: Andree
authors.initials: A
authors.lastname: Blaukat
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schermer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002460:Cell Line; D002923:Cilia / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D011506:Proteins / Q000502:physiology*; D014018:Tissue Distribution; D014443:Tyrosine / Q000737:chemistry*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C108725:NPHP1 protein, human; C491578:NPHP4 protein, human; D011506:Proteins; D014443:Tyrosine; D051418:Focal Adhesion Kinase 2