title: The ciliopathy disease protein NPHP9 promotes nuclear delivery and activation of the oncogenic transcriptional regulator TAZ.
abstract: Nephronophthisis (NPH) is a genetically heterogenous kidney disease and represents the most common genetic cause for end-stage renal disease in children. It is caused by the mutation of genes encoding for the nephrocystin proteins (NPHPs) which localize to primary cilia or centrosomes, classifying this disease as a 'ciliopathy'. Recently, it has been shown that NPHP4 acts as a potent negative regulator of mammalian Hippo signalling by interacting with the Lats protein kinase and controlling the phosphorylation of the oncogenic transcriptional activator TAZ. Here, we demonstrate that NPHP9, another NPH family member, also controls TAZ activity by a distinct mechanism. NPHP9, which is also called NEK8, directly interacted with TAZ and induced nuclear translocation of the TAZ/NPHP9 protein complex. Binding of NPHP9 to TAZ was enhanced in a TAZ mutant that lost its ability to bind 14-3-3, suggesting that 14-3-3 and NPHP9 may compete for TAZ binding, with 14-3-3 favouring cytoplasmic retention and NPHP9 mediating nuclear delivery. Consistently, co-expression of NPHP4, which inhibits TAZ phosphorylation at the 14-3-3 binding site through the inhibition of Lats kinase activity, induced efficient nuclear delivery of the TAZ/NPHP9 protein pair. Consistent with a role for TAZ in controlling proliferation and tumorigenesis, the downregulation of NPHP9 inhibited the TAZ-dependent proliferation of hippo-responsive normal epithelial and also breast cancer cells. As NPHP9 has been shown to be upregulated in breast cancer, these data do not only support a critical role for TAZ/hippo signalling in the pathogenesis of NPH but may also imply a possible role for NPHP9 in TAZ-mediated tumorigenesis.
authors.affiliation: Department II of Internal Medicine and Center for Molecular Medicine Cologne, Gerrmany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Habbig
authors.forename: Malte P
authors.initials: MP
authors.lastname: Bartram
authors.forename: Josef G
authors.initials: JG
authors.lastname: Sägmüller
authors.forename: Anabel
authors.initials: A
authors.lastname: Griessmann
authors.forename: Mareike
authors.initials: M
authors.lastname: Franke
authors.forename: Roman-Ulrich
authors.initials: RU
authors.lastname: Müller
authors.forename: Ricarda
authors.initials: R
authors.lastname: Schwarz
authors.forename: Martin
authors.initials: M
authors.lastname: Hoehne
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.forename: Claudia
authors.initials: C
authors.lastname: Tessmer
authors.forename: H Christian
authors.initials: HC
authors.lastname: Reinhardt
authors.forename: Volker
authors.initials: V
authors.lastname: Burst
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schermer
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D018385:Centrosome / Q000378:metabolism; D002923:Cilia / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D009154:Mutation; D000072379:NIMA-Related Kinases; D010766:Phosphorylation; D010957:Plasmids; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins
chemical_list: D048948:14-3-3 Proteins; D047908:Intracellular Signaling Peptides and Proteins; C491578:NPHP4 protein, human; D011506:Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D008156:Luciferases; D011494:Protein Kinases; C458529:NEK8 protein, human; D000072379:NIMA-Related Kinases