title: NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway.
abstract: The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.
authors.affiliation: Renal Division, Department of Medicine, University of Cologne, 50937 Cologne, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Habbig
authors.forename: Malte P
authors.initials: MP
authors.lastname: Bartram
authors.forename: Roman U
authors.initials: RU
authors.lastname: Müller
authors.forename: Ricarda
authors.initials: R
authors.lastname: Schwarz
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Andriopoulos
authors.forename: Shuhua
authors.initials: S
authors.lastname: Chen
authors.forename: Josef G
authors.initials: JG
authors.lastname: Sägmüller
authors.forename: Martin
authors.initials: M
authors.lastname: Hoehne
authors.forename: Volker
authors.initials: V
authors.lastname: Burst
authors.forename: Max C
authors.initials: MC
authors.lastname: Liebau
authors.forename: H Christian
authors.initials: HC
authors.lastname: Reinhardt
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 / Q000378:metabolism; D000217:Acyltransferases; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: D048948:14-3-3 Proteins; D018797:Cell Cycle Proteins; C491578:NPHP4 protein, human; D009687:Nuclear Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases