Universität zu Köln

Habbig, Sandra, Bartram, Malte P., Saegmueller, Josef G., Griessmann, Anabel, Franke, Mareike, Mueller, Roman-Ulrich, Schwarz, Ricarda, Hoehne, Martin, Bergmann, Carsten, Tessmer, Claudia, Reinhardt, H. Christian, Burst, Volker, Benzing, Thomas and Schermer, Bernhard ORCID: 0000-0002-5194-9000 (2012). The ciliopathy disease protein NPHP9 promotes nuclear delivery and activation of the oncogenic transcriptional regulator TAZ. Hum. Mol. Genet., 21 (26). S. 5528 - 5539. OXFORD: OXFORD UNIV PRESS. ISSN 0964-6906

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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 ociliopathy'. 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Habbig, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartram, Malte P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Saegmueller, Josef G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Griessmann, Anabel UNSPECIFIED UNSPECIFIED UNSPECIFIED Franke, Mareike UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Roman-Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarz, Ricarda UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoehne, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Bergmann, Carsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Tessmer, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, H. Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Burst, Volker UNSPECIFIED UNSPECIFIED UNSPECIFIED Benzing, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Schermer, Bernhard UNSPECIFIED orcid.org/0000-0002-5194-9000 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-476578
DOI:	10.1093/hmg/dds408
Journal or Publication Title:	Hum. Mol. Genet.
Volume:	21
Number:	26
Page Range:	S. 5528 - 5539
Date:	2012
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	0964-6906
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CYSTIC KIDNEY-DISEASE; BREAST-CANCER CELLS; HIPPO PATHWAY; NEPHRONOPHTHISIS; KINASE; NEK8; CILIARY; TUMORIGENESIS; ZEBRAFISH; MUTATIONS Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47657