Article
- The EMBO Journal (2005) 24, 705 - 716
- doi:10.1038/sj.emboj.7600566
Published online: 3 February 2005
Subject Categories:
Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation
Michael Köttgen1,a, Thomas Benzing1,a, Thomas Simmen2, Robert Tauber1, Björn Buchholz1, Sylvain Feliciangeli2, Tobias B Huber1, Bernhard Schermer1, Albrecht Kramer-Zucker1, Katja Höpker1, Katia Carmine Simmen2, Christoph Carl Tschucke3, Richard Sandford4, Emily Kim1, Gary Thomas2 and Gerd Walz1
- Renal Division, University Hospital of Freiburg, Freiburg, Germany
- Vollum Institute, The Oregon Health Sciences University Portland, OR, USA
- Department of Organical Chemistry and Biochemistry, University of Freiburg, Freiburg, Germany
- Department of Medical Genetics, University of Cambridge, UK
Correspondence to:
Gary Thomas, Vollum Institute, The Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. Tel.: +1 503 494 6955; Fax: +1 503 494 1218; E-mail: thomasg@ohsu.edu
Gerd Walz, Renal Division, University Hospital of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany. Tel.: +49 761 270 3250; Fax: +49 761 270 3245; E-mail: walz@med1.ukl.uni-freiburg.de
aThese authors contributed equally to this work
Received 16 July 2004; Accepted 23 December 2004
Abstract
The trafficking of ion channels to the plasma membrane is tightly controlled to ensure the proper regulation of intracellular ion homeostasis and signal transduction. Mutations of polycystin-2, a member of the TRP family of cation channels, cause autosomal dominant polycystic kidney disease, a disorder characterized by renal cysts and progressive renal failure. Polycystin-2 functions as a calcium-permeable nonselective cation channel; however, it is disputed whether polycystin-2 resides and acts at the plasma membrane or endoplasmic reticulum (ER). We show that the subcellular localization and function of polycystin-2 are directed by phosphofurin acidic cluster sorting protein (PACS)-1 and PACS-2, two adaptor proteins that recognize an acidic cluster in the carboxy-terminal domain of polycystin-2. Binding to these adaptor proteins is regulated by the phosphorylation of polycystin-2 by the protein kinase casein kinase 2, required for the routing of polycystin-2 between ER, Golgi and plasma membrane compartments. Our paradigm that polycystin-2 is sorted to and active at both ER and plasma membrane reconciles the previously incongruent views of its localization and function. Furthermore, PACS proteins may represent a novel molecular mechanism for ion channel trafficking, directing acidic cluster-containing ion channels to distinct subcellular compartments.
Keywords:
- PACS,
- polycystin-2,
- TRPP2
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
REVIEWS
Retinoid signalling in the development of the central nervous system
Nature Reviews Neuroscience Review (01 Nov 2002)
The versatile nature of the calcium-permeable cation channel TRPP2
EMBO reports Review (01 Aug 2006)
NEWS AND VIEWS
The ins and outs of polycystin-2 as a calcium release channel
Nature Cell Biology News and Views (01 Mar 2002)
RESEARCH
Phosphorylation by casein kinase 2 induces PACS-1 binding of nephrocystin and targeting to cilia
The EMBO Journal Article (21 Dec 2005)
A PACS-1, GGA3 and CK2 complex regulates CI-MPR trafficking
The EMBO Journal Article (04 Oct 2006)
