title: Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation.
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.
authors.affiliation: Renal Division, University Hospital of Freiburg, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Köttgen
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmen
authors.forename: Robert
authors.initials: R
authors.lastname: Tauber
authors.forename: Björn
authors.initials: B
authors.lastname: Buchholz
authors.forename: Sylvain
authors.initials: S
authors.lastname: Feliciangeli
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schermer
authors.forename: Albrecht
authors.initials: A
authors.lastname: Kramer-Zucker
authors.forename: Katja
authors.initials: K
authors.lastname: Höpker
authors.forename: Katia Carmine
authors.initials: KC
authors.lastname: Simmen
authors.forename: Christoph Carl
authors.initials: CC
authors.lastname: Tschucke
authors.forename: Richard
authors.initials: R
authors.lastname: Sandford
authors.forename: Emily
authors.initials: E
authors.lastname: Kim
authors.forename: Gary
authors.initials: G
authors.lastname: Thomas
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D016415:Sequence Alignment; D050396:TRPP Cation Channels; D033921:Vesicular Transport Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D050396:TRPP Cation Channels; D033921:Vesicular Transport Proteins; C491914:PACS1 protein, human; C499638:PACS2 protein, human