1. Receptor protein tyrosine phosphatases are novel components of a polycystin complex.
- Author
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Boucher CA, Ward HH, Case RL, Thurston KS, Li X, Needham A, Romero E, Hyink D, Qamar S, Roitbak T, Powell S, Ward C, Wilson PD, Wandinger-Ness A, and Sandford RN
- Subjects
- Amino Acid Sequence, Animals, Cadherins chemistry, Cadherins metabolism, Cell Line, Cell Membrane chemistry, Humans, In Vitro Techniques, Kidney metabolism, Mice, Models, Molecular, Multiprotein Complexes chemistry, Mutagenesis, Site-Directed, Peptide Library, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant metabolism, Protein Interaction Domains and Motifs, Receptor-Like Protein Tyrosine Phosphatases genetics, Receptor-Like Protein Tyrosine Phosphatases metabolism, Receptor-Like Protein Tyrosine Phosphatases, Class 2 chemistry, Receptor-Like Protein Tyrosine Phosphatases, Class 2 genetics, Receptor-Like Protein Tyrosine Phosphatases, Class 2 metabolism, Receptor-Like Protein Tyrosine Phosphatases, Class 5 chemistry, Receptor-Like Protein Tyrosine Phosphatases, Class 5 genetics, Receptor-Like Protein Tyrosine Phosphatases, Class 5 metabolism, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Signal Transduction, TRPP Cation Channels genetics, TRPP Cation Channels metabolism, Transcription Factor AP-1 metabolism, Receptor-Like Protein Tyrosine Phosphatases chemistry, TRPP Cation Channels chemistry
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutation of PKD1 and PKD2 that encode polycystin-1 and polycystin-2. Polycystin-1 is tyrosine phosphorylated and modulates multiple signaling pathways including AP-1, and the identity of the phosphatases regulating polycystin-1 are previously uncharacterized. Here we identify members of the LAR protein tyrosine phosphatase (RPTP) superfamily as members of the polycystin-1complex mediated through extra- and intracellular interactions. The first extracellular PKD1 domain of polycystin-1 interacts with the first Ig domain of RPTPσ, while the polycystin-1 C-terminus of polycystin-1 interacts with the regulatory D2 phosphatase domain of RPTPγ. Additional homo- and heterotypic interactions between RPTPs recruit RPTPδ. The multimeric polycystin protein complex is found localised in cilia. RPTPσ and RPTPδ are also part of a polycystin-1/E-cadherin complex known to be important for early events in adherens junction stabilisation. The interaction between polycystin-1 and RPTPγ is disrupted in ADPKD cells, while RPTPσ and RPTPδ remain closely associated with E-cadherin, largely in an intracellular location. The polycystin-1 C-terminus is an in vitro substrate of RPTPγ, which dephosphorylates the c-Src phosphorylated Y4237 residue and activates AP1-mediated transcription. The data identify RPTPs as novel interacting partners of the polycystins both in cilia and at adhesion complexes and demonstrate RPTPγ phosphatase activity is central to the molecular mechanisms governing polycystin-dependent signaling. This article is part of a Special Issue entitled: Polycystic Kidney Disease., (Copyright © 2010 Elsevier B.V. All rights reserved.)
- Published
- 2011
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