Receptor protein tyrosine phosphatases are novel components of a polycystin complex

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.

Graphical AbstractDiagrammatic illustration of the receptor protein tyrosine phosphatase (RPTP) type IIA subfamily and polycystin protein interactions. The cytoplasmic D1 domains of the RPTP proteins are membrane proximal and catalytic, while the D2 domains are regulatory, and serve to inactivate the phosphatase activity of the D1 domains and participate in substrate recognition. A novel interaction between RPTPγ D1 and D2 domains and the polycystins is identified and previously characterized interactions between RPTP isoforms are confirmed. The extracellular domains of the RPTPσ consist of Ig and fibronectin-like domains, which function as adhesion receptors. These domains are largely not shown except for the first Ig repeat of sigma, which serves as a ligand for the first PKD1 repeat of polycystin-1. The polycystin/RPTP protein complex can also associate with the adherens junction protein E-cadherin (not shown) and the complex can be detected at the lateral membrane and in primary cilia of normal cells. Both the complex composition and protein localisations are altered in primary ADPKD cells suggesting an important regulatory role of the RPTP in polycystin function.Figure optionsDownload high-quality image (247 K)Download as PowerPoint slideResearch Highlights
► The PKD domain of polycystin-1 interacts with receptor protein tyrosine phosphatases.
► The polycystin-RPTP complex is localised to the primary cilium.
► RPTPs regulate tyrosine phosphorylation of the C-terminus of polycystin-1.
► Tyrosine phosphorylation of polycystin-1 regulates AP-1 signalling.