Receptor protein tyrosine phosphatases are novel components of a polycystin complex

Catherine A. Boucher, Heather H. Ward, Ruth L. Case, Katie S. Thurston, Xiaohong Li, Andrew Needham, Elsa Romero, Deborah Hyink, Seema Qamar, Tamara Roitbak, Samantha Powell, Christopher Ward, Patricia D. Wilson, Angela Wandinger-Ness, Richard N. Sandford

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1225-1238
Number of pages14
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1812
Issue number10
DOIs
StatePublished - Oct 1 2011

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Keywords

  • Adherens junctions
  • G-protein coupled signaling
  • Polycystins
  • Primary cilium
  • Tyrosine kinase
  • Tyrosine phosphatase

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this

Boucher, C. A., Ward, H. H., Case, R. L., Thurston, K. S., Li, X., Needham, A., Romero, E., Hyink, D., Qamar, S., Roitbak, T., Powell, S., Ward, C., Wilson, P. D., Wandinger-Ness, A., & Sandford, R. N. (2011). Receptor protein tyrosine phosphatases are novel components of a polycystin complex. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1812(10), 1225-1238. https://doi.org/10.1016/j.bbadis.2010.11.006