Receptor protein tyrosine phosphatases are novel components of a polycystin complex

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1812

Article

Boucher, Catherine A.¹  Ward, Heather H.³  Case, Ruth L.¹  Thurston, Katie S.¹  Li, Xiaohong²  Needham, Andrew¹  Romero, Elsa³  Hyink, Deborah²  Qamar, Seema¹  Roitbak, Tamara³  Powell, Samantha¹  Ward, Christopher⁴  Wilson, Patricia D.²  Wandinger-Ness, Angela³  Sandford, Richard N.¹ 

[1] Cambridge Inst Med Res, Dept Med Genet, Cambridge CB2 2XY, England

[2] Mt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA

[3] Univ New Mexico HSC, Dept Pathol, Albuquerque, NM 87131 USA

[4] Mayo Clin, Rochester, MN 55905 USA

关键词: Polycystins;    Tyrosine kinase;    Tyrosine phosphatase;    Adherens junctions;    Primary cilium;    G-protein coupled signaling;   

DOI  :  10.1016/j.bbadis.2010.11.006

来源: Elsevier

【 摘 要 】

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 RFTP sigma, while the polycystin-1 C-terminus of polycystin-1 interacts with the regulatory D2 phosphatase domain of RFTP gamma. Additional homo- and heterotypic interactions between RPTPs recruit RPTP delta. The multimeric polycystin protein complex is found localised in cilia. RPTP sigma and RPTP delta 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 RPTP gamma is disrupted in ADPKD cells, while RPTP sigma and RFTP delta remain closely associated with E-cadherin, largely in an intracellular location. The polycystin-1 C-terminus is an in vitro substrate of RPTP-gamma, which dephosphorylates the c-Src phosphorylated Y4237 residue and activates AP1-mediated transcription. The data identify RFTPs as novel interacting partners of the polycystins both in cilia and at adhesion complexes and demonstrate RFTP gamma phosphatase activity is central to the molecular mechanisms governing polycystin-dependent signaling. This article is part of a Special Issue entitled: Polycystic Kidney Disease. (C) 2010 Elsevier B.V. All rights reserved.

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