Receptor protein tyrosine phosphatases are novel components of a polycystin complex

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• 作者：Catherine A.  ; Boucher^a ;   ; ¹ ; Heather H.  ; Ward^c ;   ; ¹ ; Ruth L.  ; Case^a ; Katie S.  ; Thurston^a ; Xiaohong  ; Li^b ; Andrew  ; Needham^a ; Elsa  ; Romero^c ; Deborah  ; Hyink^b ; Seema  ; Qamar^a ; Tamara  ; Roitbak^c ; Samantha  ; Powell^a ; Christopher  ; Ward^d ; Patricia D.  ; Wilson^b ;   ; ² ; Angela  ; Wandinger-Ness^c ;   ; ; Richard N.  ; Sandford^a ;   ; ^{rns13@cam.ac.uk}
• 关键词：Polycystins ; Tyrosine kinase ; Tyrosine phosphatase ; Adherens junctions ; Primary cilium ; G-protein coupled signaling
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：2011
• 出版时间：October 2011
• 年：2011
• 卷：1812
• 期：10
• 页码：1225-1238
• 全文大小：2404 K

文摘

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 RPTP¦Ò, while the polycystin-1 C-terminus of polycystin-1 interacts with the regulatory D2 phosphatase domain of RPTP¦Ã. Additional homo- and heterotypic interactions between RPTPs recruit RPTP¦Ä. The multimeric polycystin protein complex is found localised in cilia. RPTP¦Ò and RPTP¦Ä 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¦Ã is disrupted in ADPKD cells, while RPTP¦Ò and RPTP¦Ä remain closely associated with E-cadherin, largely in an intracellular location. The polycystin-1 C-terminus is an in vitro substrate of RPTP¦Ã, 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 RPTP¦Ã phosphatase activity is central to the molecular mechanisms governing polycystin-dependent signaling. This article is part of a Special Issue entitled: Polycystic Kidney Disease.