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.
Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, CB2 2XY, UK.
Catherine A
CA
Boucher
Heather H
HH
Ward
Ruth L
RL
Case
Katie S
KS
Thurston
Xiaohong
X
Li
Andrew
A
Needham
Elsa
E
Romero
Deborah
D
Hyink
Seema
S
Qamar
Tamara
T
Roitbak
Samantha
S
Powell
Christopher
C
Ward
Patricia D
PD
Wilson
Angela
A
Wandinger-Ness
Richard N
RN
Sandford
D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry; D016297:Mutagenesis, Site-Directed; D019151:Peptide Library; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D054557:Receptor-Like Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
D015820:Cadherins; D046912:Multiprotein Complexes; D019151:Peptide Library; D054557:Receptor-Like Protein Tyrosine Phosphatases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D011994:Recombinant Proteins; D050396:TRPP Cation Channels; D018808:Transcription Factor AP-1