Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling.
The Hippo pathway regulates the size of organs by controlling two opposing processes: proliferation and apoptosis. YAP2 (Yes kinase-associated protein 2), one of the three isoforms of YAP, is a WW domain-containing transcriptional co-activator that acts as the effector of the Hippo pathway in mammalian cells. In addition to WW domains, YAP2 has a PDZ-binding motif at its C-terminus. We reported previously that this motif was necessary for YAP2 localization in the nucleus and for promoting cell detachment and apoptosis. In the present study, we show that the tight junction protein ZO (zonula occludens)-2 uses its first PDZ domain to form a complex with YAP2. The endogenous ZO-2 and YAP2 proteins co-localize in the nucleus. We also found that ZO-2 facilitates the nuclear localization and pro-apoptotic function of YAP2, and that this activity of ZO-2 is PDZ-domain-dependent. The present paper is the first report on a PDZ-based nuclear translocation mechanism. Moreover, since the Hippo pathway acts as a tumour suppressor pathway, the YAP2-ZO-2 complex could represent a target for cancer therapy.
Oka
Tsutomu
T
Weis Center for Research, 100 North Academy Avenue, Danville, PA 17822, USA.
Remue
Eline
E
Meerschaert
Kris
K
Vanloo
Berlinda
B
Boucherie
Ciska
C
Gfeller
David
D
Bader
Gary D
GD
Sidhu
Sachdev S
SS
Vandekerckhove
Joël
J
Gettemans
Jan
J
Sudol
Marius
M
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D004285:Dogs; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D054731:PDZ Domains; D010750:Phosphoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors; D014162:Transfection; D000091102:YAP-Signaling Proteins; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein
D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D050505:Mutant Proteins; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; C569042:TJP1 protein, human; C569046:TJP2 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein