pVHL and GSK3beta are components of a primary cilium-maintenance signalling network.
Defects in the structure or function of the primary cilium, an antennae-like structure whose functional integrity has been linked to the suppression of uncontrolled kidney epithelial cell proliferation, are a common feature of genetic disorders characterized by kidney cysts. However, the mechanisms by which primary cilia are maintained remain poorly defined. von Hippel-Lindau (VHL) disease is characterized by the development of premalignant renal cysts and arises because of functional inactivation of the VHL tumour suppressor gene product, pVHL. Here, we show that pVHL and glycogen synthase kinase (GSK)3beta are key components of an interlinked signalling pathway that maintains the primary cilium. Although inactivation of either pVHL or GSK3beta alone did not affect cilia maintenance, their combined inactivation leads to loss of cilia. In VHL patients, GSK3beta is subjected to inhibitory phosphorylation in renal cysts, but not in early VHL mutant lesions, and these cysts exhibit reduced frequencies of primary cilia. We propose that pVHL and GSK3beta function together in a ciliary-maintenance signalling network, disruption of which enhances the vulnerability of cells to lose their cilia, thereby promoting cyst formation.
Thoma
Claudio R
CR
Institute of Cell Biology, ETH Zurich, 8093 Zurich, Switzerland.
Frew
Ian J
IJ
Hoerner
Christian R
CR
Montani
Matteo
M
Moch
Holger
H
Krek
Wilhelm
W
D000818:Animals; D002460:Cell Line; D002923:Cilia / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000166:cytology; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*; D006623:von Hippel-Lindau Disease / Q000378:metabolism* / Q000473:pathology
D051794:Von Hippel-Lindau Tumor Suppressor Protein; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C497446:VHL protein, human; C494469:VHL protein, mouse