Polycystin-2 regulates proliferation and branching morphogenesis in kidney epithelial cells.
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple fluid-filled cysts that expand over time and destroy the renal architecture. Loss or mutation of polycystin-1 or polycystin-2, the respective proteins encoded by the ADPKD genes PKD1 and PKD2, is associated with most cases of ADPKD. Thus, the polycystin proteins likely play a role in cell proliferation and morphogenesis. Recent studies indicate that polycystin-1 is involved in these processes, but little is known about the role played by polycystin-2. To address this question, we created a number of related cell lines variable in their expression of polycystin-2. We show that the basal and epidermal growth factor-stimulated rate of cell proliferation is higher in cells that do not express polycystin-2 versus those that do, indicating that polycystin-2 acts as a negative regulator of cell growth. In addition, cells not expressing polycystin-2 exhibit significantly more branching morphogenesis and multicellular tubule formation under basal and hepatocyte growth factor-stimulated conditions than their polycystin-2-expressing counterparts, suggesting that polycystin-2 may also play an important role in the regulation of tubulogenesis. Cells expressing a channel mutant of polycystin-2 proliferated faster than those expressing the wild-type protein, but exhibited blunted tubule formation. Thus, the channel activity of polycystin-2 may be an important component of its regulatory machinery. Finally, we show that polycystin-2 regulation of cell proliferation appears to be dependent on its ability to prevent phosphorylated extracellular-related kinase from entering the nucleus. Our results indicate that polycystin-2 is necessary for the proper growth and differentiation of kidney epithelial cells and suggest a possible mechanism for the cyst formation seen in ADPKD2.
Grimm
David H
DH
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Karihaloo
Anil
A
Cai
Yiqiang
Y
Somlo
Stefan
S
Cantley
Lloyd G
LG
Caplan
Michael J
MJ
D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003560:Cysts / Q000473:pathology / Q000503:physiopathology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology* / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D007684:Kidney Tubules / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D016891:Polycystic Kidney, Autosomal Dominant / Q000473:pathology* / Q000503:physiopathology*; D050396:TRPP Cation Channels
D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D017228:Hepatocyte Growth Factor; D008565:Membrane Proteins; D050396:TRPP Cation Channels