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 polycystin1 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.