The Aurora A kinase may contribute to polycystic kidney disease (PKD) by inactivating a key calcium channel in kidney cells, Plotnikova and Golemis say.
Aurora A is an oncogene best known as a regulator of mitotic progression. But the kinase has important functions during interphase as well, when it can promote cilia disassembly and can be activated by elevated calcium levels. Because both calcium signaling and cilia are defective in PKD, Plotnikova and Golemis wondered whether Aurora might contribute to the pathology of this common genetic disease.
The researchers found that Aurora A was up-regulated and activated in epithelial cells lining the cysts in PKD patient kidneys. In addition, Aurora A bound to and phosphorylated a calcium channel called polycystin-2, whose gene, PKD2, is often mutated in autosomal dominant forms of PKD. This interaction was enhanced by Aurora A's regulatory partner NEDD9.
Polycystin-2 mediates calcium influx into cilia and the release of calcium from storage in the endoplasmic reticulum. Inhibition or knockdown of Aurora A boosted intracellular calcium levels, but this effect was less pronounced in kidney cells lacking polycystin-2, indicating that the kinase normally lowers calcium levels by inactivating this channel. Only small doses of inhibitor were required to increase calcium levels, suggesting that Aurora A may be a viable therapeutic target for boosting polycystin-2 activity in certain PKD patients. Senior author Erica Golemis now wants to investigate how Aurora A becomes up-regulated in PKD and whether inhibitors of the kinase can slow cystogenesis in mouse models of the disease.