Cell biology of polycystin-2

Abstract

Naturally occurring mutations in two separate, but interacting loci, pkd1 and pkd2 are responsible for almost all cases of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is one of the most common genetic diseases resulting primarily in the formation of large kidney, liver, and pancreatic cysts. Homozygous deletion of either pkd1 or pkd2 results in embryonic lethality in mice due to kidney and heart defects illustrating their indispensable roles in mammalian development. However, the mechanism by which mutations in these genes cause ADPKD and other developmental defects are unknown. Research in the past several years has revealed that PKD2 has multiple functions depending on its subcellular localization. It forms a receptor-operated, non-selective cation channel in the plasma membrane, a novel intracellular Ca2+ release channel in the endoplasmic reticulum (ER), and a mechanosensitive channel in the primary cilium. This review focuses on the functional compartmentalization of PKD2, its modes of activation, and PKD2-mediated signal transduction.

Fig. 1

Functional compartmentalization of PKD2. PKD2 is thought to function as a receptor-operated non-selective cation channel at the plasma membrane, an intracellular Ca²⁺ release channel in the ER, and a mechanosensitive channel in the cilium. The location of the D511V mutation is shown in red and the putative pore (P)-forming region is shown in green.

Fig. 2

Dynamic regulation of PKD2 trafficking from the ER to the plasma membrane. Physical interactions with PKD1 and PIGEA-14 or phosphorylation at S76 by GSK3 facilitate PKD2 movement from the ER to the plasma membrane, while phosphorylation at S812 by CK2 and binding to PACS proteins sequesters PKD2 in the ER.

Fig. 3

Symmetric distribution of PKD2 between mother and daughter cells during cell division. PKD2 (shown as dark rectangular) is anchored to the mitotic spindles through a physical interaction with mdia1 (shown as open circle) during metaphase. As a result, mother and daughter cell receive equal amounts of PKD2.

Fig. 4

Hypothetical model of PKD2-mediated cell signaling. PKD2 physically associates with TRPC1 and can be activated by receptor tyrosine kinases (RTK) through the reduction of plasma membrane PIP₂. PKD2 and TRPC1 associate with Id2 and I-mfa, respectively, which can bind and suppress the transcriptional activity of two distinct subsets of bHLHs, E47 and MyoD-related proteins.