Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_345


 APKD2;  PC2;  PKD2;  PKD4;  TRPP1

Historical Background

The pkd2 gene encodes the protein polycystin-2, a member of the transient receptor potential (TRP) protein family. The genetic locus for pkd2 was elucidated in 1993 by the Kumar and Spruit groups during the search for genes involved in autosomal dominant polycystic kidney disease (ADPKD) (Kimberling et al. 1993; Peters et al. 1993). Mutations in pkd2 account for approximately 15% of the ADPKD patients, with the remainder of ADPKD patients having mutations in pkd1 or pkhd1 (Koulen and McClung 2006). Mutations in pkd2 may also contribute to inadequate heart function, a leading cause of mortality in ADPKD patients, as observed in patients, in pkd2+/− mice that lack renal deficiency, but display an age-dependent increase in cardiac dysfunction, and in pdk2+/− zebra fish, which exhibit impaired cardiac output (Chapman et al. 2010; Kuo et al. 2014, 2016; Paavola et al. 2013).

Functionally, polycystin-2 has been implicated in Ca 2+ release from intracellular stores (Koulen et al. 2002, 2005; Kaja et al. 2011). In conjunction with polycystin-1, polycystin-2 forms a receptor–calcium channel complex that is formed in the cilium of renal epithelial cells (Xia et al. 2010). In C. elegans, both polycystin-1 and polycystin-2 are expressed in the primary cilia of sensory neurons (Barr and Sternberg 1999). These receptor–channel complexes respond to inputs such as mechano-sensation, receptor tyrosine kinases, and G-coupled-protein receptor complexes and function to regulate diverse cellular processes such as differentiation and morphogenesis (Koulen and McClung 2006; Spirli et al. 2010; Zhou 2009; Montalbetti et al. 2007). Polycystin-2 localizes either to the endoplasmic reticulum (ER) or to the plasma membrane of primary cilia. This localization is dependent on cell type and the subcellular compartment in which polycystin-2 is expressed (Koulen and McClung 2006). However, expression of polycystin-2 has also been detected in the cytoplasm and the apical and basolateral membranes in the kidney (Zhou 2009). Although mutations in polycystin-1/polycystin-2 are most commonly associated with ADPKD, recent papers have shown functional genes are required for bone development, cardiac development, and left–right axis patterning (Tsiokas 2009; Xiao and Quarles 2010). Polycystin-2 functions in conjunction with other intracellular Ca2+ release channels as part of a positive feedback system during calcium-mediated signaling events (Kaja et al. 2011; Koulen et al. 2002, 2005; Koulen and McClung 2006). In adult mammals, polycystin-2 is expressed in the kidney, liver, spleen, lung, pancreas, ovary, testicular germ cells, Sertoli cells, corneal epithelium, retinal pigment epithelium, uterus, salivary glands, brain, adrenal cortex, epithelial cells of the GI tract, muscles (cardiac, vascular smooth, and skeletal), bone, and membrane particles, exosome-like vesicles, and urine (Koulen and McClung 2006; Xiao and Quarles 2010; Hogan et al. 2009). Polycystin-1/polycystin-2 functions in cilia to sense mechanical shear stress, with bending of the cilia causing increased Ca2+ entry into the cell. Additionally, it has been shown that the actin cytoskeleton directly modulates polycystin-2 activity (Tsiokas 2009). Sharif-Naeini et al. showed the dosage dependence of polycystin-1/polycystin-2 in cilia-mediated pressure sensing, further implicating the polycystin complex as a sensor of pressure and mechanical stress (Sharif-Naeini et al. 2009). In polycystin-2 knockout mice, endothelial cells could not sense fluid sheer stress and were deficient in the production of nitrous oxide in response to increased blood flow (AbouAlaiwi et al. 2009).


Polycystin-2 is a membrane-spanning protein with six transmembrane domains with both the N and C termini present in the cytoplasm (Tsiokas 2009). The polycystin-2 protein forms a voltage-dependent, calcium-dependent, large conductance calcium permeable nonselective cation channel (Koulen et al. 2002, 2005; Koulen and McClung 2006; Kaja et al. 2011). Polycystin-2 must interact with polycystin-1 to form a functional Ca2+ pore complex. The Homo sapiens PKD2 gene resides on chromosome 4q21-23 consisting of 15 exons that encode the polycystin-2 protein containing 968 amino acid residues (Gallagher et al. 2010; Miyagi et al. 2009). Residues 828–895 of the H. sapiens polycystin-2 protein form a coiled coil domain located at the C-terminus and are required for this protein–protein interaction (Tsiokas 2009; Petri et al. 2010). Additionally, the C-terminal tail of polycystin-2 contains an EF-hand domain (residues 720–797); with a linker (residues 798–827) between the coiled coil and EF-hand domains, the EF-hand domain is responsible for the calcium dependence of the pore complex (Koulen and McClung 2006; Petri et al. 2010; Allen et al. 2014). The N-terminal tail of polycystin-2 contains an RVxP motif that is responsible for localization of the protein to cilia (Geng et al. 2006). In addition to the localization signal for cilia, polycystin-2 contains several other intracellular targeting motifs that include motifs for retention in the endoplasmic reticulum and for targeting to the trans-Golgi network (Cai et al. 1999; Köttgen et al. 2005; Chapin and Caplan 2010). The specific subcellular localization of polycystin-2 is determined by distinct posttranslational modifications, alternate mRNA splicing, differential protein–protein interactions, and likely combinations thereof.

Interactions with Ligands and Other Proteins

For review of ligand and protein interactions described before 2006, see Koulen and McClung, UCSD Nature Molecule Pages (2006). Polycystin-2 forms complexes with members of other transient receptor potential (TRP) channel families forming heteromultimeric channels with unique properties. The polycystin-2/TRPC1 is a G-protein-coupled activated channel that displays a conductance, ion permeability, and amiloride sensitivity different from channel properties of either protein alone in single channel experiments. The interaction of polycystin-2/TRPV4 in cilium forms a thermo-/mechano-sensitive sensor that affects flow-induced Ca2+ transients in renal epithelium cells. α-Actinin and polycystin-2 colocalize in Madin–Darby canine kidney (MDCK) epithelium cells, medullary collecting duct cells, NIH 3 T3 fibroblasts, and human syncytiotrophoblast (hST) vesicles. In vitro electrophysiological recordings show that this interaction stimulates polycystin-2 channel activity (Zhou 2009). Polycystin-2 interacts with the inositol 1,4,5-trisphosphate receptor (IP 3R) through the acidic C-terminal domain of polycystin-2 and the N-terminal ligand domain of the IP3R. The consequence of this interaction is increased Ca2+ release via IP 3 and other Ca2+ agonists (Sammels et al. 2010). Filamin A and polycystin-2 interaction is necessary for polycystin-2’s inhibition of stretch-activated channels (SACs) which have been implicated in mechano-sensation in the kidney epithelium (Sharif-Naeini et al. 2009). Polycystin-2 acts to regulate the cell cycle by interactions between eIF2α, pancreatic ER-resident eIF2α kinase (PERK), and itself. Formation of the complex is necessary for PERK-mediated phosphorylation of eIF2α. Polycystin-2 also interacts with Id2, a member of the helix-loop-helix (HLH) protein family, whose expression suppresses p21 (Zhou 2009; Li et al. 2005). Trafficking of polycystin-2 from Golgi, ER, and the plasma membrane is achieved through phosphorylation of polycystin-2 by casein kinase 2, which regulates the interaction of phosphofurin acidic cluster sorting protein (PACS)-1 and PACS-2 with phosphorylated polycystin-2 protein. Phosphorylation of the N-terminus of polycystin-2 by glycogen synthase kinase 3 (GSK3) has been found to regulate the amount of polycystin-2 resident on the plasma membrane of MDCK cells. Finally, degradation of polycystin-2 is regulated through its interaction with ATPase p97, HERP, and glucosidase subunit beta PRKCSH (Gao et al. 2010).


Polycystin-2 is a member of the TRP channel family and along with polycystin-1(PC1) is linked to cyst formation in polycystic kidney disease. Polycystin-2 is located on the plasma membrane, on the endoplasmic reticulum membrane, and in cilia (Tsiokas et al. 2007). When located on the plasma membrane, polycystin-2 functions as a nonselective cation channel. Localization of polycystin-2 to the plasma membrane is tightly regulated by ER retention signaling and several chaperone proteins, including PC1. Epidermal growth factor has been shown to activate polycystin-2 in kidney epithelial cell lines, with increases in cytosolic calcium from extracellular, not intracellular, calcium sources (Zhou 2009; Tsiokas 2009). When localized to the ER, polycystin-2 acts as a calcium-induced calcium release channel (Koulen et al. 2002, 2005; Kaja et al. 2011). In addition, it modifies the function of other ER calcium release channels, ryanodine receptor (RyR), and inositol trisphosphate receptor (IP 3R) (Zhou 2009; Tsiokas et al. 2007). The C-terminus of polycystin-2 associates with RyR2 and inhibits calcium release in cardiomyocytes and mouse renal epithelial cells. The C-terminus of polycystin-2 associates with the IP 3Rs and enhances the duration of calcium signaling (Sammels et al. 2010; Anyatonwu et al. 2007). Association with several actin and microtubule-associated proteins within the cell changes functional release by polycystin-2 channels, suggesting a role in cytoskeletal remodeling in response to both mechanical and osmotic pressure changes (Zhou 2009; Montalbetti et al. 2007). Cell cycle regulation is also implicated as another possible function of polycystin-2. Association with the Id family directly controls cell cycle regulation, and expression on mitotic spindles has been shown to affect calcium signaling during mitosis. Whether this effect is due directly to polycystin-2 or its interaction with mammalian Diaphanous 1 (mDia1) is not known (Zhou 2009; Tsiokas et al. 2007). In the cilium, association with TRPV4 allows cations to enter the cell in response to mechanical stimulation, and removal of either subunit abolishes this response (Zhou 2009; Tsiokas et al. 2007).


Mutations of pkd2 are responsible for 15% of APKD cases. However, due to the localization of polycystin complexes to cilia, and the broad expression of these proteins in various tissues, we should not overlook the role that mutations within these complexes may play in other disease processes such as Alzheimer’s disease, glaucoma, and hypertension. The polycystin proteins act to integrate multiple inputs such as mechano-stress, G-protein-coupled receptors, perturbation of the cytoskeleton, and kinase cascades into calcium-mediated signaling events. Activation of the polycystin protein complex leads to a positive calcium feedback loop that affects the function and characteristics of other intracellular Ca2+ channels. Future research should be directed toward an examination of the regulatory elements that control induction and expression of the pkd2 gene as well as the regulatory posttranslational modifications that control the function, localization, and half-life of the polycystin protein. Researchers should also continue to identify ligands, cofactors, scaffolds, and other regulatory mechanisms in order to elucidate potential pharmacological targets for controlling diseases caused by mutated or mis-regulated polycystin-2 proteins.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Daryl L. Goad
    • 1
  • Michael A. Grillo
    • 2
  • Peter Koulen
    • 2
  1. 1.Department of Natural Science, Social Science, and MathematicsHutchinson Community CollegeHutchinsonUSA
  2. 2.Department of Ophthalmology and Department of Basic Medical ScienceUniversity of Missouri - Kansas City School of Medicine, Vision Research CenterKansas CityUSA