Polycystin and calcium signaling in cell death and survival

Abstract

Mutations in polycystin-1 (PC1) and polycystin-2 (PC2) result in a commonly occurring genetic disorder, called Autosomal Dominant Polycystic Kidney Disease (ADPKD), that is characterized by the formation and development of kidney cysts. Epithelial cells with loss-of-function of PC1 or PC2 show higher rates of proliferation and apoptosis and reduced autophagy. PC1 is a large multifunctional transmembrane protein that serves as a sensor that is usually found in complex with PC2, a calcium (Ca²⁺)-permeable cation channel. In addition to decreased Ca²⁺ signaling, several other cell fate-related pathways are de-regulated in ADPKD, including cAMP, MAPK, Wnt, JAK-STAT, Hippo, Src, and mTOR. In this review we discuss how polycystins regulate cell death and survival, highlighting the complexity of molecular cascades that are involved in ADPKD.

Keywords: ADPKD; Apoptosis; Autophagy; Calcium signaling; Polycystins; TRPP2.

Fig. 1. Polycystins lead to autosomal dominant polycystic disease

Genetic mutations in PC1 or PC2 affect many signaling cascades, causing progressive cyst growth in the kidney, leading to a dysfunctional polycystic kidney.

Fig. 2. Diagram representing signaling cascades involved in cell survival and cell death that are de-regulated in ADPKD

Proteins of related to Ca²⁺ signaling, cyclic adenosine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), Wnt, Janus kinase (JAK) and Signal Transducer and Activator of Transcription (STAT), Hippo, Src, and mechanistic target of rapamycin (mTOR) cascades are represented in the diagram. Ca²⁺, calcium; PC1, polycystin-1; PC2, polycystin-2; GSK, glycogen synthase kinase; TSC, Tuberous Sclerosis Complex; InsP3R, inositol triphosphate receptor; RYR, ryanodine receptor; TRPV4, Transient Receptor Potential cation channel subfamily V member 4; TRPC1, transient receptor potential channel 1; STIM1, stromal interaction molecule 1; YAP, Yes-associated protein.