Polycystin and calcium signaling in cell death and survival
Fernanda O Lemos1, Barbara E Ehrlich2
1Department of Pharmacology, Yale University, 333 Cedar St, New Haven, CT, 06520, USA.
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.
Insights
Mutations in polycystin-1 (PC1) and polycystin-2 (PC2) cause Autosomal Dominant Polycystic Kidney Disease (ADPKD). This review explores how polycystins regulate cell death and survival pathways disrupted in ADPKD.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder characterized by kidney cyst formation.
- Mutations in polycystin-1 (PC1) and polycystin-2 (PC2) are the primary cause of ADPKD.
- PC1 and PC2 proteins form a complex crucial for kidney cell function.
Purpose of the Study:
- To review the role of polycystins (PC1 and PC2) in regulating cell death and survival.
- To highlight the molecular pathways dysregulated in ADPKD due to polycystin dysfunction.
- To discuss the complexity of cellular mechanisms underlying ADPKD pathogenesis.
Main Methods:
- This study is a review, synthesizing existing research on polycystins and ADPKD.
- Analysis of molecular cascades involved in cell fate regulation.
- Examination of signaling pathways including Ca2+ signaling, cAMP, MAPK, Wnt, JAK-STAT, Hippo, Src, and mTOR.
Main Results:
- Loss-of-function mutations in PC1 or PC2 lead to increased epithelial cell proliferation and apoptosis.
- Autophagy is reduced in ADPKD epithelial cells.
- Dysregulation of multiple cell fate pathways, including calcium signaling, occurs in ADPKD.
Conclusions:
- Polycystins play a critical role in maintaining kidney cell homeostasis.
- Aberrant regulation of cell death and survival pathways contributes significantly to ADPKD.
- Understanding these complex molecular cascades is vital for developing ADPKD therapies.
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