High resolution

Module 12: Figure polycystins and polycystic kidney disease

Mitogen-activated protein kinase (MAPK) remodelling hypothesis of polycystic kidney disease

Polycystic kidney disease results from mutations of the polycystins that are located at the cilium, where they appear to gate Ca2+ into the cytoplasm. It is proposed that this constant influx of Ca2+ is responsible for the phenotypic stability of the mitogen-activated protein kinase (MAPK) signalling pathway by maintaining the transcription of Raf-1, which is sensitive to inhibition by cyclic AMP. When the polycystins are mutated, a reduction in the level of Ca2+ results in a phenotypic switch such that B-Raf is expressed in addition to Raf-1. Since the former is insensitive to inhibition by cyclic AMP, the MAPK pathway is now able to transmit proliferative signals into the nucleus, and the mutated cell begins the cell division cycles that produce the cysts that characterize polycystic kidney disease.