RIP-ed and ready to dance: new mechanisms for polycystin-1 signaling

Polycystin-1, the protein encoded by the principal gene involved in autosomal dominant polycystic kidney disease, has been implicated in extracellular sensing as well as in cell-cell and cell-matrix interactions. However, the precise mechanisms involved in polycystin-1 signaling are not well defined. A report in this issue of the JCI demonstrates that the C-terminal tail of polycystin-1 is cleaved from the membrane through regulated intramembrane proteolysis (RIP) and that this domain translocates to the nucleus, where it activates the AP-1 transcription pathway. This translocation appears to be modulated by polycystin-2, with which polycystin-1 is thought to interact. These findings provide what we believe to be the first evidence that polycystin-1 can signal directly to the nucleus and that polycystin-1-polycystin-2 interactions do not require colocalization of these proteins in the same membrane compartment.