Polycystin-1 Inhibits Cell Proliferation through Phosphatase PP2A/B56?.

ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is associated with a number of cellular defects such as hyperproliferation, apoptosis, and dedifferentiation. Mutations in polycystin-1 (PC1) account for ?85% of ADPKD. Here, we showed that wild-type (WT) or mutant PC1 composed of the last five transmembrane (TM) domains and the C-terminus (termed PC1-5TMC) inhibits cell proliferation and protein translation, as well as the downstream effectors of mTOR, consistent with previous reports. Knockdown of B56?, a subunit of the protein phosphatase 2A (PP2A) complex, or application of PP2A inhibitor okadaic acid or calyculin A, abolished the inhibitory effect of PC1 and PC1-5TMC on proliferation, indicating that PP2A/B56? mediates the regulation of cell proliferation by PC1. In addition to the phosphorylated S6 and 4EBP1, B56? was also downregulated by PC1 and PC1-5TMC. Furthermore, the downregulation of B56?, which may be mediated by mTOR but not AKT, can account for the dependence of PC1-inhibited proliferation on PP2A.

SUBMITTER: Tang Y 

PROVIDER: S-EPMC6770331 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature