WIP1 dephosphorylation of p27^Kip1 Serine 140 destabilizes p27^Kip1 and reverses anti-proliferative effects of ATM phosphorylation.

ABSTRACT: The phosphoinositide-3-kinase like kinases (PIKK) such as ATM and ATR play a key role in initiating the cellular DNA damage response (DDR). One key ATM target is the cyclin-dependent kinase inhibitor p27^Kip1 that promotes G1 arrest. ATM activates p27^Kip1-induced arrest in part through phosphorylation of p27^Kip1 at Serine 140. Here we show that this site is dephosphorylated by the type 2C serine/threonine phosphatase, WIP1 (Wildtype p53-Induced Phosphatase-1), encoded by the PPM1D gene. WIP1 has been shown to dephosphorylate numerous ATM target sites in DDR proteins, and its overexpression and/or mutation has often been associated with oncogenesis. We demonstrate that wildtype, but not phosphatase-dead WIP1, efficiently dephosphorylates p27^Kip1</

SUBMITTER: Choi BK 

PROVIDER: S-EPMC7100888 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature