WIP1 dephosphorylation of p27Kip1 Serine 140 destabilizes p27Kip1 and reverses anti-proliferative effects of ATM phosphorylation
- 20 January 2020
- journal article
- research article
- Published by Taylor & Francis Ltd in Cell Cycle
- Vol. 19 (4), 479-491
- https://doi.org/10.1080/15384101.2020.1717025
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 p27Kip1 that promotes G1 arrest. ATM activates p27Kip1-induced arrest in part through phosphorylation of p27Kip1 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 p27Kip1 Ser140 both in vitro and in cells and that this dephosphorylation is sensitive to the WIP1-specific inhibitor GSK 2830371. Increased expression of wildtype WIP1 reduces stability of p27Kip1 while increased expression of similar amounts of phosphatase-dead WIP1 has no effect on p27Kip1 protein stability. Overexpression of wildtype p27Kip1 reduces cell proliferation and colony forming capability relative to the S140A (constitutively non-phosphorylated) form of p27. Thus, WIP1 plays a significant role in homeostatic modulation of p27Kip1 activity following activation by ATM.Keywords
Funding Information
- Cancer Prevention and Research Institute of Texas (RP160451)
- National Cancer Institute (CA237291)
This publication has 38 references indexed in Scilit:
- PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic ChemotherapyCell Stem Cell, 2018
- Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical OutcomesCell Stem Cell, 2017
- Mdm proteins: critical regulators of embryogenesis and homoeostasisJournal of Molecular Cell Biology, 2017
- Attenuating the p53 Pathway in Human Cancers: Many Means to the Same EndCold Spring Harbor Perspectives in Medicine, 2016
- WIP1 Phosphatase as a Potential Therapeutic Target in NeuroblastomaPLOS ONE, 2015
- The type 2C phosphatase Wip1: An oncogenic regulator of tumor suppressor and DNA damage response pathwaysCancer and Metastasis Reviews, 2008
- Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphataseCell Death & Differentiation, 2005
- The p53-Induced Oncogenic Phosphatase PPM1D Interacts with Uracil DNA Glycosylase and Suppresses Base Excision RepairMolecular Cell, 2004
- Cip/Kip proteins: more than just CDKs inhibitors: Figure 1.Genes & Development, 2004
- Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activityNature Genetics, 2002