WIP1 dephosphorylation of p27Kip1 Serine 140 destabilizes p27Kip1 and reverses anti-proliferative effects of ATM phosphorylation. Issue 4 (16th February 2020)

• Record Type: Journal Article
• Authors: Choi, Byung-Kwon; Fujiwara, Kenichiro; Dayaram, Tajhal; Darlington, Yolanda; Dickerson, Joshua; Goodell, Margaret A.; Donehower, Lawrence A.
• Is Part Of: Cell cycle. Volume 19:Issue 4(2020)
• Page Start: 479
• Page End: 491
• Publication Date: 2020-02-16
• Subjects: PPM1D -- WIP1 -- ATM -- p27Kip1 -- CDKN1B -- Serine 140; Cell cycle -- Periodicals; 571.84377
• DOI: 10.1080/15384101.2020.1717025
• Languages: English
• ISSNs: 1538-4101

Abstract

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 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 p27 Kip1 while increased expression of similar amounts of phosphatase-dead WIP1 has no effect on p27 Kip1 protein stability. Overexpression of wildtype p27 Kip1 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 p27 Kip1 activity following activation by ATM.