Choi, Byung-Kwon Fujiwara, Kenichiro Dayaram, Tajhal Darlington, Yolanda Dickerson, Joshua Goodell, Margaret A. Donehower, Lawrence A. WIP1 dephosphorylation of p27<sup>Kip1</sup> Serine 140 destabilizes p27<sup>Kip1</sup> and reverses anti-proliferative effects of ATM phosphorylation <p>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<sup>Kip1</sup> that promotes G1 arrest. ATM activates p27<sup>Kip1</sup>-induced arrest in part through phosphorylation of p27<sup>Kip1</sup> 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 <i>PPM1D</i> 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<sup>Kip1</sup> 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<sup>Kip1</sup> while increased expression of similar amounts of phosphatase-dead WIP1 has no effect on p27<sup>Kip1</sup> protein stability. Overexpression of wildtype p27<sup>Kip1</sup> 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<sup>Kip1</sup> activity following activation by ATM.</p> PPM1D;WIP1;ATM;p27Kip1;CDKN1B;Serine 140 2020-01-21
    https://tandf.figshare.com/articles/dataset/WIP1_dephosphorylation_of_p27_sup_Kip1_sup_Serine_140_destabilizes_p27_sup_Kip1_sup_and_reverses_anti-proliferative_effects_of_ATM_phosphorylation/11667909
10.6084/m9.figshare.11667909.v1