Wip1 Phosphatase Modulates ATM-Dependent Signaling Pathways

Abstract

Deletion of Ppm1d, the gene encoding the Wip1 phosphatase, renders cells resistant to transformation and mice resistant to tumor development. Here, we report that deficiency of Wip1 resulted in activation of the ataxia-telangiectasia mutated (ATM) kinase. In turn, overexpression of Wip1 was sufficient to reduce activation of the ATM-dependent signaling cascade after DNA damage. Wip1 dephosphorylated ATM Ser1981, a site critical for ATM monomerization and activation, and was critical for resetting ATM phosphorylation as cells repaired damaged DNA. We propose that the Wip1 phosphatase is an integral component of an ATM-dependent signaling pathway.

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

“…PPM1D (also known as PP2Cd and WIP1) is a member of the PPM family (Fiscella et al, 1997), which is characterized by Mg 2 þ /Mn 2 þ -dependent activity and relative insensitivity to okadaic acid. PPM1D is encoded by a putative oncogene that is amplified in multiple cancer types Li et al, 2002;Hirasawa et al, 2003;Saito-Ohara et al, 2003;Mendrzyk et al, 2005;Shreeram et al, 2006), including 11-16% of human primary breast cancers, most of which express wild-type P53 Li et al, 2002).…”

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

“…Shreeram et al (2006) showed that ATM autophosphorylation and phosphorylation of p53 was slightly increased in Wip1-null MEFs compared to wild-type MEFs, as well as in Wip1-siRNA-treated human cells after IR exposure. They also showed that overexpression of Wip1 in mouse cell or human cells reduced the levels of ATM autophosphorylation, and that phosphorylated Ser1981 on ATM is directly dephosphorylated by Wip1 (Shreeram et al, 2006). These results suggest that Wip1 controls ATM kinase activity through its phosphatase activity.…”

“…Wip1 is a member of the protein phosphatase 2C (PP2C) family and is a negative regulator of p38 mitogen-activated protein kinase (MAPK) (Takekawa et al, 2000). Shreeram et al (2006) showed that ATM autophosphorylation and phosphorylation of p53 was slightly increased in Wip1-null MEFs compared to wild-type MEFs, as well as in Wip1-siRNA-treated human cells after IR exposure. They also showed that overexpression of Wip1 in mouse cell or human cells reduced the levels of ATM autophosphorylation, and that phosphorylated Ser1981 on ATM is directly dephosphorylated by Wip1 (Shreeram et al, 2006).…”

The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis

“…Previous analysis showed that Wip1 could modulate apoptotic response and proliferation (Bulavin et al, 2004;Belova et al, 2005), which could explain the early onset of tumors observed in MMTV-ErbB2/ PPM1D mice. While there was no significant difference in the rate of apoptosis between analyzed samples Several potential downstream targets of Wip1 have been identified in vitro: p38 MAPK, p53, Chk1, Chk2 and ataxia-telangiectasia mutated (ATM) (Takekawa et al, 2000;Lu et al, 2005;Fujimoto et al, 2006;Shreeram et al, 2006). The role of p38 MAPK is particularly interesting, as we previously found that Wip1-deficient mice show a p38 MAPK-dependent delay in the onset of breast cancer when crossed with MMTV-ErbB2 transgenic mice (Bulavin et al, 2004).…”

“…Further studies revealed that in addition to p38 MAPK and despite the substrate preference toward the pTXpY sequence (Yamaguchi et al, 2005), Wip1 could also efficiently dephosphorylate critical serine residues on p53, Chk1 and Chk2 in vitro (Lu et al, 2005;Fujimoto et al, 2006;Shreeram et al, 2006). Likewise, Wip1 phosphatase plays an important role in dephosphorylating ATM both in vitro and in vivo and in the regulation of ATM's ability to attenuate myc-driven lymphomagenesis (Shreeram et al, 2006;Shreeram et al, submitted). Thus, although we expected to see a substantial tumorprone phenotype in MMTV-PPM1D transgenic mice, they actually remained tumor-free.…”