Protein serine/threonine phosphatases: life, death, and sleeping

Gallego, Mónica; Virshup, David M.

doi:10.1016/j.ceb.2005.01.002

Cited by 142 publications

(111 citation statements)

References 43 publications

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“…Similar results were found in mammalian cells (Strack et al, 2004). PP2 is also a well characterised regulator of the MAP kinase signalling pathways with both positive and negative effects depending upon cell type (Gallego and Virshup, 2005). PP2 is a positive regulator of RAF1 activation (Abraham et al, 2000) and can dephosphorylate both MEK and ERK in vitro (Haccard et al, 1990;Alessi et al, 1995).…”

Section: Ppp2r1a and Phosphatase 2 (Pp2)supporting

confidence: 67%

Representational difference analysis of cDNA identifies novel genes expressed following preconditioning of the heart

Fauchon

Pell²,

Baxter³

et al. 2005

Exp Mol Med

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Preconditioning of the myocardium rapidly induces a number of transcription factors, which are likely to be responsible for a cascade of transcriptional changes underlying the development of delayed adaptation. Identifying these changes provides insight into the molecular pathways elicited by sub-lethal ischaemia and the mechanism leading to delayed adaptation. Genes up-regulated in rabbit myocardium in vivo by ischaemic preconditioning following reperfusion for 2 h, 4 h and 6 h posttreatment were identified by representational difference analysis of cDNA (cDNA. RDA). The area of the left ventricle rendered ischaemic by preconditioning or the equivalent area of sham-treated animals was isolated and cDNA.RDA performed. Three novel genes and six genes with known function where identified, including the TGFβ receptor interacting protein 1, the α isoform of the A subunit of PP2 and the cap binding protein NCBP1. To determine whether expression of these genes correlated with preconditioning per se, expression was measured in myocardium after both ischaemic as well as heat shock induced preconditioning following 2 h, 4 h, and 6 h reperfusion. These genes were induced in rabbit myocardium in vivo by both ischaemia and heat shock, consistent with a fundamental role in the development of delayed adaptation. The well described role of PP2 in modulating the mitogen-activated protein kinase pathway and promoting cell survival is consistent with our previous work, which identified the reperfusion injury salvage kinase pathway in mediating the protective effects of ischaemic preconditioning. Expression of Trip1 and Ncbp1 also implicates TGFβ signalling pathways and RNA processing and transport in delayed adaptation to stress in the myocardium.

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Section: Ppp2r1a and Phosphatase 2 (Pp2)supporting

confidence: 67%

Representational difference analysis of cDNA identifies novel genes expressed following preconditioning of the heart

Fauchon

Pell²,

Baxter³

et al. 2005

Exp Mol Med

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“…The human genome harbours over 500 putative protein kinases (Manning et al, 2002), whereas protein dephosphorylation is controlled by four structurally distinct protein families that include the serine/threonine phosphatase families PPP and PPM (Gallego and Virshup, 2005). 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.…”

Section: Introductionmentioning

confidence: 99%

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

et al. 2007

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The PPM1D gene is aberrantly amplified in a range of common cancers and encodes a protein phosphatase that is a potential therapeutic target. However, the issue of whether inhibition of PPM1D in human tumour cells that overexpress this protein compromises their viability has not yet been fully addressed. We show here, using an RNA interference (RNAi) approach, that inhibition of PPM1D can indeed reduce the viability of human tumour cells and that this effect is selective; tumour cell lines that overexpress PPM1D are sensitive to PPM1D inhibition whereas cell lines with normal levels are not. Loss of viability associated with PPM1D RNAi in human tumour cells occurs via the activation of the kinase P38. To identify chemical inhibitors of PPM1D, a high-throughput screening of a library of small molecules was performed. This strategy successfully identified a compound that selectively reduces viability of human tumour cell lines that overexpress PPM1D. As expected of a specific inhibitor, the toxicity to PPM1D overexpressing cell lines after inhibitor treatment is P38 dependent. These results further validate PPM1D as a therapeutic target and identify a proof-of-principle small molecule inhibitor.

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“…The FYVE domain-containing proteins, such as SARA (10), Hgs/Hrs (33) and endofin (34), participate in anchoring Smad2 to early endosomes and present it to T␤RI for signal transactivation. In the present work, we have shown for the first time that MTMR4, another FYVE domain-containing protein with a conserved PTP/DSP domain (35), specifically down-regulates the phosphorylation level of activated Smad2/3 in early endosomes to prevent R-Smads from being overactivated. This is particularly interesting because MTMR4 might provide an additional layer for fine-tuning the nucleocytoplasm shuttling of activated R-Smads.…”

Section: Discussionmentioning

confidence: 90%

MTMR4 Attenuates Transforming Growth Factor β (TGFβ) Signaling by Dephosphorylating R-Smads in Endosomes

Pan

Qin

et al. 2010

Journal of Biological Chemistry

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Homeostasis of Smad phosphorylation at its C-terminal SXS motif is essential for transforming growth factor ␤ (TGF␤) signaling. Whereas it is known that TGF␤ signaling can be terminated by phosphatases, which dephosphorylate R-Smads in the nucleus, it is unclear whether there are any cytoplasmic phosphatase(s) that can attenuate R-Smad phosphorylation and nuclear translocation. Here we demonstrate that myotubularinrelated protein 4 (MTMR4), a FYVE domain-containing dualspecificity protein phosphatase (DSP), attenuates TGF␤ signaling by reducing the phosphorylation level of R-Smads in early endosomes. Co-immunoprecipitation experiments showed that endogenous MTMR4 interacts with phosphorylated R-Smads, and that this interaction is correlated with dephosphorylation of R-Smads. Further analysis showed that overexpression of MTMR4 resulted in the sequestration of activated Smad3 in the early endosomes, thus reducing its nuclear translocation. However, both point mutations at the conserved catalytic site of the phosphatase (MTMR4-C407S) and small interference RNA of endogenous Mtmr4 expression led to sustained Smad3 activation. This work therefore suggests that MTMR4 plays an important role in preventing the overactivation of TGF␤ signaling by dephosphorylating activated R-Smads that have been trafficked to early endosomes. The transforming growth factor ␤ (TGF␤)3 signaling pathway involves two transmembrane serine/threonine kinases, namely type II (T␤RII) and type I TGF␤ receptors (T␤RI) (1, 2). T␤RII, a constitutively active kinase, binds TGF␤ to initiate its heterodimerization with T␤RI. T␤RI then becomes phosphorylated and activates a signaling cascade through a family of intracellular signaling mediators known as Smads.In doing so, T␤RI recruits receptor-regulated Smads (RSmads, including BMP signaling transducers Smad1, -5, and -8 and TGF␤ signaling transducers Smad2, -3) and phosphorylates the two conserved C-terminal serines (SXS) of R-Smads. Activated R-Smads form a trimeric complex with a common mediator Smad (Co-Smad, Smad4), and these complexes translocate into the nucleus to regulate the transcription of an array of target genes (3-7). Recent studies have also indicated that Smad Anchor for Receptor Activation (SARA), an early endosomal protein containing a characteristic FYVE domain (Fab1p, YO1B, Vac1p, and EEA1), serves as an anchor protein by directly recruiting Smad2 to the early endosomes (8, 9) and presenting Smad2 to the internalized T␤RI/II complex (10, 11). Phosphorylated Smad2 then dissociates from SARA and leaves the early endosome. Subsequently, it forms a Smad2-Smad4 complex for nuclear translocation.Despite the fact that TGF␤ signaling activation is surprisingly simple, there are many layers of negative regulation that fine-tune or terminate the signal. The inhibitory Smads (I-Smads, including Smad6 and -7) competitively inhibit the interaction of R-Smads with Smad4 or receptors to provide a negative checkpoint for TGF␤-signaling activation (12). Ubiquitin-dependent degradation of activated...

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Protein serine/threonine phosphatases: life, death, and sleeping

Cited by 142 publications

References 43 publications

Representational difference analysis of cDNA identifies novel genes expressed following preconditioning of the heart

Representational difference analysis of cDNA identifies novel genes expressed following preconditioning of the heart

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

MTMR4 Attenuates Transforming Growth Factor β (TGFβ) Signaling by Dephosphorylating R-Smads in Endosomes

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