The Valosin-containing Protein (VCP) Is a Target of Akt Signaling Required for Cell Survival

Vandermoere, Franck; Yazidi‐Belkoura, Ikram El; Slomianny, Christian; Demont, Yohann; Bidaux, Gabriel; Adriaenssens, Éric; Lemoine, Jérôme; Hondermarck, Hubert

doi:10.1074/jbc.m510003200

Cited by 78 publications

(78 citation statements)

References 27 publications

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“…The expression was observed in mesonephros of both male and female embryos. VCP expression in the gonad was observed in the left ovary but was not observed (Wojcik et al, 2004, Vandermoere et al, 2006. These results and the present data suggest that VCP (Fig.…”

Section: Vcp Gal10supporting

confidence: 77%

“…VCP belongs to AAA (ATPases associated with various cellular activities) family, and is essential for a wide variety of cellular functions such as ubiquitin/ proteasom-dependent protein degradation, membrane fusion, cell cycle regulation, and endoplasmic reticulum-associated degradation (Latterich et al, 1995, Zhang et al, 2000, Dai and Li, 2001, Ye et al, 2003, Wang et al, 2004, Vandermoere et al, 2006. Expression of VCP mRNA was female specific as PLCH1 is a recently discovered class of isoforms of phospholipase C (PLC) that is involved in the inocitol signaling pathway (Nakahara et al, 2005, Stewart et al, 2007.…”

Section: Discussionmentioning

confidence: 99%

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Identification of differentially expressed genes involved in the regression and development of the chicken Mllerian duct

Ha¹,

Tsukada²,

Sakai³

et al. 2008

Int. J. Dev. Biol.

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Müllerian ducts of male chickens undergo regression around day 12 of incubation, but the underlining mechanisms remain unclear. The purpose of this study was to identify factors that contribute to regression of the Müllerian duct in the chicken. We first employed annealing control primer-based RT-PCR to screen candidate genes differentially expressed in the Müllerian ducts between male and female. Four differentially expressed genes (MSX2, GAL10, VCP and PLCH1) were partially sequenced. The expression of mRNA of the latter genes and MSX1 in the male and female Müllerian ducts were compared at 7.5, 8 and 9 days of incubation using semiquantitative RT-PCR. The results indicated that both MSX1 and MSX2 mRNA was highly expressed in the male Müllerian duct at day 9 of incubation, whereas, PLCH1 mRNA was lower in the male duct at day 9 of incubation compared to that of the female duct. Although VCP mRNA was expressed in both left and right female Müllerian ducts, no expression was detected in the male duct. Whole mount in situ hybridyzation analysis showed that the expression of MSX1 and MSX2 mRNA were localized specifically in the mesenchymal cells of the male Müllerian duct at day 9 of incubation. In contrast, VCP mRNA expression was observed in both mesenchymal and epithelial cells of the female Müllerian duct but not detected in the male duct. These results suggest that both up-regulation of MSX1 and MSX2 mRNA expression is involved in the regression of the Müllerian duct in male chicken embryo, whereas VCP expression is involved in development of the female duct.

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Section: Vcp Gal10supporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Identification of differentially expressed genes involved in the regression and development of the chicken Mllerian duct

Ha¹,

Tsukada²,

Sakai³

et al. 2008

Int. J. Dev. Biol.

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“…VCP/p97 ATPase is negatively regulated by Akt phosphorylation (33,34). We phosphorylated recombinant VCP/ p97 by purified Akt and assayed PP2A reactivation of the ATPase (supplemental Fig.…”

Section: Nitration Of Tyrmentioning

confidence: 99%

Endotoxin Conditioning Induces VCP/p97-mediated and Inducible Nitric-oxide Synthase-dependent Tyr284 Nitration in Protein Phosphatase 2A

Ohama

Brautigan

2010

Journal of Biological Chemistry

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Endotoxins activate Toll-like receptors and reprogram cells to be refractory to secondary exposure. Here we found that activation of different Toll-like receptors elicited a time-and dosedependent increase in the levels of the protein phosphatase 2A catalytic subunit (PP2Ac) but not its partner A subunit. We purified the lipopolysaccharide-induced form of PP2A by chromatography plus immunoprecipitation and used mass spectrometry to identify VCP/p97 as a novel partner for PP2Ac. Endogenous VCP/p97 and PP2Ac were co-immunoprecipitated from primary murine macrophages and human lymphocytes. GST-VCP/p97 bound purified PP2A in pulldown assays, showing direct protein-protein interaction. Endotoxin conditioning of macrophages induced formation of 3-nitrotyrosine in the PP2Ac associated with VCP/p97, a response severely reduced in macrophages from iNOS knock-out mice. The reaction of purified PP2A with peroxynitrite dissociated the A subunit, and 3-nitro-Tyr 284 was identified in PP2Ac by mass spectrometry. Myc-PP2Ac (Y284F) expressed in cells was resistant to peroxynitrite-induced nitration and reduction of A subunit binding. Transient expression of either VCP/p97 or PP2Ac was sufficient to elevate levels of the dual specificity phosphatase DUSP1, reduce p38 MAPK activation, and suppress tumor necrosis factor-␣ release. We propose that VCP/p97-mediated Tyr nitration of PP2A increases the levels of phosphatases PP2A and DUSP1 to contribute to the refractory response of conditioned cells.Endotoxins are microbial components that engage Toll-like receptors (TLRs) 2 to activate MAPK signaling and stimulate cytokine release from cells of the innate immune system. Cells adapt to endotoxin and become resistant to subsequent stimulation, a response called preconditioning or tolerance. This resistant state is not well understood, but it involves the induction and suppression of many genes and has been studied in both cellular and in vivo models (1). Reduced cytokine release by preconditioned cells is attributed to diminished activation of MAPK, in particular p38 MAPK (1). The MAPKs are under the control of different classes of protein phosphatases, including protein phosphatase 2A (PP2A) and dual specificity phosphatases (DUSPs). PP2A is an essential serine/threonine phosphatase conserved from yeast to human that regulates signal transduction pathways, cell cycle, cell growth, cytoskeleton dynamics, and cell mobility (2). PP2A exists in cells as a heterotrimer comprised of a 36-kDa catalytic subunit (PP2Ac), a 65-kDa scaffolding subunit (A subunit), plus one regulatory B subunit from four different families of genes. There is good evidence that mammalian cells contain a pool of the AC dimer, as well as heterotrimer forms of PP2A (3). Biochemical and genetic analyses have shown that the regulatory B subunits control PP2A specificity by targeting the AC core dimer to substrates. Crystal structures of heterotrimeric PP2A holoenzymes revealed that the regulatory B subunits interact with PP2Ac while bound side by side on the same face...

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“…5). Based on previous reports that many Akt substrates have non-typical Akt phosphorylation motifs, [48][49][50] there might be additional non-typical motif(s) on DLK protein. The importance of this weak phosphorylation in DLK is still unknown.…”

Section: Discussionmentioning

confidence: 99%

Akt suppresses DLK for maintaining self-renewal of mouse embryonic stem cells

Wang

et al. 2015

Cell Cycle

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Mouse embryonic stem cells (ES cells) can proliferate indefinitely. To identify potential signals involved in suppression of self-renewal, we previously screened a kinase/phosphatase expression library in ES cells, and observed that inhibition of Dual Leucine zipper-bearing Kinase (DLK) increased relative cell numbers. DLK protein was detected in both the pluripotent and differentiated states of mouse ES cells while DLK kinase activity increased upon differentiation. Overexpression of DLK in mouse ES cells displayed reductions in relative cell/colony numbers and Nanog expression, suggesting a suppressive role of DLK in self-renewal. By examining protein sequences of DLK, we identified 2 putative Akt phosphorylation sites at S584 and T659. Blocking PI3K/Akt signaling with LY-294002 enhanced DLK kinase activity dramatically. We found that Akt interacts with and phosphorylates DLK. Mutations of DLK amino acid residues at putative Akt phosphorylation sites (S584A, T659A, or S584A and T659A) diminished the level of DLK phosphorylation. While the mutated DLKs (S584A, T659A, or S584A and T659A) were expressed, a further reduction in cell/colony numbers and Nanog expression appeared in mouse ES cells. In addition, these mutant DLKs (S584A, T659A, or S584A and T659A) exhibited more robust kinase activity and cell death compared to wild type DLK or green fluorescence (GFP) controls. In summary, our results show that DLK functions to suppress self-renewal of mouse ES cells and is restrained by Akt phosphorylation.

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The Valosin-containing Protein (VCP) Is a Target of Akt Signaling Required for Cell Survival

Cited by 78 publications

References 27 publications

Identification of differentially expressed genes involved in the regression and development of the chicken Mllerian duct

Identification of differentially expressed genes involved in the regression and development of the chicken Mllerian duct

Endotoxin Conditioning Induces VCP/p97-mediated and Inducible Nitric-oxide Synthase-dependent Tyr284 Nitration in Protein Phosphatase 2A

Akt suppresses DLK for maintaining self-renewal of mouse embryonic stem cells

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