Roles of mammalian protein phosphatase 2C family members in the regulation of cellular functions

Tamura, Shinji; Li, Ming Guang; Komaki, Ken-ichiro; Sato, Masato; Kobayashi, Toshihide

doi:10.1007/978-3-540-40035-6_5

Cited by 13 publications

(12 citation statements)

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“…2A). The targeting vector was designed to delete exon 4, which contains the translational initiation sites for all six alternative splicing isoforms and encodes five of the six conserved motifs known to be necessary for its catalytic activity (Tamura et al, 2004). Thus, functional PP2Cb was not expected to be expressed from the mutated allele ( Fig.…”

Section: Pp2cb D/d Embryos Exhibit Pre-implantation Lethalitymentioning

confidence: 99%

“…Protein phosphatase 2C (PP2C) and pyruvate dehydrogenase phosphatase belong to the PPM family, while PP1, PP2A, and PP2B belong to the PPP family. At least twelve distinct PP2C gene products (2Ca, 2Cb, 2Cc/ FIN13, 2Cd/ILKAP, 2Ce, 2Cf, 2Cg, Wip1, CaMKP/ hFEM2/POPX2, CaMKP-N/POPX1, NERPP-2C, and SCOP/PHLPP) have been found in mammalian cells (Tamura et al, 2004;Shimizu et al, 1999;Gao et al, 2005). Structurally, all twelve distinct PP2C gene products share all or some of the six conserved motifs that are present in most of the PP2C gene products in a wide range of species.…”

Section: Introductionmentioning

confidence: 99%

“…All of these PP2Cs have Mg 2+ -and/or Mn 2+ -dependent protein phosphatase activities against artificial substrates in vitro. These PP2C family members have been implicated in the regulation of various cellular functions including the stress response, cell cycle regulation, actin cytoskeleton organization, the Akt signaling pathway, and pre-mRNA splicing (Hanada et al, 1998(Hanada et al, , 2001Takekawa et al, 1998;Hishiya et al, 1999;Murray et al, 1999;Cheng et al, 2000;Tamura et al, 2002Tamura et al, , 2004Prajapati et al, 2004;Gao et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Disruption of the mouse protein Ser/Thr phosphatase 2Cβ gene leads to early pre-implantation lethality

Sato

Ohnishi

Tashiro

et al. 2007

Mechanisms of Development

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Protein phosphatase 2Cbeta (PP2Cbeta) is a member of a family of protein Ser/Thr phosphatases (PP2C) that is composed of at least twelve different gene products. Recent studies have revealed that PP2Cbeta mRNA accumulates in mature sperm, unfertilized metaphase II-arrested oocytes and zygotes, but that the mRNA level then decreases sharply between the early two-cell and eight-cell stages, remaining at low levels during the 16-cell to blastocyst stages of mice. These observations raised the possibility that PP2Cbeta plays a crucial role during gametogenesis, fertilization, and/or early stages of embryonic development. In this study, we employed a gene knockout technique in mice to test this possibility. We found that PP2Cbeta(Delta/wt) mice generate normal mature gametes. However, PP2Cbeta(Delta/Delta) embryos die between the two-cell and eight-cell stages. To our interest, PP2Cbeta(Delta/Delta) ES cells which had been generated by transfecting PP2Cbeta(3lox/3lox) ES cells with Cre-expressing plasmid were viable. In addition, knockdown of PP2Cbeta using siRNA did not affect the proliferation of wild-type ES cells. These observations suggest that relatively high PP2Cbeta expression is specifically required during the early stages of pre-implantation development. The possible mechanisms for the early pre-implantation lethality of PP2Cbeta(Delta/Delta) mice are discussed.

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Section: Pp2cb D/d Embryos Exhibit Pre-implantation Lethalitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Disruption of the mouse protein Ser/Thr phosphatase 2Cβ gene leads to early pre-implantation lethality

Sato

Ohnishi

Tashiro

et al. 2007

Mechanisms of Development

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“…Thus far, 13 distinct PP2C homologs (PP2C␣, PP2C␤, PP2C␥/FIN13, PP2C␦/ ILKAP, PP2C⑀, PP2C, PP2C, PP2C, Wip1, CaMKP/ hFEM2/POPX2, CaMKP-N/POPX1, NERPP-2C, and SCOP/ PHLPP) have been identified in mammalian cells (22)(23)(24)(25)(26)(27). In vivo and in vitro studies have shown that PP2Cs play important roles in the regulation of cellular functions such as stress response, cell cycle, cytoskeleton organization, mRNA splicing, and Wnt signaling (22,23).…”

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confidence: 99%

Protein Phosphatase 2Cϵ Is an Endoplasmic Reticulum Integral Membrane Protein That Dephosphorylates the Ceramide Transport Protein CERT to Enhance Its Association with Organelle Membranes

Saito

Matsui

Kawano

et al. 2008

Journal of Biological Chemistry

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Protein phosphatase 2C⑀ (PP2C⑀), a mammalian PP2C family member, is expressed in various tissues and is implicated in the negative regulation of stress-activated protein kinase pathways. We show that PP2C⑀ is an endoplasmic reticulum (ER) transmembrane protein with a transmembrane domain at the amino terminus and the catalytic domain facing the cytoplasm. Yeast two-hybrid screening of a human brain library using PP2C⑀ as bait resulted in the isolation of a cDNA that encoded vesicle-associated membrane protein-associated protein A (VAPA). VAPA is an ER resident integral membrane protein involved in recruiting lipidbinding proteins such as the ceramide transport protein CERT to the ER membrane. Expression of PP2C⑀ resulted in dephosphorylation of CERT in a VAPA expression-dependent manner, which was accompanied by redistribution of CERT from the cytoplasm to the Golgi apparatus. The expression of PP2C⑀ also enhanced the association between CERT and VAPA. In addition, knockdown of PP2C⑀ expression by short interference RNA attenuated the interaction between CERT and VAPA and the sphingomyelin synthesis. These results suggest that CERT is a physiological substrate of PP2C⑀ and that dephosphorylation of CERT by PP2C⑀ may play an important role in the regulation of ceramide trafficking from the ER to the Golgi apparatus.Vesicle-associated membrane protein-associated protein A (VAPA) 3 is an endoplasmic reticulum (ER)-resident type II transmembrane protein with homologs widely distributed from yeast to human (1-3). Recently, evidence has accumulated that in mammalian cells VAPA participates in the regulation of inter-organelle transport of membrane lipids by recruiting lipid transfer proteins to the ER membrane. VAPA associates with a short, conserved peptide sequence termed the "two phenylalanines in an acidic tract" (FFAT) motif that is found in several lipid transfer proteins including ceramide transport protein CERT, oxysterol-binding protein, Opi1 protein, and PITP/Nir/ rdgB families (4 -11). VAPA is composed of two conserved domains, an amino-terminal immunoglobulin-like ␤ sheet responsible for FFAT motif binding and a carboxyl-terminal transmembrane domain (8). In addition to its role in recruiting FFAT motif-targeted proteins to ER membranes, VAPA has been proposed to function in vesicle trafficking (1,(12)(13)(14), in the organization of the microtubule network (10, 15), and in the replication of hepatitis C virus RNA (16,17). In mammalian cells ceramide is synthesized in the ER and transported to the Golgi apparatus where it is converted to sphingomyelin (SM). The ceramide transport protein CERT plays a key role in the ER-to-Golgi trafficking of ceramide (18 -20). CERT consists of several distinct domains including a Steroidogenic acute regulator-related lipid transfer (START) domain capable of specifically extracting ceramide from membrane, a pleckstrin homology (PH) domain that serves to target the Golgi apparatus by recognizing phosphatidylinositol 4-monphophatate, and a FFAT motif, which interacts with VA...

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“…Type 2C Ser/Thr protein phosphatases (PP2C) are a group of monomeric enzymes widely found in animals, plants, and fungi (35,62,66,69). The function(s) and regulatory mechanisms for each specific PP2C isoform are largely unknown, and its study constitutes a major challenge, particularly because of the very important cellular roles played by this type of enzyme.…”

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confidence: 99%

Normal Function of the Yeast TOR Pathway Requires the Type 2C Protein Phosphatase Ptc1

González

Ruiz²,

Casamayor

et al. 2009

Molecular and Cellular Biology

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Yeast ptc1 mutants are rapamycin and caffeine sensitive, suggesting a functional connection between Ptc1 and the TOR pathway that is not shared by most members of the type 2C phosphatase family. Genome-wide profiling revealed that the ptc1 mutation largely attenuates the transcriptional response to rapamycin. The lack of Ptc1 significantly prevents the nuclear translocation of Gln3 and Msn2 transcription factors to the nucleus, as well as the dephosphorylation of the Npr1 kinase, in response to rapamycin. This could explain the observed decrease in both the basal and rapamycin-induced expression of several genes subjected to nitrogen catabolite repression (GAT1, MEP1, and GLN1) and stress response element (STRE)-driven promoters. Interestingly, this decrease is abolished in the absence of the Sit4 phosphatase. Epitasis analysis indicates that the mutation of SIT4 or TIP41, encoding a Tap42-interacting protein, abolishes the sensitivity of the ptc1 strain to rapamycin and caffeine. All of these results suggest that Ptc1 is required for normal TOR signaling, possibly by regulating a step upstream of Sit4 function. According to this hypothesis, we observe that the mutation of PTC1 drastically diminishes the rapamycin-induced interaction between Tap42 and Tip41, and this can be explained by lower-than-normal levels of Tip41 in ptc1 cells. Ptc1 is not necessary for the normal expression of the TIP41 gene; instead, its absence dramatically affects the stability of Tip41. The lack of Ptc1 partially abolishes the rapamycin-induced dephosphorylation of Tip41, which may further decrease Tap42 binding. Reduced Tip41 levels contribute to the ptc1 phenotypes, although additional Ptc1 targets must exist. All of these results provide the first evidence showing that a type 2C protein phosphatase is required for the normal functioning of the TOR pathway.

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Roles of mammalian protein phosphatase 2C family members in the regulation of cellular functions

Cited by 13 publications

References 60 publications

Disruption of the mouse protein Ser/Thr phosphatase 2Cβ gene leads to early pre-implantation lethality

Disruption of the mouse protein Ser/Thr phosphatase 2Cβ gene leads to early pre-implantation lethality

Protein Phosphatase 2Cϵ Is an Endoplasmic Reticulum Integral Membrane Protein That Dephosphorylates the Ceramide Transport Protein CERT to Enhance Its Association with Organelle Membranes

Normal Function of the Yeast TOR Pathway Requires the Type 2C Protein Phosphatase Ptc1

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