Rheb protein binds CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase) protein in a GTP- and effector domain-dependent manner and influences its cellular localization and carbamoyl-phosphate synthetase (CPSase) activity.
Identifieur interne : 000C25 ( Main/Exploration ); précédent : 000C24; suivant : 000C26Rheb protein binds CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase) protein in a GTP- and effector domain-dependent manner and influences its cellular localization and carbamoyl-phosphate synthetase (CPSase) activity.
Auteurs : Tatsuhiro Sato [Japon] ; Hitomi Akasu ; Wataru Shimono ; Chisa Matsu ; Yuki Fujiwara ; Yoshio Shibagaki ; Jeffrey J. Heard ; Fuyuhiko Tamanoi ; Seisuke HattoriSource :
- The Journal of biological chemistry [ 1083-351X ] ; 2015.
Descripteurs français
- KwdFr :
- Animaux (MeSH), Aspartate carbamoyltransferase (métabolisme), Carbamoyl-phosphate synthase (ammonia) (métabolisme), Carbamoyl-phosphate synthase (glutamine-hydrolyzing) (métabolisme), Complexe-1 cible mécanistique de la rapamycine (MeSH), Complexes multiprotéiques (métabolisme), Dihydro-orotase (métabolisme), Humains (MeSH), Liaison aux protéines (MeSH), Lysosomes (anatomopathologie), Lysosomes (métabolisme), Neuropeptides (génétique), Neuropeptides (métabolisme), Nucléosides pyrimidiques (biosynthèse), Prolifération cellulaire (génétique), Protéine homologue de Ras enrichie dans le cerveau (MeSH), Protéines G monomériques (génétique), Protéines G monomériques (métabolisme), Protéines G ras (génétique), Protéines G ras (métabolisme), Souris (MeSH), Sérine-thréonine kinases TOR (métabolisme).
- MESH :
- anatomopathologie : Lysosomes.
- biosynthèse : Nucléosides pyrimidiques.
- génétique : Neuropeptides, Prolifération cellulaire, Protéines G monomériques, Protéines G ras.
- métabolisme : Aspartate carbamoyltransferase, Carbamoyl-phosphate synthase (ammonia), Carbamoyl-phosphate synthase (glutamine-hydrolyzing), Complexes multiprotéiques, Dihydro-orotase, Lysosomes, Neuropeptides, Protéines G monomériques, Protéines G ras, Sérine-thréonine kinases TOR.
- Animaux, Complexe-1 cible mécanistique de la rapamycine, Humains, Liaison aux protéines, Protéine homologue de Ras enrichie dans le cerveau, Souris.
English descriptors
- KwdEn :
- Animals (MeSH), Aspartate Carbamoyltransferase (metabolism), Carbamoyl-Phosphate Synthase (Ammonia) (metabolism), Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) (metabolism), Cell Proliferation (genetics), Dihydroorotase (metabolism), Humans (MeSH), Lysosomes (metabolism), Lysosomes (pathology), Mechanistic Target of Rapamycin Complex 1 (MeSH), Mice (MeSH), Monomeric GTP-Binding Proteins (genetics), Monomeric GTP-Binding Proteins (metabolism), Multiprotein Complexes (metabolism), Neuropeptides (genetics), Neuropeptides (metabolism), Protein Binding (MeSH), Pyrimidine Nucleosides (biosynthesis), Ras Homolog Enriched in Brain Protein (MeSH), TOR Serine-Threonine Kinases (metabolism), ras Proteins (genetics), ras Proteins (metabolism).
- MESH :
- chemical , biosynthesis : Pyrimidine Nucleosides.
- chemical , genetics : Monomeric GTP-Binding Proteins, Neuropeptides, ras Proteins.
- chemical , metabolism : Aspartate Carbamoyltransferase, Carbamoyl-Phosphate Synthase (Ammonia), Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing), Dihydroorotase, Monomeric GTP-Binding Proteins, Multiprotein Complexes, Neuropeptides, TOR Serine-Threonine Kinases, ras Proteins.
- genetics : Cell Proliferation.
- metabolism : Lysosomes.
- pathology : Lysosomes.
- Animals, Humans, Mechanistic Target of Rapamycin Complex 1, Mice, Protein Binding, Ras Homolog Enriched in Brain Protein.
Abstract
Rheb small GTPases, which consist of Rheb1 and Rheb2 (also known as RhebL1) in mammalian cells, are unique members of the Ras superfamily and play central roles in regulating protein synthesis and cell growth by activating mTOR. To gain further insight into the function of Rheb, we carried out a search for Rheb-binding proteins and found that Rheb binds to CAD protein (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase), a multifunctional enzyme required for the de novo synthesis of pyrimidine nucleotides. CAD binding is more pronounced with Rheb2 than with Rheb1. Rheb binds CAD in a GTP- and effector domain-dependent manner. The region of CAD where Rheb binds is located at the C-terminal region of the carbamoyl-phosphate synthetase domain and not in the dihydroorotase and aspartate transcarbamoylase domains. Rheb stimulated carbamoyl-phosphate synthetase activity of CAD in vitro. In addition, an elevated level of intracellular UTP pyrimidine nucleotide was observed in Tsc2-deficient cells, which was attenuated by knocking down of Rheb. Immunostaining analysis showed that expression of Rheb leads to increased accumulation of CAD on lysosomes. Both a farnesyltransferase inhibitor that blocks membrane association of Rheb and knockdown of Rheb mislocalized CAD. These results establish CAD as a downstream effector of Rheb and suggest a possible role of Rheb in regulating de novo pyrimidine nucleotide synthesis.
DOI: 10.1074/jbc.M114.592402
PubMed: 25422319
PubMed Central: PMC4294477
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Rheb protein binds CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase) protein in a GTP- and effector domain-dependent manner and influences its cellular localization and carbamoyl-phosphate synthetase (CPSase) activity.</title><author><name sortKey="Sato, Tatsuhiro" sort="Sato, Tatsuhiro" uniqKey="Sato T" first="Tatsuhiro" last="Sato">Tatsuhiro Sato</name><affiliation wicri:level="1"><nlm:affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and satot@pharm.kitasato-u.ac.jp.</nlm:affiliation><country wicri:rule="url">Japon</country><wicri:regionArea>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Akasu, Hitomi" sort="Akasu, Hitomi" uniqKey="Akasu H" first="Hitomi" last="Akasu">Hitomi Akasu</name><affiliation><nlm:affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</nlm:affiliation><wicri:noCountry code="subField">Japan and</wicri:noCountry></affiliation></author><author><name sortKey="Shimono, Wataru" sort="Shimono, Wataru" uniqKey="Shimono W" first="Wataru" last="Shimono">Wataru Shimono</name><affiliation><nlm:affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</nlm:affiliation><wicri:noCountry code="subField">Japan and</wicri:noCountry></affiliation></author><author><name sortKey="Matsu, Chisa" sort="Matsu, Chisa" uniqKey="Matsu C" first="Chisa" last="Matsu">Chisa Matsu</name><affiliation><nlm:affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</nlm:affiliation><wicri:noCountry code="subField">Japan and</wicri:noCountry></affiliation></author><author><name sortKey="Fujiwara, Yuki" sort="Fujiwara, Yuki" uniqKey="Fujiwara Y" first="Yuki" last="Fujiwara">Yuki Fujiwara</name><affiliation><nlm:affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</nlm:affiliation><wicri:noCountry code="subField">Japan and</wicri:noCountry></affiliation></author><author><name sortKey="Shibagaki, Yoshio" sort="Shibagaki, Yoshio" uniqKey="Shibagaki Y" first="Yoshio" last="Shibagaki">Yoshio Shibagaki</name><affiliation><nlm:affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</nlm:affiliation><wicri:noCountry code="subField">Japan and</wicri:noCountry></affiliation></author><author><name sortKey="Heard, Jeffrey J" sort="Heard, Jeffrey J" uniqKey="Heard J" first="Jeffrey J" last="Heard">Jeffrey J. Heard</name><affiliation><nlm:affiliation>Department of Microbiology, Immunology, and Molecular Genetics, Molecular Biology Institute, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, 90095.</nlm:affiliation><wicri:noCountry code="subField">90095</wicri:noCountry></affiliation></author><author><name sortKey="Tamanoi, Fuyuhiko" sort="Tamanoi, Fuyuhiko" uniqKey="Tamanoi F" first="Fuyuhiko" last="Tamanoi">Fuyuhiko Tamanoi</name><affiliation><nlm:affiliation>Department of Microbiology, Immunology, and Molecular Genetics, Molecular Biology Institute, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, 90095.</nlm:affiliation><wicri:noCountry code="subField">90095</wicri:noCountry></affiliation></author><author><name sortKey="Hattori, Seisuke" sort="Hattori, Seisuke" uniqKey="Hattori S" first="Seisuke" last="Hattori">Seisuke Hattori</name><affiliation><nlm:affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</nlm:affiliation><wicri:noCountry code="subField">Japan and</wicri:noCountry></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:25422319</idno><idno type="pmid">25422319</idno><idno type="doi">10.1074/jbc.M114.592402</idno><idno type="pmc">PMC4294477</idno><idno type="wicri:Area/Main/Corpus">000D54</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000D54</idno><idno type="wicri:Area/Main/Curation">000D54</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000D54</idno><idno type="wicri:Area/Main/Exploration">000D54</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Rheb protein binds CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase) protein in a GTP- and effector domain-dependent manner and influences its cellular localization and carbamoyl-phosphate synthetase (CPSase) activity.</title><author><name sortKey="Sato, Tatsuhiro" sort="Sato, Tatsuhiro" uniqKey="Sato T" first="Tatsuhiro" last="Sato">Tatsuhiro Sato</name><affiliation wicri:level="1"><nlm:affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and satot@pharm.kitasato-u.ac.jp.</nlm:affiliation><country wicri:rule="url">Japon</country><wicri:regionArea>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Akasu, Hitomi" sort="Akasu, Hitomi" uniqKey="Akasu H" first="Hitomi" last="Akasu">Hitomi Akasu</name><affiliation><nlm:affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</nlm:affiliation><wicri:noCountry code="subField">Japan and</wicri:noCountry></affiliation></author><author><name sortKey="Shimono, Wataru" sort="Shimono, Wataru" uniqKey="Shimono W" first="Wataru" last="Shimono">Wataru Shimono</name><affiliation><nlm:affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</nlm:affiliation><wicri:noCountry code="subField">Japan and</wicri:noCountry></affiliation></author><author><name sortKey="Matsu, Chisa" sort="Matsu, Chisa" uniqKey="Matsu C" first="Chisa" last="Matsu">Chisa Matsu</name><affiliation><nlm:affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</nlm:affiliation><wicri:noCountry code="subField">Japan and</wicri:noCountry></affiliation></author><author><name sortKey="Fujiwara, Yuki" sort="Fujiwara, Yuki" uniqKey="Fujiwara Y" first="Yuki" last="Fujiwara">Yuki Fujiwara</name><affiliation><nlm:affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</nlm:affiliation><wicri:noCountry code="subField">Japan and</wicri:noCountry></affiliation></author><author><name sortKey="Shibagaki, Yoshio" sort="Shibagaki, Yoshio" uniqKey="Shibagaki Y" first="Yoshio" last="Shibagaki">Yoshio Shibagaki</name><affiliation><nlm:affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</nlm:affiliation><wicri:noCountry code="subField">Japan and</wicri:noCountry></affiliation></author><author><name sortKey="Heard, Jeffrey J" sort="Heard, Jeffrey J" uniqKey="Heard J" first="Jeffrey J" last="Heard">Jeffrey J. Heard</name><affiliation><nlm:affiliation>Department of Microbiology, Immunology, and Molecular Genetics, Molecular Biology Institute, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, 90095.</nlm:affiliation><wicri:noCountry code="subField">90095</wicri:noCountry></affiliation></author><author><name sortKey="Tamanoi, Fuyuhiko" sort="Tamanoi, Fuyuhiko" uniqKey="Tamanoi F" first="Fuyuhiko" last="Tamanoi">Fuyuhiko Tamanoi</name><affiliation><nlm:affiliation>Department of Microbiology, Immunology, and Molecular Genetics, Molecular Biology Institute, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, 90095.</nlm:affiliation><wicri:noCountry code="subField">90095</wicri:noCountry></affiliation></author><author><name sortKey="Hattori, Seisuke" sort="Hattori, Seisuke" uniqKey="Hattori S" first="Seisuke" last="Hattori">Seisuke Hattori</name><affiliation><nlm:affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</nlm:affiliation><wicri:noCountry code="subField">Japan and</wicri:noCountry></affiliation></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="eISSN">1083-351X</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term><term>Aspartate Carbamoyltransferase (metabolism)</term><term>Carbamoyl-Phosphate Synthase (Ammonia) (metabolism)</term><term>Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) (metabolism)</term><term>Cell Proliferation (genetics)</term><term>Dihydroorotase (metabolism)</term><term>Humans (MeSH)</term><term>Lysosomes (metabolism)</term><term>Lysosomes (pathology)</term><term>Mechanistic Target of Rapamycin Complex 1 (MeSH)</term><term>Mice (MeSH)</term><term>Monomeric GTP-Binding Proteins (genetics)</term><term>Monomeric GTP-Binding Proteins (metabolism)</term><term>Multiprotein Complexes (metabolism)</term><term>Neuropeptides (genetics)</term><term>Neuropeptides (metabolism)</term><term>Protein Binding (MeSH)</term><term>Pyrimidine Nucleosides (biosynthesis)</term><term>Ras Homolog Enriched in Brain Protein (MeSH)</term><term>TOR Serine-Threonine Kinases (metabolism)</term><term>ras Proteins (genetics)</term><term>ras Proteins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term><term>Aspartate carbamoyltransferase (métabolisme)</term><term>Carbamoyl-phosphate synthase (ammonia) (métabolisme)</term><term>Carbamoyl-phosphate synthase (glutamine-hydrolyzing) (métabolisme)</term><term>Complexe-1 cible mécanistique de la rapamycine (MeSH)</term><term>Complexes multiprotéiques (métabolisme)</term><term>Dihydro-orotase (métabolisme)</term><term>Humains (MeSH)</term><term>Liaison aux protéines (MeSH)</term><term>Lysosomes (anatomopathologie)</term><term>Lysosomes (métabolisme)</term><term>Neuropeptides (génétique)</term><term>Neuropeptides (métabolisme)</term><term>Nucléosides pyrimidiques (biosynthèse)</term><term>Prolifération cellulaire (génétique)</term><term>Protéine homologue de Ras enrichie dans le cerveau (MeSH)</term><term>Protéines G monomériques (génétique)</term><term>Protéines G monomériques (métabolisme)</term><term>Protéines G ras (génétique)</term><term>Protéines G ras (métabolisme)</term><term>Souris (MeSH)</term><term>Sérine-thréonine kinases TOR (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Pyrimidine Nucleosides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Monomeric GTP-Binding Proteins</term><term>Neuropeptides</term><term>ras Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Aspartate Carbamoyltransferase</term><term>Carbamoyl-Phosphate Synthase (Ammonia)</term><term>Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)</term><term>Dihydroorotase</term><term>Monomeric GTP-Binding Proteins</term><term>Multiprotein Complexes</term><term>Neuropeptides</term><term>TOR Serine-Threonine Kinases</term><term>ras Proteins</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Lysosomes</term></keywords><keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Nucléosides pyrimidiques</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Cell Proliferation</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Neuropeptides</term><term>Prolifération cellulaire</term><term>Protéines G monomériques</term><term>Protéines G ras</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lysosomes</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Aspartate carbamoyltransferase</term><term>Carbamoyl-phosphate synthase (ammonia)</term><term>Carbamoyl-phosphate synthase (glutamine-hydrolyzing)</term><term>Complexes multiprotéiques</term><term>Dihydro-orotase</term><term>Lysosomes</term><term>Neuropeptides</term><term>Protéines G monomériques</term><term>Protéines G ras</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Lysosomes</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Humans</term><term>Mechanistic Target of Rapamycin Complex 1</term><term>Mice</term><term>Protein Binding</term><term>Ras Homolog Enriched in Brain Protein</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Complexe-1 cible mécanistique de la rapamycine</term><term>Humains</term><term>Liaison aux protéines</term><term>Protéine homologue de Ras enrichie dans le cerveau</term><term>Souris</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Rheb small GTPases, which consist of Rheb1 and Rheb2 (also known as RhebL1) in mammalian cells, are unique members of the Ras superfamily and play central roles in regulating protein synthesis and cell growth by activating mTOR. To gain further insight into the function of Rheb, we carried out a search for Rheb-binding proteins and found that Rheb binds to CAD protein (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase), a multifunctional enzyme required for the de novo synthesis of pyrimidine nucleotides. CAD binding is more pronounced with Rheb2 than with Rheb1. Rheb binds CAD in a GTP- and effector domain-dependent manner. The region of CAD where Rheb binds is located at the C-terminal region of the carbamoyl-phosphate synthetase domain and not in the dihydroorotase and aspartate transcarbamoylase domains. Rheb stimulated carbamoyl-phosphate synthetase activity of CAD in vitro. In addition, an elevated level of intracellular UTP pyrimidine nucleotide was observed in Tsc2-deficient cells, which was attenuated by knocking down of Rheb. Immunostaining analysis showed that expression of Rheb leads to increased accumulation of CAD on lysosomes. Both a farnesyltransferase inhibitor that blocks membrane association of Rheb and knockdown of Rheb mislocalized CAD. These results establish CAD as a downstream effector of Rheb and suggest a possible role of Rheb in regulating de novo pyrimidine nucleotide synthesis. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25422319</PMID><DateCompleted><Year>2015</Year><Month>04</Month><Day>21</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1083-351X</ISSN><JournalIssue CitedMedium="Internet"><Volume>290</Volume><Issue>2</Issue><PubDate><Year>2015</Year><Month>Jan</Month><Day>09</Day></PubDate></JournalIssue><Title>The Journal of biological chemistry</Title><ISOAbbreviation>J Biol Chem</ISOAbbreviation></Journal><ArticleTitle>Rheb protein binds CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase) protein in a GTP- and effector domain-dependent manner and influences its cellular localization and carbamoyl-phosphate synthetase (CPSase) activity.</ArticleTitle><Pagination><MedlinePgn>1096-105</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1074/jbc.M114.592402</ELocationID><Abstract><AbstractText>Rheb small GTPases, which consist of Rheb1 and Rheb2 (also known as RhebL1) in mammalian cells, are unique members of the Ras superfamily and play central roles in regulating protein synthesis and cell growth by activating mTOR. To gain further insight into the function of Rheb, we carried out a search for Rheb-binding proteins and found that Rheb binds to CAD protein (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase), a multifunctional enzyme required for the de novo synthesis of pyrimidine nucleotides. CAD binding is more pronounced with Rheb2 than with Rheb1. Rheb binds CAD in a GTP- and effector domain-dependent manner. The region of CAD where Rheb binds is located at the C-terminal region of the carbamoyl-phosphate synthetase domain and not in the dihydroorotase and aspartate transcarbamoylase domains. Rheb stimulated carbamoyl-phosphate synthetase activity of CAD in vitro. In addition, an elevated level of intracellular UTP pyrimidine nucleotide was observed in Tsc2-deficient cells, which was attenuated by knocking down of Rheb. Immunostaining analysis showed that expression of Rheb leads to increased accumulation of CAD on lysosomes. Both a farnesyltransferase inhibitor that blocks membrane association of Rheb and knockdown of Rheb mislocalized CAD. These results establish CAD as a downstream effector of Rheb and suggest a possible role of Rheb in regulating de novo pyrimidine nucleotide synthesis. </AbstractText><CopyrightInformation>© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Sato</LastName><ForeName>Tatsuhiro</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and satot@pharm.kitasato-u.ac.jp.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Akasu</LastName><ForeName>Hitomi</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shimono</LastName><ForeName>Wataru</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Matsu</LastName><ForeName>Chisa</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fujiwara</LastName><ForeName>Yuki</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shibagaki</LastName><ForeName>Yoshio</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Heard</LastName><ForeName>Jeffrey J</ForeName><Initials>JJ</Initials><AffiliationInfo><Affiliation>Department of Microbiology, Immunology, and Molecular Genetics, Molecular Biology Institute, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, 90095.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tamanoi</LastName><ForeName>Fuyuhiko</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Department of Microbiology, Immunology, and Molecular Genetics, Molecular Biology Institute, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, 90095.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hattori</LastName><ForeName>Seisuke</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>From the Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan and.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 CA041996</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>CA41996</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2014</Year><Month>11</Month><Day>24</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Biol Chem</MedlineTA><NlmUniqueID>2985121R</NlmUniqueID><ISSNLinking>0021-9258</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C033626">CAD trifunctional enzyme</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D046912">Multiprotein Complexes</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D009479">Neuropeptides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011741">Pyrimidine Nucleosides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C490211">RHEB protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C504241">RHEBL1 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000076205">Ras Homolog Enriched in Brain Protein</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.1.3.2</RegistryNumber><NameOfSubstance UI="D001221">Aspartate Carbamoyltransferase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="C546842">MTOR protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="D058570">TOR Serine-Threonine Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D000076222">Mechanistic Target of Rapamycin Complex 1</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.5.2.3</RegistryNumber><NameOfSubstance UI="D004080">Dihydroorotase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.6.5.2</RegistryNumber><NameOfSubstance UI="D020559">Monomeric GTP-Binding Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.6.5.2</RegistryNumber><NameOfSubstance UI="D018631">ras Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 6.3.4.16</RegistryNumber><NameOfSubstance UI="D002222">Carbamoyl-Phosphate Synthase (Ammonia)</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 6.3.5.5</RegistryNumber><NameOfSubstance UI="D002223">Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001221" MajorTopicYN="N">Aspartate Carbamoyltransferase</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002222" MajorTopicYN="N">Carbamoyl-Phosphate Synthase (Ammonia)</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002223" MajorTopicYN="N">Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D049109" MajorTopicYN="N">Cell Proliferation</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004080" MajorTopicYN="N">Dihydroorotase</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008247" MajorTopicYN="N">Lysosomes</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000076222" MajorTopicYN="N">Mechanistic Target of Rapamycin Complex 1</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020559" MajorTopicYN="N">Monomeric GTP-Binding Proteins</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D046912" MajorTopicYN="N">Multiprotein Complexes</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D009479" MajorTopicYN="N">Neuropeptides</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011485" MajorTopicYN="N">Protein Binding</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011741" MajorTopicYN="N">Pyrimidine Nucleosides</DescriptorName><QualifierName UI="Q000096" MajorTopicYN="Y">biosynthesis</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000076205" MajorTopicYN="N">Ras Homolog Enriched in Brain Protein</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018631" MajorTopicYN="N">ras Proteins</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">CAD</Keyword><Keyword MajorTopicYN="N">Cell Growth</Keyword><Keyword MajorTopicYN="N">Insulin</Keyword><Keyword MajorTopicYN="N">Mammalian Target of Rapamycin (mTOR)</Keyword><Keyword MajorTopicYN="N">Nucleoside/Nucleotide Biosynthesis</Keyword><Keyword MajorTopicYN="N">Rheb</Keyword><Keyword 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uniqKey="Heard J" first="Jeffrey J" last="Heard">Jeffrey J. Heard</name><name sortKey="Matsu, Chisa" sort="Matsu, Chisa" uniqKey="Matsu C" first="Chisa" last="Matsu">Chisa Matsu</name><name sortKey="Shibagaki, Yoshio" sort="Shibagaki, Yoshio" uniqKey="Shibagaki Y" first="Yoshio" last="Shibagaki">Yoshio Shibagaki</name><name sortKey="Shimono, Wataru" sort="Shimono, Wataru" uniqKey="Shimono W" first="Wataru" last="Shimono">Wataru Shimono</name><name sortKey="Tamanoi, Fuyuhiko" sort="Tamanoi, Fuyuhiko" uniqKey="Tamanoi F" first="Fuyuhiko" last="Tamanoi">Fuyuhiko Tamanoi</name></noCountry><country name="Japon"><region name="Région de Kantō"><name sortKey="Sato, Tatsuhiro" sort="Sato, Tatsuhiro" uniqKey="Sato T" first="Tatsuhiro" last="Sato">Tatsuhiro Sato</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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|texte= Rheb protein binds CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase) protein in a GTP- and effector domain-dependent manner and influences its cellular localization and carbamoyl-phosphate synthetase (CPSase) activity.
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