An oncogenic mutant of RHEB, RHEB Y35N, exhibits an altered interaction with BRAF resulting in cancer transformation.
Identifieur interne : 000662 ( Main/Exploration ); précédent : 000661; suivant : 000663An oncogenic mutant of RHEB, RHEB Y35N, exhibits an altered interaction with BRAF resulting in cancer transformation.
Auteurs : Jeffrey J. Heard [États-Unis] ; Ivy Phung [États-Unis] ; Mark I. Potes [États-Unis] ; Fuyuhiko Tamanoi [États-Unis, Japon]Source :
- BMC cancer [ 1471-2407 ] ; 2018.
Descripteurs français
- KwdFr :
- Carcinogenèse (génétique), Complexe-1 cible mécanistique de la rapamycine (génétique), Humains (MeSH), Inhibiteurs de protéines kinases (usage thérapeutique), Lignée cellulaire tumorale (MeSH), Mutation (MeSH), Phosphorylation (MeSH), Prolifération cellulaire (génétique), Protéine homologue de Ras enrichie dans le cerveau (génétique), Protéines proto-oncogènes B-raf (génétique), Régulation de l'expression des gènes tumoraux (génétique), Système de signalisation des MAP kinases (génétique), Tumeurs (anatomopathologie), Tumeurs (génétique).
- MESH :
- anatomopathologie : Tumeurs.
- génétique : Carcinogenèse, Complexe-1 cible mécanistique de la rapamycine, Prolifération cellulaire, Protéine homologue de Ras enrichie dans le cerveau, Protéines proto-oncogènes B-raf, Régulation de l'expression des gènes tumoraux, Système de signalisation des MAP kinases, Tumeurs.
- usage thérapeutique : Inhibiteurs de protéines kinases.
- Humains, Lignée cellulaire tumorale, Mutation, Phosphorylation.
English descriptors
- KwdEn :
- Carcinogenesis (genetics), Cell Line, Tumor (MeSH), Cell Proliferation (genetics), Gene Expression Regulation, Neoplastic (genetics), Humans (MeSH), MAP Kinase Signaling System (genetics), Mechanistic Target of Rapamycin Complex 1 (genetics), Mutation (MeSH), Neoplasms (genetics), Neoplasms (pathology), Phosphorylation (MeSH), Protein Kinase Inhibitors (therapeutic use), Proto-Oncogene Proteins B-raf (genetics), Ras Homolog Enriched in Brain Protein (genetics).
- MESH :
- chemical , genetics : Mechanistic Target of Rapamycin Complex 1, Proto-Oncogene Proteins B-raf, Ras Homolog Enriched in Brain Protein.
- genetics : Carcinogenesis, Cell Proliferation, Gene Expression Regulation, Neoplastic, MAP Kinase Signaling System, Neoplasms.
- pathology : Neoplasms.
- chemical , therapeutic use : Protein Kinase Inhibitors.
- Cell Line, Tumor, Humans, Mutation, Phosphorylation.
Abstract
BACKGROUND
RHEB is a unique member of the RAS superfamily of small GTPases expressed in all tissues and conserved from yeast to humans. Early studies on RHEB indicated a possible RHEB-RAF interaction, but this has not been fully explored. Recent work on cancer genome databases has revealed a reoccurring mutation in RHEB at the Tyr35 position, and a recent study points to the oncogenic potential of this mutant that involves activation of RAF/MEK/ERK signaling. These developments prompted us to reassess the significance of RHEB effect on RAF, and to compare mutant and wild type RHEB.
METHODS
To study RHEB-RAF interaction, and the effect of the Y35N mutation on this interaction, we used transfection, immunoprecipitation, and Western blotting techniques. We generated cell lines stably expressing RHEB WT, RHEB Y35N, and KRAS G12V, and monitored cellular transforming properties through cell proliferation, anchorage independent growth, cell cycle analysis, and foci formation assays.
RESULTS
We observe a strong interaction between RHEB and BRAF, but not with CRAF. This interaction is dependent on an intact RHEB effector domain and RHEB-GTP loading status. RHEB overexpression decreases RAF activation of the RAF/MEK/ERK pathway and RHEB knockdown results in an increase in RAF/MEK/ERK activation. RHEB Y35N mutation has decreased interaction with BRAF, and RHEB Y35N cells exhibit greater BRAF/CRAF heterodimerization resulting in increased RAF/MEK/ERK signaling. This leads to cancer transformation of RHEB Y35N stably expressing cell lines, similar to KRAS G12 V expressing cell lines.
CONCLUSIONS
RHEB interaction with BRAF is crucial for inhibiting RAF/MEK/ERK signaling. The RHEB Y35N mutant sustains RAF/MEK/ERK signaling due to a decreased interaction with BRAF, leading to increased BRAF/CRAF heterodimerization. RHEB Y35N expressing cells undergo cancer transformation due to decreased interaction between RHEB and BRAF resulting in overactive RAF/MEK/ERK signaling. Taken together with the previously established function of RHEB to activate mTORC1 signaling, it appears that RHEB performs a dual function; one is to suppress the RAF/MEK/ERK signaling and the other is to activate mTORC1 signaling.
DOI: 10.1186/s12885-017-3938-5
PubMed: 29320991
PubMed Central: PMC5763582
Affiliations:
Links toward previous steps (curation, corpus...)
Le document en format XML
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Heard</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, Immunology, and Molecular Genetics, University of California, 1602 Molecular Sciences Bldg, 609 Charles E. Young Dr. East, Los Angeles, CA, 90095-1489, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Immunology, and Molecular Genetics, University of California, 1602 Molecular Sciences Bldg, 609 Charles E. Young Dr. East, Los Angeles, CA, 90095-1489</wicri:regionArea><wicri:noRegion>90095-1489</wicri:noRegion></affiliation></author><author><name sortKey="Phung, Ivy" sort="Phung, Ivy" uniqKey="Phung I" first="Ivy" last="Phung">Ivy Phung</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, Immunology, and Molecular Genetics, University of California, 1602 Molecular Sciences Bldg, 609 Charles E. Young Dr. East, Los Angeles, CA, 90095-1489, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Immunology, and Molecular Genetics, University of California, 1602 Molecular Sciences Bldg, 609 Charles E. Young Dr. East, Los Angeles, CA, 90095-1489</wicri:regionArea><wicri:noRegion>90095-1489</wicri:noRegion></affiliation></author><author><name sortKey="Potes, Mark I" sort="Potes, Mark I" uniqKey="Potes M" first="Mark I" last="Potes">Mark I. Potes</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, Immunology, and Molecular Genetics, University of California, 1602 Molecular Sciences Bldg, 609 Charles E. Young Dr. East, Los Angeles, CA, 90095-1489, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Immunology, and Molecular Genetics, University of California, 1602 Molecular Sciences Bldg, 609 Charles E. Young Dr. East, Los Angeles, CA, 90095-1489</wicri:regionArea><wicri:noRegion>90095-1489</wicri:noRegion></affiliation></author><author><name sortKey="Tamanoi, Fuyuhiko" sort="Tamanoi, Fuyuhiko" uniqKey="Tamanoi F" first="Fuyuhiko" last="Tamanoi">Fuyuhiko Tamanoi</name><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology, Immunology, and Molecular Genetics, University of California, 1602 Molecular Sciences Bldg, 609 Charles E. Young Dr. East, Los Angeles, CA, 90095-1489, USA. fuyut@microbio.ucla.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Immunology, and Molecular Genetics, University of California, 1602 Molecular Sciences Bldg, 609 Charles E. Young Dr. East, Los Angeles, CA, 90095-1489</wicri:regionArea><wicri:noRegion>90095-1489</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:affiliation>Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan. fuyut@microbio.ucla.edu.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto</wicri:regionArea><orgName type="university">Université de Kyoto</orgName><placeName><settlement type="city">Kyoto</settlement><region type="prefecture">Région du Kansai</region></placeName></affiliation></author></analytic><series><title level="j">BMC cancer</title><idno type="eISSN">1471-2407</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Carcinogenesis (genetics)</term><term>Cell Line, Tumor (MeSH)</term><term>Cell Proliferation (genetics)</term><term>Gene Expression Regulation, Neoplastic (genetics)</term><term>Humans (MeSH)</term><term>MAP Kinase Signaling System (genetics)</term><term>Mechanistic Target of Rapamycin Complex 1 (genetics)</term><term>Mutation (MeSH)</term><term>Neoplasms (genetics)</term><term>Neoplasms (pathology)</term><term>Phosphorylation (MeSH)</term><term>Protein Kinase Inhibitors (therapeutic use)</term><term>Proto-Oncogene Proteins B-raf (genetics)</term><term>Ras Homolog Enriched in Brain Protein (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Carcinogenèse (génétique)</term><term>Complexe-1 cible mécanistique de la rapamycine (génétique)</term><term>Humains (MeSH)</term><term>Inhibiteurs de protéines kinases (usage thérapeutique)</term><term>Lignée cellulaire tumorale (MeSH)</term><term>Mutation (MeSH)</term><term>Phosphorylation (MeSH)</term><term>Prolifération cellulaire (génétique)</term><term>Protéine homologue de Ras enrichie dans le cerveau (génétique)</term><term>Protéines proto-oncogènes B-raf (génétique)</term><term>Régulation de l'expression des gènes tumoraux (génétique)</term><term>Système de signalisation des MAP kinases (génétique)</term><term>Tumeurs (anatomopathologie)</term><term>Tumeurs (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Mechanistic Target of Rapamycin Complex 1</term><term>Proto-Oncogene Proteins B-raf</term><term>Ras Homolog Enriched in Brain Protein</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Tumeurs</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Carcinogenesis</term><term>Cell Proliferation</term><term>Gene Expression Regulation, Neoplastic</term><term>MAP Kinase Signaling System</term><term>Neoplasms</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Carcinogenèse</term><term>Complexe-1 cible mécanistique de la rapamycine</term><term>Prolifération cellulaire</term><term>Protéine homologue de Ras enrichie dans le cerveau</term><term>Protéines proto-oncogènes B-raf</term><term>Régulation de l'expression des gènes tumoraux</term><term>Système de signalisation des MAP kinases</term><term>Tumeurs</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Neoplasms</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Protein Kinase Inhibitors</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Inhibiteurs de protéines kinases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term><term>Humans</term><term>Mutation</term><term>Phosphorylation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Mutation</term><term>Phosphorylation</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><b>BACKGROUND</b></p><p>RHEB is a unique member of the RAS superfamily of small GTPases expressed in all tissues and conserved from yeast to humans. Early studies on RHEB indicated a possible RHEB-RAF interaction, but this has not been fully explored. Recent work on cancer genome databases has revealed a reoccurring mutation in RHEB at the Tyr35 position, and a recent study points to the oncogenic potential of this mutant that involves activation of RAF/MEK/ERK signaling. These developments prompted us to reassess the significance of RHEB effect on RAF, and to compare mutant and wild type RHEB.</p></div><div type="abstract" xml:lang="en"><p><b>METHODS</b></p><p>To study RHEB-RAF interaction, and the effect of the Y35N mutation on this interaction, we used transfection, immunoprecipitation, and Western blotting techniques. We generated cell lines stably expressing RHEB WT, RHEB Y35N, and KRAS G12V, and monitored cellular transforming properties through cell proliferation, anchorage independent growth, cell cycle analysis, and foci formation assays.</p></div><div type="abstract" xml:lang="en"><p><b>RESULTS</b></p><p>We observe a strong interaction between RHEB and BRAF, but not with CRAF. This interaction is dependent on an intact RHEB effector domain and RHEB-GTP loading status. RHEB overexpression decreases RAF activation of the RAF/MEK/ERK pathway and RHEB knockdown results in an increase in RAF/MEK/ERK activation. RHEB Y35N mutation has decreased interaction with BRAF, and RHEB Y35N cells exhibit greater BRAF/CRAF heterodimerization resulting in increased RAF/MEK/ERK signaling. This leads to cancer transformation of RHEB Y35N stably expressing cell lines, similar to KRAS G12 V expressing cell lines.</p></div><div type="abstract" xml:lang="en"><p><b>CONCLUSIONS</b></p><p>RHEB interaction with BRAF is crucial for inhibiting RAF/MEK/ERK signaling. The RHEB Y35N mutant sustains RAF/MEK/ERK signaling due to a decreased interaction with BRAF, leading to increased BRAF/CRAF heterodimerization. RHEB Y35N expressing cells undergo cancer transformation due to decreased interaction between RHEB and BRAF resulting in overactive RAF/MEK/ERK signaling. Taken together with the previously established function of RHEB to activate mTORC1 signaling, it appears that RHEB performs a dual function; one is to suppress the RAF/MEK/ERK signaling and the other is to activate mTORC1 signaling.</p></div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">29320991</PMID><DateCompleted><Year>2018</Year><Month>08</Month><Day>14</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">1471-2407</ISSN><JournalIssue CitedMedium="Internet"><Volume>18</Volume><Issue>1</Issue><PubDate><Year>2018</Year><Month>01</Month><Day>10</Day></PubDate></JournalIssue><Title>BMC cancer</Title><ISOAbbreviation>BMC Cancer</ISOAbbreviation></Journal><ArticleTitle>An oncogenic mutant of RHEB, RHEB Y35N, exhibits an altered interaction with BRAF resulting in cancer transformation.</ArticleTitle><Pagination><MedlinePgn>69</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1186/s12885-017-3938-5</ELocationID><Abstract><AbstractText Label="BACKGROUND">RHEB is a unique member of the RAS superfamily of small GTPases expressed in all tissues and conserved from yeast to humans. Early studies on RHEB indicated a possible RHEB-RAF interaction, but this has not been fully explored. Recent work on cancer genome databases has revealed a reoccurring mutation in RHEB at the Tyr35 position, and a recent study points to the oncogenic potential of this mutant that involves activation of RAF/MEK/ERK signaling. These developments prompted us to reassess the significance of RHEB effect on RAF, and to compare mutant and wild type RHEB.</AbstractText><AbstractText Label="METHODS">To study RHEB-RAF interaction, and the effect of the Y35N mutation on this interaction, we used transfection, immunoprecipitation, and Western blotting techniques. We generated cell lines stably expressing RHEB WT, RHEB Y35N, and KRAS G12V, and monitored cellular transforming properties through cell proliferation, anchorage independent growth, cell cycle analysis, and foci formation assays.</AbstractText><AbstractText Label="RESULTS">We observe a strong interaction between RHEB and BRAF, but not with CRAF. This interaction is dependent on an intact RHEB effector domain and RHEB-GTP loading status. RHEB overexpression decreases RAF activation of the RAF/MEK/ERK pathway and RHEB knockdown results in an increase in RAF/MEK/ERK activation. RHEB Y35N mutation has decreased interaction with BRAF, and RHEB Y35N cells exhibit greater BRAF/CRAF heterodimerization resulting in increased RAF/MEK/ERK signaling. This leads to cancer transformation of RHEB Y35N stably expressing cell lines, similar to KRAS G12 V expressing cell lines.</AbstractText><AbstractText Label="CONCLUSIONS">RHEB interaction with BRAF is crucial for inhibiting RAF/MEK/ERK signaling. The RHEB Y35N mutant sustains RAF/MEK/ERK signaling due to a decreased interaction with BRAF, leading to increased BRAF/CRAF heterodimerization. RHEB Y35N expressing cells undergo cancer transformation due to decreased interaction between RHEB and BRAF resulting in overactive RAF/MEK/ERK signaling. Taken together with the previously established function of RHEB to activate mTORC1 signaling, it appears that RHEB performs a dual function; one is to suppress the RAF/MEK/ERK signaling and the other is to activate mTORC1 signaling.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Heard</LastName><ForeName>Jeffrey J</ForeName><Initials>JJ</Initials><AffiliationInfo><Affiliation>Department of Microbiology, Immunology, and Molecular Genetics, University of California, 1602 Molecular Sciences Bldg, 609 Charles E. Young Dr. East, Los Angeles, CA, 90095-1489, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Phung</LastName><ForeName>Ivy</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Department of Microbiology, Immunology, and Molecular Genetics, University of California, 1602 Molecular Sciences Bldg, 609 Charles E. Young Dr. East, Los Angeles, CA, 90095-1489, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Potes</LastName><ForeName>Mark I</ForeName><Initials>MI</Initials><AffiliationInfo><Affiliation>Department of Microbiology, Immunology, and Molecular Genetics, University of California, 1602 Molecular Sciences Bldg, 609 Charles E. Young Dr. East, Los Angeles, CA, 90095-1489, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tamanoi</LastName><ForeName>Fuyuhiko</ForeName><Initials>F</Initials><Identifier Source="ORCID">0000-0002-4220-6408</Identifier><AffiliationInfo><Affiliation>Department of Microbiology, Immunology, and Molecular Genetics, University of California, 1602 Molecular Sciences Bldg, 609 Charles E. Young Dr. East, Los Angeles, CA, 90095-1489, USA. fuyut@microbio.ucla.edu.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan. fuyut@microbio.ucla.edu.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>UCLA Dissertation Year Fellowship</GrantID><Agency>University of California, Los Angeles</Agency><Country>International</Country></Grant><Grant><GrantID>CA41996</GrantID><Acronym>NH</Acronym><Agency>NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P30 CA016042</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P30 AI028697</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>JP15K21764</GrantID><Agency>JSPS KAKENHI</Agency><Country>International</Country></Grant><Grant><GrantID>5T32GM067555</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 CA041996</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>T32 GM067555</GrantID><Acronym>GM</Acronym><Agency>NIGMS 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>2018</Year><Month>01</Month><Day>10</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>BMC Cancer</MedlineTA><NlmUniqueID>100967800</NlmUniqueID><ISSNLinking>1471-2407</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D047428">Protein Kinase Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C490211">RHEB protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000076205">Ras Homolog Enriched in Brain Protein</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="C482119">BRAF protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D000076222">Mechanistic Target of Rapamycin Complex 1</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D048493">Proto-Oncogene Proteins 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Heard</name></noRegion><name sortKey="Phung, Ivy" sort="Phung, Ivy" uniqKey="Phung I" first="Ivy" last="Phung">Ivy Phung</name><name sortKey="Potes, Mark I" sort="Potes, Mark I" uniqKey="Potes M" first="Mark I" last="Potes">Mark I. Potes</name><name sortKey="Tamanoi, Fuyuhiko" sort="Tamanoi, Fuyuhiko" uniqKey="Tamanoi F" first="Fuyuhiko" last="Tamanoi">Fuyuhiko Tamanoi</name></country><country name="Japon"><region name="Région du Kansai"><name sortKey="Tamanoi, Fuyuhiko" sort="Tamanoi, Fuyuhiko" uniqKey="Tamanoi F" first="Fuyuhiko" last="Tamanoi">Fuyuhiko Tamanoi</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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