Mitogen-Inducible Gene-6 Mediates Feedback Inhibition from Mutated BRAF towards the Epidermal Growth Factor Receptor and Thereby Limits Malignant Transformation
BRAF functions in the RAS-extracellular signal-regulated kinase (ERK) signaling cascade. Activation of this pathway is necessary to mediate the transforming potential of oncogenic BRAF, however, it may also cause a negative feedback that inhibits the epidermal growth factor receptor (EGFR). Mitogen-...
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| creator | Milewska, Malgorzata Romano, David Herrero, Ana Guerriero, Maria Luisa Birtwistle, Marc Quehenberger, Franz Hatzl, Stefan Kholodenko, Boris N Segatto, Oreste Kolch, Walter Zebisch, Armin |
| description | BRAF functions in the RAS-extracellular signal-regulated kinase (ERK) signaling cascade. Activation of this pathway is necessary to mediate the transforming potential of oncogenic BRAF, however, it may also cause a negative feedback that inhibits the epidermal growth factor receptor (EGFR). Mitogen-inducible gene-6 (MIG-6) is a potent inhibitor of the EGFR and has been demonstrated to function as a tumor suppressor. As MIG-6 can be induced via RAS-ERK signaling, we investigated its potential involvement in this negative regulatory loop. Focus formation assays were performed and demonstrated that MIG-6 significantly reduces malignant transformation induced by oncogenic BRAF. Although this genetic interaction was mirrored by a physical interaction between MIG-6 and BRAF, we did not observe a direct regulation of BRAF kinase activity by MIG-6. Interestingly, a selective chemical EGFR inhibitor suppressed transformation to a similar degree as MIG-6, whereas combining these approaches had no synergistic effect. By analyzing a range of BRAF mutated and wildtype cell line models, we could show that BRAF V600E causes a strong upregulation of MIG-6, which was mediated at the transcriptional level via the RAS-ERK pathway and resulted in downregulation of EGFR activation. This feedback loop is operational in tumors, as shown by the analysis of almost 400 patients with papillary thyroid cancer (PTC). Presence of BRAF V600E correlated with increased MIG-6 expression on the one hand, and with inactivation of the EGFR and of PI3K/AKT signaling on the other hand. Importantly, we also observed a more aggressive disease phenotype when BRAF V600E coexisted with low MIG-6 expression. Finally, analysis of methylation data was performed and revealed that higher methylation of MIG-6 correlated to its decreased expression. Taken together, we demonstrate that MIG-6 efficiently reduces cellular transformation driven by oncogenic BRAF by orchestrating a negative feedback circuit directed towards the EGFR. |
| doi_str_mv | 10.1371/journal.pone.0129859 |
| format | Article |
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Activation of this pathway is necessary to mediate the transforming potential of oncogenic BRAF, however, it may also cause a negative feedback that inhibits the epidermal growth factor receptor (EGFR). Mitogen-inducible gene-6 (MIG-6) is a potent inhibitor of the EGFR and has been demonstrated to function as a tumor suppressor. As MIG-6 can be induced via RAS-ERK signaling, we investigated its potential involvement in this negative regulatory loop. Focus formation assays were performed and demonstrated that MIG-6 significantly reduces malignant transformation induced by oncogenic BRAF. Although this genetic interaction was mirrored by a physical interaction between MIG-6 and BRAF, we did not observe a direct regulation of BRAF kinase activity by MIG-6. Interestingly, a selective chemical EGFR inhibitor suppressed transformation to a similar degree as MIG-6, whereas combining these approaches had no synergistic effect. By analyzing a range of BRAF mutated and wildtype cell line models, we could show that BRAF V600E causes a strong upregulation of MIG-6, which was mediated at the transcriptional level via the RAS-ERK pathway and resulted in downregulation of EGFR activation. This feedback loop is operational in tumors, as shown by the analysis of almost 400 patients with papillary thyroid cancer (PTC). Presence of BRAF V600E correlated with increased MIG-6 expression on the one hand, and with inactivation of the EGFR and of PI3K/AKT signaling on the other hand. Importantly, we also observed a more aggressive disease phenotype when BRAF V600E coexisted with low MIG-6 expression. Finally, analysis of methylation data was performed and revealed that higher methylation of MIG-6 correlated to its decreased expression. Taken together, we demonstrate that MIG-6 efficiently reduces cellular transformation driven by oncogenic BRAF by orchestrating a negative feedback circuit directed towards the EGFR.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0129859</identifier><identifier>PMID: 26065894</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Phosphatidylinositol 3-kinase ; 3T3 Cells ; Activation ; Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; Adult ; AKT protein ; Analysis ; Animals ; Cell culture ; Cell Transformation, Neoplastic - genetics ; Cell Transformation, Neoplastic - metabolism ; Chlorocebus aethiops ; COS Cells ; Data processing ; Deactivation ; Epidermal growth factor ; Epidermal growth factor receptors ; Epidermal growth factors ; ErbB Receptors - antagonists & inhibitors ; ErbB Receptors - metabolism ; Extracellular signal-regulated kinase ; Feedback circuits ; Feedback inhibition ; Feedback loops ; Feedback, Physiological ; Gene Expression Regulation, Neoplastic ; Genetic transformation ; HEK293 Cells ; Humans ; Inactivation ; Inhibitors ; Kinases ; Metabolic pathways ; Methylation ; Mice ; Middle Aged ; Mitogens ; Mutation ; Mutation, Missense ; Negative feedback ; Papillary thyroid cancer ; Phenotypes ; Proto-Oncogene Proteins B-raf - genetics ; Proto-Oncogene Proteins B-raf - metabolism ; Rodents ; Signal transduction ; Signaling ; Synergistic effect ; Thyroid ; Thyroid cancer ; Thyroid Neoplasms - genetics ; Thyroid Neoplasms - metabolism ; Thyroid Neoplasms - pathology ; Transcription ; Transformation ; Tumor suppressor genes ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism ; Tumors</subject><ispartof>PloS one, 2015-06, Vol.10 (6), p.e0129859</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Milewska et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Milewska et al 2015 Milewska et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-7fd8da19ce383bccc9cb2c195311d67051fe18571f72cb89037b518b5b17668f3</citedby><cites>FETCH-LOGICAL-c692t-7fd8da19ce383bccc9cb2c195311d67051fe18571f72cb89037b518b5b17668f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466796/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466796/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26065894$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Boucher, Marie-Josée</contributor><creatorcontrib>Milewska, Malgorzata</creatorcontrib><creatorcontrib>Romano, David</creatorcontrib><creatorcontrib>Herrero, Ana</creatorcontrib><creatorcontrib>Guerriero, Maria Luisa</creatorcontrib><creatorcontrib>Birtwistle, Marc</creatorcontrib><creatorcontrib>Quehenberger, Franz</creatorcontrib><creatorcontrib>Hatzl, Stefan</creatorcontrib><creatorcontrib>Kholodenko, Boris N</creatorcontrib><creatorcontrib>Segatto, Oreste</creatorcontrib><creatorcontrib>Kolch, Walter</creatorcontrib><creatorcontrib>Zebisch, Armin</creatorcontrib><title>Mitogen-Inducible Gene-6 Mediates Feedback Inhibition from Mutated BRAF towards the Epidermal Growth Factor Receptor and Thereby Limits Malignant Transformation</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>BRAF functions in the RAS-extracellular signal-regulated kinase (ERK) signaling cascade. Activation of this pathway is necessary to mediate the transforming potential of oncogenic BRAF, however, it may also cause a negative feedback that inhibits the epidermal growth factor receptor (EGFR). Mitogen-inducible gene-6 (MIG-6) is a potent inhibitor of the EGFR and has been demonstrated to function as a tumor suppressor. As MIG-6 can be induced via RAS-ERK signaling, we investigated its potential involvement in this negative regulatory loop. Focus formation assays were performed and demonstrated that MIG-6 significantly reduces malignant transformation induced by oncogenic BRAF. Although this genetic interaction was mirrored by a physical interaction between MIG-6 and BRAF, we did not observe a direct regulation of BRAF kinase activity by MIG-6. Interestingly, a selective chemical EGFR inhibitor suppressed transformation to a similar degree as MIG-6, whereas combining these approaches had no synergistic effect. By analyzing a range of BRAF mutated and wildtype cell line models, we could show that BRAF V600E causes a strong upregulation of MIG-6, which was mediated at the transcriptional level via the RAS-ERK pathway and resulted in downregulation of EGFR activation. This feedback loop is operational in tumors, as shown by the analysis of almost 400 patients with papillary thyroid cancer (PTC). Presence of BRAF V600E correlated with increased MIG-6 expression on the one hand, and with inactivation of the EGFR and of PI3K/AKT signaling on the other hand. Importantly, we also observed a more aggressive disease phenotype when BRAF V600E coexisted with low MIG-6 expression. Finally, analysis of methylation data was performed and revealed that higher methylation of MIG-6 correlated to its decreased expression. Taken together, we demonstrate that MIG-6 efficiently reduces cellular transformation driven by oncogenic BRAF by orchestrating a negative feedback circuit directed towards the EGFR.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>3T3 Cells</subject><subject>Activation</subject><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Adult</subject><subject>AKT protein</subject><subject>Analysis</subject><subject>Animals</subject><subject>Cell culture</subject><subject>Cell Transformation, Neoplastic - genetics</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Chlorocebus aethiops</subject><subject>COS Cells</subject><subject>Data processing</subject><subject>Deactivation</subject><subject>Epidermal growth factor</subject><subject>Epidermal growth factor receptors</subject><subject>Epidermal growth factors</subject><subject>ErbB Receptors - antagonists & inhibitors</subject><subject>ErbB Receptors - metabolism</subject><subject>Extracellular signal-regulated kinase</subject><subject>Feedback circuits</subject><subject>Feedback inhibition</subject><subject>Feedback loops</subject><subject>Feedback, Physiological</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genetic transformation</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Inactivation</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Metabolic pathways</subject><subject>Methylation</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Mitogens</subject><subject>Mutation</subject><subject>Mutation, Missense</subject><subject>Negative feedback</subject><subject>Papillary thyroid cancer</subject><subject>Phenotypes</subject><subject>Proto-Oncogene Proteins B-raf - genetics</subject><subject>Proto-Oncogene Proteins B-raf - metabolism</subject><subject>Rodents</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Synergistic effect</subject><subject>Thyroid</subject><subject>Thyroid cancer</subject><subject>Thyroid Neoplasms - genetics</subject><subject>Thyroid Neoplasms - metabolism</subject><subject>Thyroid Neoplasms - pathology</subject><subject>Transcription</subject><subject>Transformation</subject><subject>Tumor suppressor genes</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - metabolism</subject><subject>Tumors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9-KEzEUxgdR3HX1DUQDguBF62T-ZDI3Ql22tdCysFZvQyY56aTOJDXJuO7b-Kimtru0oCC5SEh-33eSj5wkeYnTMc4r_H5jB2d4N95aA-MUZzUt60fJOa7zbESyNH98tD5Lnnm_SdMyp4Q8Tc4ykpKS1sV58mupg12DGc2NHIRuOkAzMDAiaAlS8wAeTQFkw8U3NDetbnTQ1iDlbI-WQ4iARB9vJlMU7C130qPQArraagmu5x2aOXsbWjTlIliHbkDAdrfgRqJVCw6aO7TQvQ4eLXmn14abgFaOG69s1O9KPU-eKN55eHGYL5Iv06vV5afR4no2v5wsRoLUWRhVSlLJcS0gp3kjhKhFkwlclznGklRpiRVgWlZYVZloaJ3mVVNi2pQNrgihKr9IXu99t5317BCuZ5jQimaYkjwS8z0hLd-wrdM9d3fMcs3-bFi3ZtwFLTpgKqN1DFgWJIOiFoJTrgoBKhOUlBxI9PpwqDY0PUgBJjjenZienhjdsrX9wYqCkKreGbw5GDj7fQAf_nHlA7Xm8VbaKBvNRK-9YJMiPrwkNMeRGv-FikNCr0X8XkrH_RPBuxNBZAL8DGs-eM_mn2_-n73-esq-PWJb4F1ove2G3T_wp2CxB4Wz3jtQD8nhlO264z4NtusOduiOKHt1nPqD6L4d8t8V8Qye</recordid><startdate>20150612</startdate><enddate>20150612</enddate><creator>Milewska, Malgorzata</creator><creator>Romano, David</creator><creator>Herrero, Ana</creator><creator>Guerriero, Maria Luisa</creator><creator>Birtwistle, Marc</creator><creator>Quehenberger, Franz</creator><creator>Hatzl, Stefan</creator><creator>Kholodenko, Boris N</creator><creator>Segatto, Oreste</creator><creator>Kolch, Walter</creator><creator>Zebisch, Armin</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150612</creationdate><title>Mitogen-Inducible Gene-6 Mediates Feedback Inhibition from Mutated BRAF towards the Epidermal Growth Factor Receptor and Thereby Limits Malignant Transformation</title><author>Milewska, Malgorzata ; Romano, David ; Herrero, Ana ; Guerriero, Maria Luisa ; Birtwistle, Marc ; Quehenberger, Franz ; Hatzl, Stefan ; Kholodenko, Boris N ; Segatto, Oreste ; Kolch, Walter ; Zebisch, Armin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-7fd8da19ce383bccc9cb2c195311d67051fe18571f72cb89037b518b5b17668f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>3T3 Cells</topic><topic>Activation</topic><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Adult</topic><topic>AKT protein</topic><topic>Analysis</topic><topic>Animals</topic><topic>Cell culture</topic><topic>Cell Transformation, Neoplastic - genetics</topic><topic>Cell Transformation, Neoplastic - metabolism</topic><topic>Chlorocebus aethiops</topic><topic>COS Cells</topic><topic>Data processing</topic><topic>Deactivation</topic><topic>Epidermal growth factor</topic><topic>Epidermal growth factor receptors</topic><topic>Epidermal growth factors</topic><topic>ErbB Receptors - antagonists & inhibitors</topic><topic>ErbB Receptors - metabolism</topic><topic>Extracellular signal-regulated kinase</topic><topic>Feedback circuits</topic><topic>Feedback inhibition</topic><topic>Feedback loops</topic><topic>Feedback, Physiological</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genetic transformation</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Inactivation</topic><topic>Inhibitors</topic><topic>Kinases</topic><topic>Metabolic pathways</topic><topic>Methylation</topic><topic>Mice</topic><topic>Middle Aged</topic><topic>Mitogens</topic><topic>Mutation</topic><topic>Mutation, Missense</topic><topic>Negative feedback</topic><topic>Papillary thyroid cancer</topic><topic>Phenotypes</topic><topic>Proto-Oncogene Proteins B-raf - genetics</topic><topic>Proto-Oncogene Proteins B-raf - metabolism</topic><topic>Rodents</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Synergistic effect</topic><topic>Thyroid</topic><topic>Thyroid cancer</topic><topic>Thyroid Neoplasms - genetics</topic><topic>Thyroid Neoplasms - metabolism</topic><topic>Thyroid Neoplasms - pathology</topic><topic>Transcription</topic><topic>Transformation</topic><topic>Tumor suppressor genes</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Milewska, Malgorzata</creatorcontrib><creatorcontrib>Romano, David</creatorcontrib><creatorcontrib>Herrero, Ana</creatorcontrib><creatorcontrib>Guerriero, Maria Luisa</creatorcontrib><creatorcontrib>Birtwistle, Marc</creatorcontrib><creatorcontrib>Quehenberger, Franz</creatorcontrib><creatorcontrib>Hatzl, Stefan</creatorcontrib><creatorcontrib>Kholodenko, Boris N</creatorcontrib><creatorcontrib>Segatto, Oreste</creatorcontrib><creatorcontrib>Kolch, Walter</creatorcontrib><creatorcontrib>Zebisch, Armin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale_Opposing Viewpoints In Context</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database (ProQuest)</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection (Proquest)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database (Proquest)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>https://resources.nclive.org/materials</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agriculture Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>ProQuest Biological Science Journals</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest advanced technologies & aerospace journals</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials science collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Milewska, Malgorzata</au><au>Romano, David</au><au>Herrero, Ana</au><au>Guerriero, Maria Luisa</au><au>Birtwistle, Marc</au><au>Quehenberger, Franz</au><au>Hatzl, Stefan</au><au>Kholodenko, Boris N</au><au>Segatto, Oreste</au><au>Kolch, Walter</au><au>Zebisch, Armin</au><au>Boucher, Marie-Josée</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mitogen-Inducible Gene-6 Mediates Feedback Inhibition from Mutated BRAF towards the Epidermal Growth Factor Receptor and Thereby Limits Malignant Transformation</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-06-12</date><risdate>2015</risdate><volume>10</volume><issue>6</issue><spage>e0129859</spage><pages>e0129859-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>BRAF functions in the RAS-extracellular signal-regulated kinase (ERK) signaling cascade. Activation of this pathway is necessary to mediate the transforming potential of oncogenic BRAF, however, it may also cause a negative feedback that inhibits the epidermal growth factor receptor (EGFR). Mitogen-inducible gene-6 (MIG-6) is a potent inhibitor of the EGFR and has been demonstrated to function as a tumor suppressor. As MIG-6 can be induced via RAS-ERK signaling, we investigated its potential involvement in this negative regulatory loop. Focus formation assays were performed and demonstrated that MIG-6 significantly reduces malignant transformation induced by oncogenic BRAF. Although this genetic interaction was mirrored by a physical interaction between MIG-6 and BRAF, we did not observe a direct regulation of BRAF kinase activity by MIG-6. Interestingly, a selective chemical EGFR inhibitor suppressed transformation to a similar degree as MIG-6, whereas combining these approaches had no synergistic effect. By analyzing a range of BRAF mutated and wildtype cell line models, we could show that BRAF V600E causes a strong upregulation of MIG-6, which was mediated at the transcriptional level via the RAS-ERK pathway and resulted in downregulation of EGFR activation. This feedback loop is operational in tumors, as shown by the analysis of almost 400 patients with papillary thyroid cancer (PTC). Presence of BRAF V600E correlated with increased MIG-6 expression on the one hand, and with inactivation of the EGFR and of PI3K/AKT signaling on the other hand. Importantly, we also observed a more aggressive disease phenotype when BRAF V600E coexisted with low MIG-6 expression. Finally, analysis of methylation data was performed and revealed that higher methylation of MIG-6 correlated to its decreased expression. Taken together, we demonstrate that MIG-6 efficiently reduces cellular transformation driven by oncogenic BRAF by orchestrating a negative feedback circuit directed towards the EGFR.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26065894</pmid><doi>10.1371/journal.pone.0129859</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-06, Vol.10 (6), p.e0129859 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1687821863 |
| source | MEDLINE; Public Library of Science; DOAJ Directory of Open Access Journals; PubMed Central; Free Full-Text Journals in Chemistry; EZB Electronic Journals Library |
| subjects | 1-Phosphatidylinositol 3-kinase 3T3 Cells Activation Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Adult AKT protein Analysis Animals Cell culture Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - metabolism Chlorocebus aethiops COS Cells Data processing Deactivation Epidermal growth factor Epidermal growth factor receptors Epidermal growth factors ErbB Receptors - antagonists & inhibitors ErbB Receptors - metabolism Extracellular signal-regulated kinase Feedback circuits Feedback inhibition Feedback loops Feedback, Physiological Gene Expression Regulation, Neoplastic Genetic transformation HEK293 Cells Humans Inactivation Inhibitors Kinases Metabolic pathways Methylation Mice Middle Aged Mitogens Mutation Mutation, Missense Negative feedback Papillary thyroid cancer Phenotypes Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins B-raf - metabolism Rodents Signal transduction Signaling Synergistic effect Thyroid Thyroid cancer Thyroid Neoplasms - genetics Thyroid Neoplasms - metabolism Thyroid Neoplasms - pathology Transcription Transformation Tumor suppressor genes Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Tumors |
| title | Mitogen-Inducible Gene-6 Mediates Feedback Inhibition from Mutated BRAF towards the Epidermal Growth Factor Receptor and Thereby Limits Malignant Transformation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-01T11%3A03%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Mitogen-Inducible%20Gene-6%20Mediates%20Feedback%20Inhibition%20from%20Mutated%20BRAF%20towards%20the%20Epidermal%20Growth%20Factor%20Receptor%20and%20Thereby%20Limits%20Malignant%20Transformation&rft.jtitle=PloS%20one&rft.au=Milewska,%20Malgorzata&rft.date=2015-06-12&rft.volume=10&rft.issue=6&rft.spage=e0129859&rft.pages=e0129859-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0129859&rft_dat=%3Cgale_plos_%3EA417656831%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1687821863&rft_id=info:pmid/26065894&rft_galeid=A417656831&rft_doaj_id=oai_doaj_org_article_f289658d462e49cca8af4cef2c865ae6&rfr_iscdi=true |