Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma

dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)
dc.contributor.authorLissanu Deribe, Yonathan
dc.contributor.authorShi, Yanxia
dc.contributor.authorRai, Kunal
dc.contributor.authorNezi, Luigi
dc.contributor.authorAmin, Samir B.
dc.contributor.authorWu, Chia-Chin
dc.contributor.authorAkdemir, Kadir C.
dc.contributor.authorMahdavi, Mozhdeh
dc.contributor.authorPeng, Qian
dc.contributor.authorChang, Qing Edward
dc.contributor.authorHornigold, Kirsti
dc.contributor.authorArold, Stefan T.
dc.contributor.authorWelch, Heidi C. E.
dc.contributor.authorGarraway, Levi A.
dc.contributor.authorChin, Lynda
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Division
dc.contributor.departmentBioscience Program
dc.contributor.departmentComputational Bioscience Research Center (CBRC)
dc.contributor.institutionDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
dc.contributor.institutionSun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborate Center for Cancer Medicine, Guangzhou 510060, China
dc.contributor.institutionInstitute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, TX 77030
dc.contributor.institutionThe Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom
dc.contributor.institutionDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
dc.contributor.institutionBroad Institute of MIT and Harvard, Boston, MA 02141
dc.date.accessioned2016-03-08T12:48:44Z
dc.date.available2016-03-08T12:48:44Z
dc.date.issued2016-02-16
dc.date.published-online2016-02-16
dc.date.published-print2016-03-01
dc.description.abstractPREX2 (phosphatidylinositol-3,4,5-triphosphate-dependent Rac-exchange factor 2) is a PTEN (phosphatase and tensin homolog deleted on chromosome 10) binding protein that is significantly mutated in cutaneous melanoma and pancreatic ductal adenocarcinoma. Here, genetic and biochemical analyses were conducted to elucidate the nature and mechanistic basis of PREX2 mutation in melanoma development. By generating an inducible transgenic mouse model we showed an oncogenic role for a truncating PREX2 mutation (PREX2E824*) in vivo in the context of mutant NRAS. Using integrative cross-species gene expression analysis, we identified deregulated cell cycle and cytoskeleton organization as significantly perturbed biological pathways in PREX2 mutant tumors. Mechanistically, truncation of PREX2 activated its Rac1 guanine nucleotide exchange factor activity, abolished binding to PTEN and activated the PI3K (phosphatidyl inositol 3 kinase)/Akt signaling pathway. We further showed that PREX2 truncating mutations or PTEN deletion induces down-regulation of the tumor suppressor and cell cycle regulator CDKN1C (also known as p57KIP2). This down-regulation occurs, at least partially, through DNA hypomethylation of a differentially methylated region in chromosome 11 that is a known regulatory region for expression of the CDKN1C gene. Together, these findings identify PREX2 as a mediator of NRAS-mutant melanoma development that acts through the PI3K/PTEN/Akt pathway to regulate gene expression of a cell cycle regulator.
dc.description.sponsorshipWe thank Timothy Heffernan and Trang Tieu of the Institute for Applied Cancer Science for help with various plasmids, Jim Horner and Erin Paul of the MD Anderson GEM facility for pronuclear injection of PREX2 transgene, and Chang-Gong Liu of MD Anderson Sequencing and Non-coding RNA Core Facility for microarray profiling and Denise Spring for critical reading of the manuscript. L.C is a recipient of the Cancer Prevention and Research Institute of Texas (CPRIT) Established Investigator Recruitment Award. S.T.A. was supported by the King Abdullah University of Science and Technology.
dc.eprint.versionPost-print
dc.identifier.citationTruncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma 2016, 113 (9):E1296 Proceedings of the National Academy of Sciences
dc.identifier.doi10.1073/pnas.1513801113
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.journalProceedings of the National Academy of Sciences
dc.identifier.pmid26884185
dc.identifier.urihttp://hdl.handle.net/10754/600889
dc.language.isoen
dc.publisherProceedings of the National Academy of Sciences
dc.relation.urlhttp://www.pnas.org/lookup/doi/10.1073/pnas.1513801113
dc.rightsArchived with thanks to Proceedings of the National Academy of Sciences
dc.subjectPREX2
dc.subjectmelanoma
dc.subjectRac1
dc.subjectPI3K/Akt
dc.subjectmouse models of cancer
dc.titleTruncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma
dc.typeArticle
display.details.left<span><h5>Type</h5>Article<br><br><h5>Authors</h5><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Lissanu Deribe, Yonathan,equals">Lissanu Deribe, Yonathan</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Shi, Yanxia,equals">Shi, Yanxia</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Rai, Kunal,equals">Rai, Kunal</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Nezi, Luigi,equals">Nezi, Luigi</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Amin, Samir B.,equals">Amin, Samir B.</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Wu, Chia-Chin,equals">Wu, Chia-Chin</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Akdemir, Kadir C.,equals">Akdemir, Kadir C.</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Mahdavi, Mozhdeh,equals">Mahdavi, Mozhdeh</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Peng, Qian,equals">Peng, Qian</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Chang, Qing Edward,equals">Chang, Qing Edward</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Hornigold, Kirsti,equals">Hornigold, Kirsti</a><br><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0001-5278-0668&spc.sf=dc.date.issued&spc.sd=DESC">Arold, Stefan T.</a> <a href="https://orcid.org/0000-0001-5278-0668" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Welch, Heidi C. E.,equals">Welch, Heidi C. E.</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Garraway, Levi A.,equals">Garraway, Levi A.</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Chin, Lynda,equals">Chin, Lynda</a><br><br><h5>KAUST Department</h5><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.department=Biological and Environmental Sciences and Engineering (BESE) Division,equals">Biological and Environmental Sciences and Engineering (BESE) Division</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.department=Bioscience Program,equals">Bioscience Program</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.department=Computational Bioscience Research Center (CBRC),equals">Computational Bioscience Research Center (CBRC)</a><br><br><h5>Online Publication Date</h5>2016-02-16<br><br><h5>Print Publication Date</h5>2016-03-01<br><br><h5>Date</h5>2016-02-16</span>
display.details.right<span><h5>Abstract</h5>PREX2 (phosphatidylinositol-3,4,5-triphosphate-dependent Rac-exchange factor 2) is a PTEN (phosphatase and tensin homolog deleted on chromosome 10) binding protein that is significantly mutated in cutaneous melanoma and pancreatic ductal adenocarcinoma. Here, genetic and biochemical analyses were conducted to elucidate the nature and mechanistic basis of PREX2 mutation in melanoma development. By generating an inducible transgenic mouse model we showed an oncogenic role for a truncating PREX2 mutation (PREX2E824*) in vivo in the context of mutant NRAS. Using integrative cross-species gene expression analysis, we identified deregulated cell cycle and cytoskeleton organization as significantly perturbed biological pathways in PREX2 mutant tumors. Mechanistically, truncation of PREX2 activated its Rac1 guanine nucleotide exchange factor activity, abolished binding to PTEN and activated the PI3K (phosphatidyl inositol 3 kinase)/Akt signaling pathway. We further showed that PREX2 truncating mutations or PTEN deletion induces down-regulation of the tumor suppressor and cell cycle regulator CDKN1C (also known as p57KIP2). This down-regulation occurs, at least partially, through DNA hypomethylation of a differentially methylated region in chromosome 11 that is a known regulatory region for expression of the CDKN1C gene. Together, these findings identify PREX2 as a mediator of NRAS-mutant melanoma development that acts through the PI3K/PTEN/Akt pathway to regulate gene expression of a cell cycle regulator.<br><br><h5>Citation</h5>Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma 2016, 113 (9):E1296 Proceedings of the National Academy of Sciences<br><br><h5>Acknowledgements</h5>We thank Timothy Heffernan and Trang Tieu of the Institute for Applied Cancer Science for help with various plasmids, Jim Horner and Erin Paul of the MD Anderson GEM facility for pronuclear injection of PREX2 transgene, and Chang-Gong Liu of MD Anderson Sequencing and Non-coding RNA Core Facility for microarray profiling and Denise Spring for critical reading of the manuscript. L.C is a recipient of the Cancer Prevention and Research Institute of Texas (CPRIT) Established Investigator Recruitment Award. S.T.A. was supported by the King Abdullah University of Science and Technology.<br><br><h5>Publisher</h5><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.publisher=Proceedings of the National Academy of Sciences,equals">Proceedings of the National Academy of Sciences</a><br><br><h5>Journal</h5><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.journal=Proceedings of the National Academy of Sciences,equals">Proceedings of the National Academy of Sciences</a><br><br><h5>DOI</h5><a href="https://doi.org/10.1073/pnas.1513801113">10.1073/pnas.1513801113</a><br><br><h5>PubMed ID</h5><a href="https://www.ncbi.nlm.nih.gov/pubmed/26884185">26884185</a><br><br><h5>Additional Links</h5>http://www.pnas.org/lookup/doi/10.1073/pnas.1513801113</span>
kaust.personArold, Stefan T.
orcid.authorLissanu Deribe, Yonathan
orcid.authorShi, Yanxia
orcid.authorRai, Kunal
orcid.authorNezi, Luigi
orcid.authorAmin, Samir B.
orcid.authorWu, Chia-Chin
orcid.authorAkdemir, Kadir C.
orcid.authorMahdavi, Mozhdeh
orcid.authorPeng, Qian
orcid.authorChang, Qing Edward
orcid.authorHornigold, Kirsti
orcid.authorArold, Stefan T.::0000-0001-5278-0668
orcid.authorWelch, Heidi C. E.
orcid.authorGarraway, Levi A.
orcid.authorChin, Lynda
orcid.id0000-0001-5278-0668
refterms.dateFOA2016-09-01T00:00:00Z
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