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

Handle URI:
http://hdl.handle.net/10754/600889
Title:
Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma
Authors:
Lissanu Deribe, Yonathan; Shi, Yanxia; Rai, Kunal; Nezi, Luigi; Amin, Samir B.; Wu, Chia-Chin; Akdemir, Kadir C.; Mahdavi, Mozhdeh; Peng, Qian; Chang, Qing Edward; Hornigold, Kirsti; Arold, Stefan T. ( 0000-0001-5278-0668 ) ; Welch, Heidi C. E.; Garraway, Levi A.; Chin, Lynda
Abstract:
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.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division
Citation:
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
Publisher:
Proceedings of the National Academy of Sciences
Journal:
Proceedings of the National Academy of Sciences
Issue Date:
1-Mar-2016
DOI:
10.1073/pnas.1513801113
Type:
Article
ISSN:
0027-8424; 1091-6490
Sponsors:
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.
Additional Links:
http://www.pnas.org/lookup/doi/10.1073/pnas.1513801113
Appears in Collections:
Articles; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorLissanu Deribe, Yonathanen
dc.contributor.authorShi, Yanxiaen
dc.contributor.authorRai, Kunalen
dc.contributor.authorNezi, Luigien
dc.contributor.authorAmin, Samir B.en
dc.contributor.authorWu, Chia-Chinen
dc.contributor.authorAkdemir, Kadir C.en
dc.contributor.authorMahdavi, Mozhdehen
dc.contributor.authorPeng, Qianen
dc.contributor.authorChang, Qing Edwarden
dc.contributor.authorHornigold, Kirstien
dc.contributor.authorArold, Stefan T.en
dc.contributor.authorWelch, Heidi C. E.en
dc.contributor.authorGarraway, Levi A.en
dc.contributor.authorChin, Lyndaen
dc.date.accessioned2016-03-08T12:48:44Zen
dc.date.available2016-03-08T12:48:44Zen
dc.date.issued2016-03-01en
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 Sciencesen
dc.identifier.issn0027-8424en
dc.identifier.issn1091-6490en
dc.identifier.doi10.1073/pnas.1513801113en
dc.identifier.urihttp://hdl.handle.net/10754/600889en
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.en
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.en
dc.language.isoenen
dc.publisherProceedings of the National Academy of Sciencesen
dc.relation.urlhttp://www.pnas.org/lookup/doi/10.1073/pnas.1513801113en
dc.rightsArchived with thanks to Proceedings of the National Academy of Sciencesen
dc.subjectPREX2en
dc.subjectmelanomaen
dc.subjectRac1en
dc.subjectPI3K/Akten
dc.subjectmouse models of canceren
dc.titleTruncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanomaen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.identifier.journalProceedings of the National Academy of Sciencesen
dc.eprint.versionPost-printen
dc.contributor.institutionDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030en
dc.contributor.institutionSun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborate Center for Cancer Medicine, Guangzhou 510060, Chinaen
dc.contributor.institutionInstitute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, TX 77030en
dc.contributor.institutionThe Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdomen
dc.contributor.institutionDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215en
dc.contributor.institutionBroad Institute of MIT and Harvard, Boston, MA 02141en
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en
kaust.authorArold, Stefan T.en
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