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

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    Type
    Article
    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. cc
    Welch, Heidi C. E.
    Garraway, Levi A.
    Chin, Lynda
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    Computational Bioscience Research Center (CBRC)
    Date
    2016-02-16
    Online Publication Date
    2016-02-16
    Print Publication Date
    2016-03-01
    Permanent link to this record
    http://hdl.handle.net/10754/600889
    
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    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.
    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
    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.
    Publisher
    Proceedings of the National Academy of Sciences
    Journal
    Proceedings of the National Academy of Sciences
    DOI
    10.1073/pnas.1513801113
    PubMed ID
    26884185
    Additional Links
    http://www.pnas.org/lookup/doi/10.1073/pnas.1513801113
    ae974a485f413a2113503eed53cd6c53
    10.1073/pnas.1513801113
    Scopus Count
    Collections
    Articles; Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program; Computational Bioscience Research Center (CBRC)

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