Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma
AuthorsLissanu Deribe, Yonathan
Amin, Samir B.
Akdemir, Kadir C.
Chang, Qing Edward
Arold, Stefan T.
Welch, Heidi C. E.
Garraway, Levi A.
Permanent link to this recordhttp://hdl.handle.net/10754/600889
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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.
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
SponsorsWe 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.
- Interplay between PREX2 mutations and the PI3K pathway and its effect on epigenetic regulation of gene expression in NRAS-mutant melanoma.
- Authors: Lissanu Deribe Y
- Issue date: 2016 Jul 2
- PTEN inhibits PREX2-catalyzed activation of RAC1 to restrain tumor cell invasion.
- Authors: Mense SM, Barrows D, Hodakoski C, Steinbach N, Schoenfeld D, Su W, Hopkins BD, Su T, Fine B, Hibshoosh H, Parsons R
- Issue date: 2015 Mar 31
- Mechanistic insights into the role of truncating PREX2 mutations in melanoma.
- Authors: Lissanu Deribe Y
- Issue date: 2016 May
- p21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase.
- Authors: Barrows D, Schoenfeld SM, Hodakoski C, Silkov A, Honig B, Couvillon A, Shymanets A, Nürnberg B, Asara JM, Parsons R
- Issue date: 2015 Nov 27
- Replication Study: Melanoma genome sequencing reveals frequent <i>PREX2</i> mutations.
- Authors: Horrigan SK, Courville P, Sampey D, Zhou F, Cai S, Reproducibility Project: Cancer Biology.
- Issue date: 2017 Jan 19