Phosphorylation of guanosine monophosphate reductase triggers a GTP-dependent switch from pro- to anti-oncogenic function of EPHA4

dc.contributor.authorWolff, David W.en
dc.contributor.authorDeng, Zhiyongen
dc.contributor.authorBianchi-Smiraglia, Annaen
dc.contributor.authorFoley, Colleen E.en
dc.contributor.authorHan, Zhannanen
dc.contributor.authorWang, Xingyouen
dc.contributor.authorShen, Shichenen
dc.contributor.authorRosenberg, Masha M.en
dc.contributor.authorMoparthy, Sudhaen
dc.contributor.authorYun, Dong Hyunen
dc.contributor.authorChen, Jialinen
dc.contributor.authorBaker, Brian K.en
dc.contributor.authorRoll, Matthewen
dc.contributor.authorMagiera, Andrew J.en
dc.contributor.authorLi, Junen
dc.contributor.authorHurley, Edwarden
dc.contributor.authorFeltri, Maria Lauraen
dc.contributor.authorCox, Anderson O.en
dc.contributor.authorLee, Jingyunen
dc.contributor.authorFurdui, Cristina M.en
dc.contributor.authorLiu, Liangen
dc.contributor.authorBshara, Wiamen
dc.contributor.authorLaConte, Leslie E. W.en
dc.contributor.authorKandel, Eugene S.en
dc.contributor.authorPasquale, Elena B.en
dc.contributor.authorQu, Junen
dc.contributor.authorHedstrom, Lizbethen
dc.contributor.authorNikiforov, Mikhail A.en
dc.date.accessioned2024-02-01T13:45:00Zen
dc.date.available2024-02-01T13:45:00Zen
dc.date.issued2022-02-10en
dc.description.abstractSignal transduction pathways post-translationally regulating nucleotide metabolism remain largely unknown. Guanosine monophosphate reductase (GMPR) is a nucleotide metabolism enzyme that decreases GTP pools by converting GMP to IMP. We observed that phosphorylation of GMPR at Tyr267 is critical for its activity and found that this phosphorylation by ephrin receptor tyrosine kinase EPHA4 decreases GTP pools in cell protrusions and levels of GTP-bound RAC1. EPHs possess oncogenic and tumor-suppressor activities, although the mechanisms underlying switches between these two modes are poorly understood. We demonstrated that GMPR plays a key role in EPHA4-mediated RAC1 suppression. This supersedes GMPR-independent activation of RAC1 by EPHA4, resulting in a negative overall effect on melanoma cell invasion and tumorigenicity. Accordingly, EPHA4 levels increase during melanoma progression and inversely correlate with GMPR levels in individual melanoma tumors. Therefore, phosphorylation of GMPR at Tyr267 is a metabolic signal transduction switch controlling GTP biosynthesis and transformed phenotypes.en
dc.description.versionAccepted versionen
dc.format.extentPages 970-+en
dc.format.extent22 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1016/j.chembiol.2022.01.007en
dc.identifier.eissn2451-9448en
dc.identifier.issn2451-9456en
dc.identifier.issue6en
dc.identifier.orcidLaConte, Leslie [0000-0003-3747-0973]en
dc.identifier.otherS2451-9456(22)00049-6 (PII)en
dc.identifier.pmid35148834en
dc.identifier.urihttps://hdl.handle.net/10919/117773en
dc.identifier.volume29en
dc.language.isoenen
dc.publisherCell Pressen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/35148834en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectEPHA4en
dc.subjectGEVAL GTP sensorsen
dc.subjectGMPRen
dc.subjectGTPen
dc.subject.meshHumansen
dc.subject.meshMelanomaen
dc.subject.meshReceptor, EphA4en
dc.subject.meshNucleotidesen
dc.subject.meshGuanosine Triphosphateen
dc.subject.meshPhosphorylationen
dc.subject.meshGMP Reductaseen
dc.titlePhosphorylation of guanosine monophosphate reductase triggers a GTP-dependent switch from pro- to anti-oncogenic function of EPHA4en
dc.title.serialCell Chemical Biologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2022-01-11en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicineen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/VTC School of Medicine - Instr Pgmsen
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