Phosphorylation of guanosine monophosphate reductase triggers a GTP-dependent switch from pro- to anti-oncogenic function of EPHA4.
EPHA4
GEVAL GTP sensors
GMPR
GTP
RAC1
RHOA
RHOC
invasion
melanoma
Journal
Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030
Informations de publication
Date de publication:
16 06 2022
16 06 2022
Historique:
received:
06
04
2021
revised:
19
11
2021
accepted:
11
01
2022
pubmed:
13
2
2022
medline:
22
6
2022
entrez:
12
2
2022
Statut:
ppublish
Résumé
Signal 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.
Identifiants
pubmed: 35148834
pii: S2451-9456(22)00049-6
doi: 10.1016/j.chembiol.2022.01.007
pmc: PMC9620470
mid: NIHMS1780090
pii:
doi:
Substances chimiques
Nucleotides
0
Guanosine Triphosphate
86-01-1
GMP Reductase
EC 1.7.1.7
Receptor, EphA4
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
970-984.e6Subventions
Organisme : NCI NIH HHS
ID : R01 CA264984
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA248018
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016056
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA224434
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA012197
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM054403
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI125362
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG062617
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA247819
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing financial interests.
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