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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Wolff, DW; Deng, Z; Bianchi-Smiraglia, A; Foley, CE; Han, Z; Wang, X; Shen, S; Rosenberg, MM; Moparthy, S; Yun, DH; Chen, J; Baker, BK; Roll, MV; Magiera, AJ; Li, J; Hurley, E; Feltri, ML; Cox, AO; Lee, J; Furdui, CM; Liu, L; Bshara, W; LaConte, LEW; Kandel, ES; Pasquale, EB; Qu, J; Hedstrom, L; Nikiforov, MA

Published Date

  • June 16, 2022

Published In

Volume / Issue

  • 29 / 6

Start / End Page

  • 970 - 984.e6

PubMed ID

  • 35148834

Electronic International Standard Serial Number (EISSN)

  • 2451-9448

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2022.01.007


  • eng

Conference Location

  • United States