Persistence without turnover: the RhoG G12E mutant highlights the role of nucleotide cycling in RhoG signaling

Abstract

Small GTPases of the Ras superfamily act as molecular switches cycling between GDP-bound inactive and GTP-bound active states. Their signaling output depends not only on GTP loading but on continuous nucleotide cycling controlled by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). While Glycine 12 substitutions in Ras typically confer constitutive activation, the effects of equivalent mutations in Rho-family GTPases remain poorly defined. Here, we characterize a ClinVar-reported RhoGG12E variant. Quantitative kinetic studies show that RhoGG12E has strongly impaired intrinsic and GAP-stimulated GTP hydrolysis but it can still be activated by GEFs. Effector binding is preserved in vitro and RhoGG12E accumulates in a GTP-bound state in cells. Yet, RhoGG12E induces enhanced spreading, increased focal adhesions, and reduced collective migration-phenotypes consistent with previously reported consequences of reduced RhoG signaling rather than hyperactivation. These findings indicate that accumulation of the GTP-bound form of small GTPases does not necessarily translate into productive output, supporting a model in which impaired nucleotide cycling compromises RhoG-dependent cellular behaviors.

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BibTeX RIS

BibTeX

@article{wajed2026persistence,
  title = {{Persistence without turnover: the RhoG G12E mutant highlights the role of nucleotide cycling in RhoG signaling}},
  author = {Shah Wajed and Yann Ferrandez and Mahel Zeghouf and Rasta Ghasemi and Cylia Puertas and Agata Nawrotek and Franck Gesbert},
  journal = {Biochemical Journal},
  year = {2026},
  month = aug,
  doi = {10.1042/bcj20260225},
  url = {https://hal.science/hal-05746792v1},
  note = {CC BY},
}

RIS

TY  - JOUR
TI  - Persistence without turnover: the RhoG G12E mutant highlights the role of nucleotide cycling in RhoG signaling
AU  - Shah Wajed
AU  - Yann Ferrandez
AU  - Mahel Zeghouf
AU  - Rasta Ghasemi
AU  - Cylia Puertas
AU  - Agata Nawrotek
AU  - Franck Gesbert
PY  - 2026
DA  - 2026/08/05
JO  - Biochemical Journal
DO  - 10.1042/bcj20260225
UR  - https://hal.science/hal-05746792v1
AB  - Small GTPases of the Ras superfamily act as molecular switches cycling between GDP-bound inactive and GTP-bound active states. Their signaling output depends not only on GTP loading but on continuous nucleotide cycling controlled by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). While Glycine 12 substitutions in Ras typically confer constitutive activation, the effects of equivalent mutations in Rho-family GTPases remain poorly defined. Here, we characterize a ClinVar-reported RhoGG12E variant. Quantitative kinetic studies show that RhoGG12E has strongly impaired intrinsic and GAP-stimulated GTP hydrolysis but it can still be activated by GEFs. Effector binding is preserved in vitro and RhoGG12E accumulates in a GTP-bound state in cells. Yet, RhoGG12E induces enhanced spreading, increased focal adhesions, and reduced collective migration-phenotypes consistent with previously reported consequences of reduced RhoG signaling rather than hyperactivation. These findings indicate that accumulation of the GTP-bound form of small GTPases does not necessarily translate into productive output, supporting a model in which impaired nucleotide cycling compromises RhoG-dependent cellular behaviors.
SN  - 0264-6021
SN  - 1470-8728
ER  -

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