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Regulation of local GTP availability controls RAC1 activity and cell invasion.

Publication ,  Journal Article
Bianchi-Smiraglia, A; Wolff, DW; Marston, DJ; Deng, Z; Han, Z; Moparthy, S; Wombacher, RM; Mussell, AL; Shen, S; Chen, J; Yun, D-H; Furdui, CM ...
Published in: Nature communications
October 2021

Physiological changes in GTP levels in live cells have never been considered a regulatory step of RAC1 activation because intracellular GTP concentration (determined by chromatography or mass spectrometry) was shown to be substantially higher than the in vitro RAC1 GTP dissociation constant (RAC1-GTP Kd). Here, by combining genetically encoded GTP biosensors and a RAC1 activity biosensor, we demonstrated that GTP levels fluctuating around RAC1-GTP Kd correlated with changes in RAC1 activity in live cells. Furthermore, RAC1 co-localized in protrusions of invading cells with several guanylate metabolism enzymes, including rate-limiting inosine monophosphate dehydrogenase 2 (IMPDH2), which was partially due to direct RAC1-IMPDH2 interaction. Substitution of endogenous IMPDH2 with IMPDH2 mutants incapable of binding RAC1 did not affect total intracellular GTP levels but suppressed RAC1 activity. Targeting IMPDH2 away from the plasma membrane did not alter total intracellular GTP pools but decreased GTP levels in cell protrusions, RAC1 activity, and cell invasion. These data provide a mechanism of regulation of RAC1 activity by local GTP pools in live cells.

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Published In

Nature communications

DOI

EISSN

2041-1723

ISSN

2041-1723

Publication Date

October 2021

Volume

12

Issue

1

Start / End Page

6091

Related Subject Headings

  • rac1 GTP-Binding Protein
  • Protein Binding
  • Kinetics
  • IMP Dehydrogenase
  • Humans
  • HEK293 Cells
  • Guanosine Triphosphate
  • Cell Movement
  • Cell Membrane
 

Citation

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ICMJE
MLA
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Bianchi-Smiraglia, A., Wolff, D. W., Marston, D. J., Deng, Z., Han, Z., Moparthy, S., … Nikiforov, M. A. (2021). Regulation of local GTP availability controls RAC1 activity and cell invasion. Nature Communications, 12(1), 6091. https://doi.org/10.1038/s41467-021-26324-6
Bianchi-Smiraglia, Anna, David W. Wolff, Daniel J. Marston, Zhiyong Deng, Zhannan Han, Sudha Moparthy, Rebecca M. Wombacher, et al. “Regulation of local GTP availability controls RAC1 activity and cell invasion.Nature Communications 12, no. 1 (October 2021): 6091. https://doi.org/10.1038/s41467-021-26324-6.
Bianchi-Smiraglia A, Wolff DW, Marston DJ, Deng Z, Han Z, Moparthy S, et al. Regulation of local GTP availability controls RAC1 activity and cell invasion. Nature communications. 2021 Oct;12(1):6091.
Bianchi-Smiraglia, Anna, et al. “Regulation of local GTP availability controls RAC1 activity and cell invasion.Nature Communications, vol. 12, no. 1, Oct. 2021, p. 6091. Epmc, doi:10.1038/s41467-021-26324-6.
Bianchi-Smiraglia A, Wolff DW, Marston DJ, Deng Z, Han Z, Moparthy S, Wombacher RM, Mussell AL, Shen S, Chen J, Yun D-H, O’Brien Cox A, Furdui CM, Hurley E, Feltri ML, Qu J, Hollis T, Kengne JBN, Fongang B, Sousa RJ, Kandel ME, Kandel ES, Hahn KM, Nikiforov MA. Regulation of local GTP availability controls RAC1 activity and cell invasion. Nature communications. 2021 Oct;12(1):6091.

Published In

Nature communications

DOI

EISSN

2041-1723

ISSN

2041-1723

Publication Date

October 2021

Volume

12

Issue

1

Start / End Page

6091

Related Subject Headings

  • rac1 GTP-Binding Protein
  • Protein Binding
  • Kinetics
  • IMP Dehydrogenase
  • Humans
  • HEK293 Cells
  • Guanosine Triphosphate
  • Cell Movement
  • Cell Membrane