Regulation of local GTP availability controls RAC1 activity and cell invasion

Anna Bianchi-Smiraglia (), David W. Wolff, Daniel J. Marston, Zhiyong Deng, Zhannan Han, Sudha Moparthy, Rebecca M. Wombacher, Ashley L. Mussell, Shichen Shen, Jialin Chen, Dong-Hyun Yun, Anderson O’Brien Cox, Cristina M. Furdui, Edward Hurley, Maria Laura Feltri, Jun Qu, Thomas Hollis, Jules Berlin Nde Kengne, Bernard Fongang, Rui J. Sousa, Mikhail E. Kandel, Eugene S. Kandel, Klaus M. Hahn and Mikhail A. Nikiforov ()
Additional contact information
Anna Bianchi-Smiraglia: Roswell Park Comprehensive Cancer Center
David W. Wolff: Wake Forest University Baptist Medical Center
Daniel J. Marston: University of North Carolina at Chapel Hill
Zhiyong Deng: Wake Forest University Baptist Medical Center
Zhannan Han: Wake Forest University Baptist Medical Center
Sudha Moparthy: Wake Forest University Baptist Medical Center
Rebecca M. Wombacher: Roswell Park Comprehensive Cancer Center
Ashley L. Mussell: Roswell Park Comprehensive Cancer Center
Shichen Shen: State University of New York at Buffalo
Jialin Chen: Wake Forest University Baptist Medical Center
Dong-Hyun Yun: Wake Forest University Baptist Medical Center
Anderson O’Brien Cox: Wake Forest University Baptist Medical Center
Cristina M. Furdui: Wake Forest University Baptist Medical Center
Edward Hurley: Department of Biochemistry and Neurology, Hunter James Kelly Research Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo
Maria Laura Feltri: Department of Biochemistry and Neurology, Hunter James Kelly Research Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo
Jun Qu: State University of New York at Buffalo
Thomas Hollis: Wake Forest School of Medicine
Jules Berlin Nde Kengne: University of Houston
Bernard Fongang: University of Texas Health Science Center at San Antonio
Rui J. Sousa: University of Texas Health Science Center at San Antonio
Mikhail E. Kandel: Groq, 400 Castro St #600
Eugene S. Kandel: Roswell Park Comprehensive Cancer Center
Klaus M. Hahn: University of North Carolina at Chapel Hill
Mikhail A. Nikiforov: Wake Forest University Baptist Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26324-6

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