» Articles » PMID: 27304967

Structural Mechanisms and Drug Discovery Prospects of Rho GTPases

Overview
Journal Cells
Publisher MDPI
Date 2016 Jun 16
PMID 27304967
Citations 23
Authors
Affiliations
Soon will be listed here.
Abstract

Rho GTPases regulate cellular morphology and dynamics, and some are key drivers of cancer progression. This superfamily offers attractive potential targets for therapeutic intervention, with RhoA, Rac1 and Cdc42 being prime examples. The challenges in developing agents that act on these signaling enzymes include the lack of obvious druggable pockets and their membrane-bound activities. However, progress in targeting the similar Ras protein is illuminating new strategies for specifically inhibiting oncogenic GTPases. The structures of multiple signaling and regulatory states of Rho proteins have been determined, and the post-translational modifications including acylation and phosphorylation points have been mapped and their functional effects examined. The development of inhibitors to probe the significance of overexpression and mutational hyperactivation of these GTPases underscores their importance in cancer progression. The ability to integrate in silico, in vitro, and in vivo investigations of drug-like molecules indicates the growing tractability of GTPase systems for lead optimization. Although no Rho-targeted drug molecules have yet been clinically approved, this family is clearly showing increasing promise for the development of precision medicine and combination cancer therapies.

Citing Articles

Effect of silencing Ras homolog family member C on proliferation, invasion, and migration of salivary adenoid cystic carcinoma.

Yu W, Zhao P, Shao Y, Xu Y, Xu J, Xie L Hua Xi Kou Qiang Yi Xue Za Zhi. 2024; 42(6):723-734.

PMID: 39610069 PMC: 11669934. DOI: 10.7518/hxkq.2024.2024092.


Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma.

Hao J, Han X, Huang H, Yu X, Fang J, Zhao J Nat Commun. 2023; 14(1):2262.

PMID: 37080989 PMC: 10119166. DOI: 10.1038/s41467-023-37397-w.


Light Activates Cdc42-Mediated Needle-Shaped Filopodia Formation the Integration of Small GTPases.

Liu L, Sui R, Li L, Zhang L, Zeng D, Ni X Cell Mol Bioeng. 2022; 15(6):599-609.

PMID: 36531863 PMC: 9751244. DOI: 10.1007/s12195-022-00743-x.


The Small GTPase CsRAC1 Is Important for Fungal Development and Pepper Anthracnose in Colletotrichum scovillei.

Lee N, Fu T, Shin J, Song Y, Jang D, Kim K Plant Pathol J. 2021; 37(6):607-618.

PMID: 34897252 PMC: 8666242. DOI: 10.5423/PPJ.OA.09.2021.0140.


Rho GTPase signalling networks in cancer cell transendothelial migration.

Rodenburg W, van Buul J Vasc Biol. 2021; 3(1):R77-R95.

PMID: 34738075 PMC: 8558887. DOI: 10.1530/VB-21-0008.


References
1.
Michaelson D, Silletti J, Murphy G, DEustachio P, Rush M, Philips M . Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding. J Cell Biol. 2001; 152(1):111-26. PMC: 2193662. DOI: 10.1083/jcb.152.1.111. View

2.
Parri M, Chiarugi P . Rac and Rho GTPases in cancer cell motility control. Cell Commun Signal. 2010; 8:23. PMC: 2941746. DOI: 10.1186/1478-811X-8-23. View

3.
Nassar N, Cancelas J, Zheng J, Williams D, Zheng Y . Structure-function based design of small molecule inhibitors targeting Rho family GTPases. Curr Top Med Chem. 2006; 6(11):1109-16. DOI: 10.2174/156802606777812095. View

4.
Kapp G, Liu S, Stein A, Wong D, Remenyi A, Yeh B . Control of protein signaling using a computationally designed GTPase/GEF orthogonal pair. Proc Natl Acad Sci U S A. 2012; 109(14):5277-82. PMC: 3325720. DOI: 10.1073/pnas.1114487109. View

5.
Rojas A, Fuentes G, Rausell A, Valencia A . The Ras protein superfamily: evolutionary tree and role of conserved amino acids. J Cell Biol. 2012; 196(2):189-201. PMC: 3265948. DOI: 10.1083/jcb.201103008. View