Lipidation of Small GTPase Cdc42 As Regulator of Its Physiological and Pathophysiological Functions

Overview

Journal Front Physiol

Date 2023 Jan 26

PMID 36699687

Authors

Alexander Wirth

Evgeni Ponimaskin

Affiliations

Soon will be listed here.

Abstract

The protein cell division cycle 42 (Cdc42) is a small GTPase of the Rho family regulating a plethora of physiological functions in a tissue, cell and subcellular-specific manner participating in multiple signaling pathways. Since the corresponding signaling hubs are mainly organized along the cellular membranes, cytosolic proteins like Cdc42 need to be properly targeted and held at the membrane. Here, lipid modifications come into play: Cdc42 can be associated with membranes by different lipid anchors including prenylation (Cdc42-prenyl) and palmitoylation (Cdc42-palm). While Cdc42-prenyl is ubiquitously expressed, Cdc42-palm splicing variant in mainly expressed in the brain. Mechanisms underlying Cdc42 lipidation as well as its regulation are the main topic of this review. Furthermore, we will discuss the functional importance of Cdc42 lipid modifications with the focus on the role of different lipids in regulating defined Cdc42 functions. Finally, we will provide an overview of the possible implementation of Cdc42 lipidation in pathological conditions and different diseases.

Citing Articles

CDC42 Regulates the ERK Pathway to Improve Oxygen‒Glucose Deprivation/Reoxygenation-Induced Neural Oxidative Stress and Apoptosis.

Hao L, Jia H, Wei F, Zhang J, Zhang J, Guo C Mol Neurobiol. 2025; .

PMID: 40035949 DOI: 10.1007/s12035-025-04768-x.

The influences of ARHGEF9 on myoblasts migration and differentiation.

Li S, Xu J, Zhang W, Liu Y, Tong H, Liu B J Muscle Res Cell Motil. 2025; .

PMID: 39992578 DOI: 10.1007/s10974-025-09692-0.

Oleate Promotes Triple-Negative Breast Cancer Cell Migration by Enhancing Filopodia Formation through a PLD/Cdc42-Dependent Pathway.

Guo Z, Bergeron K, Mounier C Int J Mol Sci. 2024; 25(7).

PMID: 38612766 PMC: 11012533. DOI: 10.3390/ijms25073956.

References

Zhang F, Casey P . Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem. 1996; 65:241-69. DOI: 10.1146/annurev.bi.65.070196.001325. View

Yang W, Di Vizio D, Kirchner M, Steen H, Freeman M . Proteome scale characterization of human S-acylated proteins in lipid raft-enriched and non-raft membranes. Mol Cell Proteomics. 2009; 9(1):54-70. PMC: 2808267. DOI: 10.1074/mcp.M800448-MCP200. View

Bekhouche B, Tourville A, Ravichandran Y, Tacine R, Abrami L, Dussiot M . A toxic palmitoylation of Cdc42 enhances NF-κB signaling and drives a severe autoinflammatory syndrome. J Allergy Clin Immunol. 2020; 146(5):1201-1204.e8. DOI: 10.1016/j.jaci.2020.03.020. View

Casey P, Seabra M . Protein prenyltransferases. J Biol Chem. 1996; 271(10):5289-92. DOI: 10.1074/jbc.271.10.5289. View

Chen F, Ma L, Parrini M, Mao X, Lopez M, Wu C . Cdc42 is required for PIP(2)-induced actin polymerization and early development but not for cell viability. Curr Biol. 2000; 10(13):758-65. DOI: 10.1016/s0960-9822(00)00571-6. View

Gorenberg E, Tieze S, Yucel B, Zhao H, Chou V, Wirak G . Identification of substrates of palmitoyl protein thioesterase 1 highlights roles of depalmitoylation in disulfide bond formation and synaptic function. PLoS Biol. 2022; 20(3):e3001590. PMC: 9004782. DOI: 10.1371/journal.pbio.3001590. View

Evans T, Brown M, Fraser E, Northup J . Purification of the major GTP-binding proteins from human placental membranes. J Biol Chem. 1986; 261(15):7052-9. View

Scott E, Reuter J, Luo L . Small GTPase Cdc42 is required for multiple aspects of dendritic morphogenesis. J Neurosci. 2003; 23(8):3118-23. PMC: 6742332. View

Marks P, Kwiatkowski D . Genomic organization and chromosomal location of murine Cdc42. Genomics. 1996; 38(1):13-8. DOI: 10.1006/geno.1996.0586. View

10.

Adams A, Johnson D, Longnecker R, Sloat B, Pringle J . CDC42 and CDC43, two additional genes involved in budding and the establishment of cell polarity in the yeast Saccharomyces cerevisiae. J Cell Biol. 1990; 111(1):131-42. PMC: 2116161. DOI: 10.1083/jcb.111.1.131. View

11.

Mattioli C, Rom A, Franke V, Imami K, Arrey G, Terne M . Alternative 3' UTRs direct localization of functionally diverse protein isoforms in neuronal compartments. Nucleic Acids Res. 2018; 47(5):2560-2573. PMC: 6411841. DOI: 10.1093/nar/gky1270. View

12.

Etienne-Manneville S, Hall A . Rho GTPases in cell biology. Nature. 2002; 420(6916):629-35. DOI: 10.1038/nature01148. View

13.

Shinjo K, Koland J, Hart M, Narasimhan V, Johnson D, Evans T . Molecular cloning of the gene for the human placental GTP-binding protein Gp (G25K): identification of this GTP-binding protein as the human homolog of the yeast cell-division-cycle protein CDC42. Proc Natl Acad Sci U S A. 1990; 87(24):9853-7. PMC: 55272. DOI: 10.1073/pnas.87.24.9853. View

14.

Nishitani-Isa M, Mukai K, Honda Y, Nihira H, Tanaka T, Shibata H . Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation. J Exp Med. 2022; 219(6). PMC: 9059393. DOI: 10.1084/jem.20211889. View

15.

Wirth A, Chen-Wacker C, Wu Y, Gorinski N, Filippov M, Pandey G . Dual lipidation of the brain-specific Cdc42 isoform regulates its functional properties. Biochem J. 2013; 456(3):311-22. DOI: 10.1042/BJ20130788. View

16.

Yap K, Xiao Y, Friedman B, Je H, Makeyev E . Polarizing the Neuron through Sustained Co-expression of Alternatively Spliced Isoforms. Cell Rep. 2016; 15(6):1316-28. PMC: 4870516. DOI: 10.1016/j.celrep.2016.04.012. View

17.

Stypulkowski E, Asangani I, Witze E . The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division. Sci Signal. 2018; 11(511). PMC: 5914505. DOI: 10.1126/scisignal.aam8705. View

18.

Kanadome T, Yokoi N, Fukata Y, Fukata M . Systematic Screening of Depalmitoylating Enzymes and Evaluation of Their Activities by the Acyl-PEGyl Exchange Gel-Shift (APEGS) Assay. Methods Mol Biol. 2019; 2009:83-98. DOI: 10.1007/978-1-4939-9532-5_7. View

19.

Scandaglia M, Benito E, Morenilla-Palao C, Fiorenza A, Del Blanco B, Coca Y . Fine-tuned SRF activity controls asymmetrical neuronal outgrowth: implications for cortical migration, neural tissue lamination and circuit assembly. Sci Rep. 2015; 5:17470. PMC: 4671020. DOI: 10.1038/srep17470. View

20.

Chen L, Liao G, Yang L, Campbell K, Nakafuku M, Kuan C . Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly. Proc Natl Acad Sci U S A. 2006; 103(44):16520-5. PMC: 1637614. DOI: 10.1073/pnas.0603533103. View