Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011 Sep;23(9):1415-23.
doi: 10.1016/j.cellsig.2011.04.001. Epub 2011 Apr 16.

Cdc42 in oncogenic transformation, invasion, and tumorigenesis

Kristy Stengel  1 , Yi Zheng
Affiliations
Review

Cdc42 in oncogenic transformation, invasion, and tumorigenesis

Kristy Stengel et al. Cell Signal. 2011 Sep.

Abstract

The Rho family of GTPases represents a class of Ras-related signaling molecules often deregulated in cancer. Rho GTPases switch from a GDP-bound, inactive state to a GTP-bound, active state in response to extracellular stimuli such as mitogens and extracellular matrix. In addition, Rho GTPase signaling can be altered in response to cell intrinsic factors such as changes in oncogenic or tumor suppressor signaling. In their active form, these proteins bind to a number of effector molecules, activating signaling cascades which regulate a variety of cellular processes including cytoskeletal reorganization, cell cycle progression, cell polarity and transcription. Here, we focus on one Rho family member, Cdc42, which is overexpressed in a number of human cancers. Consistent with a role in the promotion of tumorigenesis, activating mutations in Cdc42 and guanine nucleotide exchange factors are transforming, while inhibition of Cdc42 activity can impinge on cellular transformation following the activation of oncoproteins or loss of tumor suppressor function. Furthermore, Cdc42 activity has been implicated in the invasive phenotype which characterizes tumor metastasis, further suggesting that Cdc42 may be a useful target for therapeutic intervention. However, several recent studies in mice have unveiled a putative tumor suppressor function of Cdc42 in several tissue types which may involve cell polarity maintenance, suggesting that the role of Cdc42 in cancer development is complex and may be cell type specific.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Biochemical regulation of Cdc42 activity by three classes of regulators
In response to stimulatory signals, activated GEFs catalyze the dissociation of GDP and binding of GTP to Cdc42. In its active, GTP-bound form, Cdc42 binds to effector molecules, leading to the activation of a variety of signaling cascades regulating cellular processes such as proliferation, survival, invasion and migration. GAP proteins enhance the intrinsic GTPase activity of Cdc42, resulting in GTP hydrolysis and inactivation of Cdc42. Cdc42 activity is further inhibited by GDIs which sequester Cdc42 away from cell membranes, thus preventing its activation.
Figure 2
Figure 2. Cdc42 and its regulators are deregulated in cancer cells
While fast-cycling Cdc42 mutant can transform NIH 3T3 cells, Cdc42 is found overexpressed in a variety of human tumors, consistent with its role as an oncoprotein. Although no activating mutation of Cdc42 has been detected in primary tumors, inappropriate activation of GEFs, which activate Cdc42, is associated with tumorigenesis, while negative regulators of Cdc42 activity, GAPs and GDIs, can suppress tumorigenesis.
Figure 3
Figure 3. Cdc42 mediates cellular transformation by oncogenic mutations of EGFR or Ras
Loss of Cdc42 prevents transformation by oncogenic Ras, possibly mediated by its ability to enhance the activity PI3K and Raf, two well-characterized Ras effector pathways. In addition, Cdc42 is required for EGFR-mediated cellular transformation. Normal level of Cdc42 activity, through the regulation of the ubiquitin ligase c-Cbl, is necessary for the endocytosis, degradation, and/or recycling of EGFR receptor. In the absence of Cdc42, EGFR is rapidly degraded, suppressing EGFR-mediated transformation.
Figure 4
Figure 4. Cdc42 activation contributes to tumor cell invasion and migration
Cdc42 activation promotes cancer cell invasion through the regulation of invadopodia formation (A). Via its activity in mediating actin polymerization through N-WASP-Arp2/3 complex, Cdc42 promotes invadopodia structure formation. Additionally, through the IQGAP-mediated regulation of exocyst function, Cdc42 regulates the accumulation of matrix metalloproteinases at the tips of invadopodia, facilitating extracellular matrix degradation. Cdc42 activity is involved in both mesenchymal and amoeboid cell migration, while its ability to regulate MMP-mediated matrix degradation may be important for both mesenchymal and collective cell migration (B).
Figure 5
Figure 5. Cdc42 can be tumor suppressive by maintaining proper tissue/cell polarity
Cdc42 modulates the activity of a variety of effector pathways to control cell polarity. The ability of Cdc42 to maintain epithelial cell polarity and associated cell adhesion through the maintenance of adherens junctions, and its regulatory role in asymmetric cell division of stem and progenitor cells, are possible mechanisms for Cdc42-mediated tumor suppression.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Sinha S, Yang W. Cell Signal. 2008;20:1927–1934. - PubMed
    1. Dovas A, Cox D. Commun Integr Biol. 2010;3:101–105. - PMC - PubMed
    1. Peterson FC, Penkert RR, Volkman BF, Prehoda KE. Mol Cell. 2004;13:665–676. - PubMed
    1. Tcherkezian J, Lamarche-Vane N. Biol Cell. 2007;99:67–86. - PubMed
    1. Olofsson B. Cell Signal. 1999;11:545–554. - PubMed