Targeting Cdc42 in cancer

Abstract

Introduction The Rho GTPases are a family of proteins that control fundamental cellular processes in response to extracellular stimuli and internal programs. Rho GTPases function as molecular switches in which the GTP-bound proteins are active and GDP-bound proteins are inactive. This review will focus on one Rho family member, Cdc42, which is overexpressed in a number of human cancers, and which might provide new therapeutic targets in malignancies. Areas covered In this review the key regulators and effectors of Cdc42 and their molecular alterations are described. The complex interactions between the signaling cascades regulated by Cdc42 are also analyzed. Expert opinion While mutations in Cdc42 have not been reported in human cancer, aberrant expression of Cdc42 has been reported in a variety of tumor types and in some instances has been correlated with poor prognosis. Recently, it has been shown that Cdc42 activation by oncogenic Ras is crucial for Ras-mediated tumorigenesis, suggesting that targeting Cdc42 or its effectors might be useful in tumors harboring activating Ras mutations.

Early Steps of Jaagsiekte Sheep Retrovirus-Mediated Cell Transformation Involve the Interaction between Env and the RALBP1 Cellular Protein

“…By its GAP domain, it inactivates Rho GTPases such as CDC42 (a small GTPase of the Rho family) by hydrolyzing its GTP into GDP (51,52). In its active form (bound to GTP), CDC42 is able to mediate signaling cascades leading to activation of more than 20 downstream effectors involved in proliferation, migration, adhesion, and cytoskeleton remodeling (51); mTOR and p70S6K are among the effectors activated by CDC42 (53,54).…”

Two Small Molecules, ZCL278 and AZA197 Show Promise in Influencing Protein Interactions Involving the Ras-Related Protein Cell division cycle 42 [Cdc42] to Modulate Its Oncogenic Potential

“…As such, Cdc42 is a model protein system to characterize molecular details of Ras-related Protein-Protein Interactions [PPIs]. Progress has been made in understanding the pathogenesis of Cdc42-stimulated hyperactivity [5]. However, targeting small molecules towards PPIs involving Cdc42 have remained difficult, mainly because of the challenges in determining the most appropriate binding interfaces on the protein to target [6] [7].…”

“…Specifically targeting Cdc42 for therapeutic purposes has seen some recent progress [12] [13] [14], and a few reviews have highlighted the promise of these new approaches [5] [15]. Cdc42, which is post-translationally modified to target the periphery of the inner cell membrane where it functions, cycles between active GTP-bound and inactive GDP-bound states, and this process is regulated by Cdc42 has a six-stranded β-sheet, five α-helices, and a guanine nucleotidebinding site with a conserved sequence that recognizes the guanine base, the β-phosphate and a magnesium ion [16 Targeting these protein-binding surfaces to influence Cdc42 involved PPIs, while still a daunting challenge, remains vital as Cdc42-stimulated hyperactivity has been a hallmark of this protein's involvement in various cancers [23].…”

The Roles of Two miRNAs in Regulating the Immune Response of Sea Cucumber

“…In human, miR-137 has been extensively investigated and shown to play important roles in various cancers, cell cycle signaling, and embryonic stem cell development. Studies have demonstrated that miR-137 targets cell division control protein 42 (Cdc42), a Rho GTPase family protein up-regulated in many human cancer types, such as colorectal, lung, and breast cancers (Arias-Romero and Chernoff 2013). Through the inhibition of the Cdc42/PAK signaling pathway, miR-137 decreases the proliferation, invasion, and G0/G1 cell cycle progression of colorectal cancer cells (Liu et al 2011;Zhu et al 2013).…”