The Role of Rho GTPases in VEGF Signaling in Cancer Cells

Abstract

Vascular endothelial growth factors (VEGFs) consist of five molecules (VEGFA through D as well as placental growth factor) which are crucial for regulating key cellular and tissue functions. The role of VEGF and its intracellular signaling and downstream molecular pathways have been thoroughly studied. Activation of VEGF signal transduction can be initiated by the molecules’ binding to two classes of transmembrane receptors: (1) the VEGF tyrosine kinase receptors (VEGF receptors 1 through 3) and (2) the neuropilins (NRP1 and 2). The involvement of Rho GTPases in modulating VEGFA signaling in both cancer cells and endothelial cells has also been well established. Additionally, different isoforms of Rho GTPases, namely, RhoA, RhoC, and RhoG, have been shown to regulate VEGF expression as well as blood vessel formation. This review article will explore how Rho GTPases modulate VEGF signaling and the consequences of such interaction on cancer progression.

Targeting neuropilin-1 interactions is a promising anti-tumor strategy

“…[ 92 – 96 ] Binding of VEGFA to NRP1 promotes RhoA activation and then, activated RhoA contributes to the degradation of p27kip1, which in turn, promotes tumor cell proliferation. This has been demonstrated in skin cancer, prostate cancer, and glioblastoma [ 60 , 97 – 99 ] [Figure 4 ]. In addition, PDGF and its receptor (PDGFR) are angiogenic factors closely associated with tumorigenesis and progression, and their overexpression is a common feature in different cancers.…”

Novel engineered, membrane‐tethered VEGF‐A variants promote formation of filopodia, proliferation, survival, and cord or tube formation by endothelial cells via persistent VEGFR2/ERK signaling and activation of CDC42/ROCK pathways

“…47,48 Our findings are consistent with those of previous studies that implicate activation of receptor tyrosine kinases by different growth factors in the polymerization of F-actin filaments (reviewed in Refs. [37,49]), which make up the supporting cytoskeletal elements of filopodia.…”

“…CDC42 is a small Rho-GTPase that regulates remodeling of the actin cytoskeleton and extension of filopodia in many cell types, RhoA is implicated in the formation of stress fibers and focal adhesions, and Rac1 promotes lamellipodium formation. 36,37 Using AAV2-transduced hRECs to maximize the percentage (80%-90%) of cells expressing the eVEGF-38 protein, we measured activated GTP-bound forms of CDC42 and RhoA with the G-LISA® assay. CDC42, but not RhoA, was significantly activated in hRECs expressing eVEGF-38 relative to the GFP control; the total levels of CDC42 and RhoA proteins were similar for both groups (Figure 5A).…”

In vivo Functional Genomics for Undiagnosed Patients: The Impact of Small GTPases Signaling Dysregulation at Pan-Embryo Developmental Scale

“…On the other hand, RHOA is fundamental for the reorganization of the F-actin during cytoskeleton remodeling in endothelial cells and angiogenesis, which is highly relevant for pathology onset and progression (Merajver and Usmani, 2005). Importantly, both in vitro and in vivo models showed that cytoskeletal dynamics tuned by RHO molecules act under direct VEGF signaling to impact migratory movements and trafficking of endothelial cells during angiogenesis (Soga et al, 2001;van Nieuw Amerongen et al, 2003;Garret et al, 2007;Lamalice et al, 2007;El Baba et al, 2020). In this regard, inhibitors acting on the RHO/ROCK-mediated pathway are becoming a promising therapeutic approach for vascular endothelial growth factor (VEGF)-induced angiogenesis in the context of tumor progression and invasion (van der Meel et al, 2011;Chen et al, 2014).…”