Pathophysiological Functions of Rnd 3/ RhoE

Abstract

Rnd3, also known as RhoE, belongs to the Rnd subclass of the Rho family of small GTP-binding proteins. Rnd proteins are unique due to their inability to switch from a GTP-bound to GDP-bound conformation. Even though studies of the biological function of Rnd3 are far from being concluded, information is available regarding its expression pattern, cellular localization, and its activity, which can be altered depending on the conditions. The compiled data from these studies implies that Rnd3 may not be a traditional small GTPase. The basic role of Rnd3 is to report as an endogenous antagonist of RhoA signaling-mediated actin cytoskeleton dynamics, which specifically contributes to cell migration and neuron polarity. In addition, Rnd3 also plays a critical role in arresting cell cycle distribution, inhibiting cell growth, and inducing apoptosis and differentiation. Increasing data have shown that aberrant Rnd3 expression may be the leading cause of some systemic diseases; particularly highlighted in apoptotic cardiomyopathy, developmental arrhythmogenesis and heart failure, hydrocephalus, as well as tumor metastasis and chemotherapy resistance. Therefore, a better understanding of the function of Rnd3 under different physiological and pathological conditions, through the use of suitable models, would provide a novel insight into the origin and treatment of multiple human diseases.

Retracted Article: MiR-182-5p and miR-96-5p increased hepatocellular carcinoma cell mobility, proliferation and cisplatin resistance partially by targeting RND3

“…16 In addition, in HCC, RND3 has also been proposed as either an oncogene or tumor suppressor gene in other cancer types. 13,18 In the present research, we rst veried that miR-182-5p and miR-96-5p increased HCC cell mobility, proliferation and cisplatin resistance partially by targeting RND3. Using a selective ROCK1/2 kinase inhibitor, YC-S 7001, as well as specic knockdown of ROCK1 and ROCK2, we found that both ROCK paralogs are involved in the HCC cell mobility-promoting effect of RND3 knockdown.…”

“…RND3 (Rho Family GTPase 3, also named RhoE) is a member of the RND protein subgroup belonging to the Ras homologous (Rho) family of GTPases although the RND proteins exhibit no GTPase activity. 12,13 Mechanistically, RND3 was found to competitively bind with Rho Associated Coiled-Coil Containing Protein Kinase 1 (ROCK1), preventing the activation of the latter by Ras Homolog Family Member A (RhoA) although the existence of RhoA-ROCK1-independent activity of RND3 has also been anticipated. 13 The clinical signicance of RND3 as a tumor suppressor gene in HCC was rst reported by Luo et al, who documented a signicant association between RND3 downregulation and HCC progression, resulting in patients' shortened survival.…”

“…12,13 Mechanistically, RND3 was found to competitively bind with Rho Associated Coiled-Coil Containing Protein Kinase 1 (ROCK1), preventing the activation of the latter by Ras Homolog Family Member A (RhoA) although the existence of RhoA-ROCK1-independent activity of RND3 has also been anticipated. 13 The clinical signicance of RND3 as a tumor suppressor gene in HCC was rst reported by Luo et al, who documented a signicant association between RND3 downregulation and HCC progression, resulting in patients' shortened survival. 14 Downregulation of RND3 gene expression in HCC was later conrmed by Grise et al and Ma et al; both of them also reported a signicant increase in HCC cell mobility in vitro aer RND3 knockdown.…”

Upregulation of RND3 Affects Trophoblast Proliferation, Apoptosis, and Migration at the Maternal-Fetal Interface

“…An in depth understanding of the molecular mechanisms and functions of RND3 in different tissues is required to identify novel therapeutic targets for the diagnosis and treatment of human diseases (Jie et al, 2015). RND3 plays a complex role in cells.…”

“…Most members of the Rho family can cycle by the ratio of an active, GTP-bound conformation and an inactive, GDP-bound conformation, and GDP/GTP exchange process is regulated by several classes of regulators, including GDP/GTP exchange factors (GEFs) and GTPase-activating proteins (GAPs) (David et al, 2012). But RND3 (also known as RhoE), a unique member of the Rnd subfamily, is found that it do not hydrolyze GTP, and thus remains constitutively active upon expression without regulation by GEFs/GAPs cycling (Jie et al, 2015). Foster et al (1996) firstly cloned RND3 which was shown to display no detectable GTPase activity, similar to RND1 and RND2, indicating that RND3 has a different manner in which to regulate its activity.…”