Spatiotemporal Control of Intracellular Membrane Trafficking by Rho GTPases

Abstract

As membrane-associated master regulators of cytoskeletal remodeling, Rho GTPases coordinate a wide range of biological processes such as cell adhesion, motility, and polarity. In the last years, Rho GTPases have also been recognized to control intracellular membrane sorting and trafficking steps directly; however, how Rho GTPase signaling is regulated at endomembranes is still poorly understood. In this review, we will specifically address the local Rho GTPase pools coordinating intracellular membrane trafficking with a focus on the endo-and exocytic pathways. We will further highlight the spatiotemporal molecular regulation of Rho signaling at endomembrane sites through Rho regulatory proteins, the GEFs and GAPs. Finally, we will discuss the contribution of dysregulated Rho signaling emanating from endomembranes to the development and progression of cancer.an inactive GDP-bound and an active GTP-bound state. Rho GDP/GTP cycling is tightly regulated by guanine nucleotide exchange factors (GEFs) that promote the formation of the active GTP-bound form through exchanging GDP for GTP. On the contrary, GTPase-activating proteins (GAPs) catalyze the intrinsic GTPase activity and promote the formation of inactive GDP-bound Rho. This inactive state can be subsequently recognized by guanine nucleotide dissociation inhibitors (GDIs), which sequester Rho GTPases in the cytosol [5,6] (Figure 1). Whereas classical Rho GTPases are regulated by GDP/GTP cycling, atypical Rho GTPases are regulated by other mechanisms that occur in particular at the transcriptional and post-translational level [7]. In the case of atypical Rho GTPases, GTP is usually constitutively bound, either because these Rho GTPases possess high intrinsic nucleotide exchange activity or have substitutions in their GTPase domain that prevent GTP hydrolysis.

Activin A and Cell-Surface GRP78 Are Novel Targetable RhoA Activators for Diabetic Kidney Disease

“…Downregulation by siRNA of MTJ-1, a co-chaperone required for cell-surface translocation of GRP78 [ 32 ], further supported a role for csGRP78 in HG-induced ROCK activation ( Figure 2 D). Given the important role of RhoA/ROCK in cytoskeletal reorganization and intracellular trafficking [ 33 ], we further assessed whether the movement of GRP78 to the cell surface in response to longer-term HG exposure could also be regulated by RhoA signaling. Interestingly, Figure 2 E shows that HG-induced csGRP78 localization, as assessed by the biotinylation of cell-surface proteins followed by immunoblotting for GRP78, was prevented by the ROCK inhibitor Y27632.…”

“…Interestingly, cell-surface expression of GRP78 was also significantly reduced by ROCK inhibition, suggesting that RhoA/ROCK activation promotes further translocation of GRP78 to the cell surface. The regulation of cellular trafficking through cytoskeletal changes by RhoA [ 33 ] is likely to be important for these observations, but this needs to be confirmed experimentally. Alternatively, ROCK inhibition was shown to downregulate the expression of cellular GRP78 in human pulmonary microvascular endothelial cells [ 48 ].…”

<p>Long Noncoding RNA <em>EBLN3P</em> Promotes the Progression of Liver Cancer via Alteration of microRNA-144-3p/DOCK4 Signal</p>

“…miRNAs control gene expression by binding to the 3′-UTR of the target gene, which causes mRNA cleavage or translational repression. 31 Rho GTPases play critical roles in the initiation and progression of various tumors; 32 however, the regulation of Rho GTPases in liver cancer remains largely unknown. Additionally, the role and molecular mechanism of DOCK4, an atypical Rho GEF, 33 in liver cancer are unknown.…”

TRP Channels Regulation of Rho GTPases in Brain Context and Diseases

“…However, detailed mechanisms by which TRPML1 regulates these processes are poorly understood. Rho GTPases are signaling nodes that coordinate membrane trafficking and lipid homeostasis (reviewed in Ridley, 2001;Olayioye et al, 2019). TRPML1 interactome reports (Figure 2) might reveal the mechanisms related to the coordination of cellular processes that lead to the neuropathological phenotype observed in MLIV (Krogsaeter et al, 2019).…”