Role Of GTPases Research Articles

Role of GTPases in Driving Mitoribosome Assembly.

Mitoribosomes catalyze essential protein synthesis within mitochondria. Mitoribosome biogenesis is assisted by an increasing number of assembly factors, among which guanosine triphosphate hydrolases (GTPases) are the most abundant class. Here, we review recent progress in our understanding of mitoribosome assembly GTPases. We describe their shared and specific features and mechanisms of action, compare them with their bacterial counterparts, and discuss their possible roles in the assembly of small or large mitoribosomal subunits and the formation of the monosome by establishing quality-control checkpoints during these processes. Furthermore, following the recent unification of the nomenclature for the mitoribosomal proteins, we also propose a unified nomenclature for mitoribosome assembly GTPases.

Role of GTPases in the Regulation of Mitochondrial Dynamics in Alzheimer's Disease and CNS-Related Disorders.

Data obtained from several studies have shown that mitochondria are involved and play a central role in the progression of several distinct pathological conditions. Morphological alterations and disruptions on the functionality of mitochondria may be related to metabolic and energy deficiency in neurons in a neurodegenerative disorder. Several recent studies demonstrate the linkage between neurodegeneration and mitochondrial dynamics in the spectrum of a promising era called precision mitochondrial medicine. In this review paper, an analysis of the correlation between mitochondria, Alzheimer's disease, and other central nervous system (CNS)-related disorders like the Parkinson's disease and the autism spectrum disorder is under discussion. The role of GTPases like the mfn1, mfn2, opa1, and dlp1 in mitochondrial fission and fusion is also under investigation, influencing mitochondrial population and leading to oxidative stress and neuronal damage.

Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis?

Autism spectrum disorder is a heterogeneous disease, and numerous alterations of gene expression come into play to attempt to explain potential molecular and pathophysiological causes. Abnormalities of brain development and connectivity associated with alterations in cytoskeletal rearrangement, neuritogenesis and elongation of axons and dendrites might represent or contribute to the structural basis of autism pathology. Slit/Robo signaling regulates cytoskeletal remodeling related to axonal and dendritic branching. Components of its signaling pathway (ABL and Cdc42) are suspected to be molecular bases of alterations of normal development. The present review describes the most important mechanisms underlying neuritogenesis, axon pathfinding and the role of GTPases in neurite outgrowth, with special emphasis on alterations associated with autism spectrum disorders. On the basis of analysis of publicly available microarray data, potential biomarkers of autism are discussed.

Detection of Small GTP Binding Proteins Showing GTPase and GTP/ATP Binding Activities in the Ovary of the American Cockroach, Periplaneta Americana, during Oogenesis

In the present study, the small GTP binding proteins involved in the regulatory mechanism of vitellogenin (Vg) endocytotic vesicles trafficking were detected, for the first time, in ovaries of the most basal hemimetabolus insect, Periplaneta americana during oogenesis. The ovarian GTPase activities were peaked during previtellogenic and early vitellogenic periods. Such activity coincides with vitellogenin receptors (VgRs) and clathrin early expression during these developmental periods, suggesting the importance of GTPases not only in the process of vesicle formation and fusion but also in the process of early fluid phase endocytosis. Two small peaks of activities were monitored during the late vitellogenic period (days 8 and 10), suggesting a possible role of GTPases in VgRs and clathrin recycling process. The [α32P]-GTP binding assay analysis in different tissues revealed the presence of small GTP binding proteins of molecular weights 25, 23 and 21 kDa in ovaries and head. However, a single binding signal band of 21 and 25 kDa was each detected in the fat bodies and muscles, respectively. No binding was detected in the midgut and Malpighian tubules. However, the 23 kDa protein detected was suggested as a probable cytosolic form of the 25 kDa protein. The competition assay results indicated that the small ovarian GTP binding proteins could also bind ATP, suggesting that like GTP, ATP is a regulatory nucleotide for the ovarian small proteins detected during oogenesis. The present study will pave the way for more understanding of the mechanisms that regulate Vg transport machinery in hemimetabolous insects.

Role of GTPases in control of microvascular permeability

Inflammatory mediators increase vascular permeability primarily by formation of intercellular gaps between endothelial cells of post-capillary venules. Under these conditions, endothelial cell-cell contacts such as adherens and tight junctions open to allow paracellular fluid passage. Small guanosine triphosphatases (GTPases) from the ras superfamily, primarily Rho GTPases (RhoA, Rac1, Cdc42) or Rap1 are known to regulate cell adhesion, in part by reorganization of the junction-associated cortical actin cytoskeleton. In this review, we will discuss the role of small GTPases for the maintenance of microvascular barrier functions under resting conditions as well as under conditions of increased permeability and their involvement in signalling pathways downstream of both barrier-stabilizing and inflammatory mediators. Rac1 and Cdc42 are the main GTPases required for barrier maintenance and stabilization, whereas RhoA negatively regulates barrier properties under both resting and inflammatory conditions. For Rac1 and RhoA, contrary functions under certain conditions have also been described. However, Rac1-mediated barrier destabilization in microvascular endothelium appears to be largely restricted to conditions of enhanced endothelial cell migration and thus to be more closely related to angiogenesis rather than to inflammation. Recent studies revealed that cAMP signalling, which is well known to be barrier protective, enhances barrier functions in part via Rap1-mediated activation of Rac1 and Cdc42 as well as by inhibition of RhoA. Moreover, barrier-stabilizing mediators directly activate Rac1 and Cdc42 or increase cAMP levels. On the other hand, several barrier-disruptive components appear to increase permeability by reduced formation of cAMP, leading to both inactivation of Rac1 and activation of RhoA.

Role of GTPases in Bacterial Ribosome Assembly

The assembly of the ribosome, a complex molecular machine composed of RNA and protein, is a poorly understood process. Recent work has demonstrated that GTPases are likely to play key roles in the assembly of ribosomes in bacteria and eukaryotes. This review highlights several bacterial ribosome assembly GTPases (RA-GTPases) and discusses possible functions for these proteins in the biogenesis of individual ribosomal subunits and subunit joining. RA-GTPases appear to link various aspects of the cell cycle and metabolism with translation. How these RA-GTPases may coordinate these connections are discussed.

Repression of ROCKII by GATA-1 Inhibits Cell Proliferation during Erythroid Maturation.

Rho family GTPases are key regulators of many different biological processes including cell motility, growth, and differentiation. Cdc42, Rac and Rho are the most extensively studied members of this family. Although the role of GTPases is becoming increasingly clear in blood cells, virtually nothing is known about the role of downstream effectors of Rho GTPases in hematopoiesis. Rho activates the serine/threonine protein kinases ROCKI and ROCKII. To determine the role of ROCK kinases in hematopoiesis, we generated mice deficient in the expression of ROCKI. Under steady state conditions, deficiency of ROCKI did not demonstrate any significant changes in peripheral blood white cell counts nor defects in the production of red cells compared to controls were observed. Since deficiency of ROCKI alone did not result in perturbed steady state erythropoiesis, we examined the role of ROCKII in this process. For these studies, we used an erythroid progenitor cell line derived from GATA-1 (G1E) null mice. These cells proliferate continuously in culture as developmentally arrested erythroid precursors and upon restoration of GATA-1 activity, undergo cell cycle arrest and terminal maturation in a fashion that largely recapitulates normal erythropoiesis. Using these cells, we generated a conditionally regulated system to study the consequences of ROCKII inactivation on erythropoiesis. We utilized a retroviral vector encoding the activated and kinase dead version of ROCKII by swapping the COOH-terminal negative regulatory portion of ROCKII with the estrogen receptor hormone binding domain. Specifically, we utilized a fused active and kinase dead ROCKII mutant to EGFP and to the estrogen receptor hormone binding domain, which can be stimulated by the estrogen analogs tamoxifen or 4-hydroxytamoxifen (4-HT). In contrast to a lack of a positive role for ROCKI in erythropoiesis, inactivation of ROCKII in erythroid progenitors in the absence of GATA-1 activation resulted in complete repression of cytokine mediated growth (n=4, p<0.001). Consistently, a dose dependent repression in the growth of these cells was also observed in the presence of two distinct ROCK kinase inhibitors (n=3, p<0.001). Importantly, when these cells were induced to differentiate by conditionally activating GATA-1, cells expressing the empty vector or the dominant negative version of ROCKII under went cell cycle arrest and terminal maturation as expected. In contrast, cells expressing the activated version of ROCKII, also under went terminal differentiation, however these cells continued to proliferate throughout the course of differentiation (n=3, p<0.005). To determine the mechanism(s) of growth repression in the absence of GATA-1 activation, we conducted survival and cell cycle analysis. Surprisingly, expression of dominant negative (DN) ROCKII in these cells did not induce apoptosis, but significantly impaired cell cycle entry, with majority of cells falling in the G1/G0 phase of cell cycle (n=5, p<0.005). The extensive arrest in cell cycle progression due to ROCKII inactivation in these cells was associated with complete loss of cyclinD1 expression. Our results reveal that ROCKI and ROCKII play distinct roles in erythropoiesis. Furthermore, in addition to its well established function as an activator of erythroid genes, GATA-1 also participates in a genetic program that inhibits cell proliferation by repressing the activation of ROCKII kinase. In summary, we demonstrate a novel aspect of cross talk between GATA-1 and Rho kinase ROCKII in erythropoietic development.

Role of GTPases in ribosome assembly

GTPases are a universally conserved class of regulatory proteins involved in such diverse cellular functions as signal transduction, translation, cytoskeleton formation, and intracellular transport. GTPases are also required for ribosome assembly in eukaryotes and bacteria, where they present themselves as possible regulatory molecules. Strikingly, in bacteria they represent the largest class of essential assembly factors. A review of their common structural, biochemical and genetic interactions is presented and integrated with models for their function in ribosome assembly.