Small GTPases最新文献

A growing body of evidence implicates requisite roles for GTP and its binding proteins (Rho GTPases) in the cascade of events leading to physiological insulin secretion from the islet beta cell. Interestingly, chronic exposure of these cells to hyperglycaemic conditions appears to result in sustained activation of specific Rho GTPases (e.g. Rac1) leading to significant alterations in cellular functions including defects in mitochondrial function and nuclear collapse culminating in beta cell demise. One of the objectives of this review is to highlight our current understanding of the regulatory roles of GTP and Rho GTPases in normal islet function (e.g. proliferation and insulin secretion) as well potential defects in these signalling molecules and metabolic pathways that could contribute islet beta cell dysfunction and loss of functional beta cell mass leading to the onset of diabetes. Potential knowledge gaps in this field and possible avenues for future research are also highlighted.Abbreviations: ARNO: ADP-ribosylation factor nucleotide binding site opener; CML: carboxyl methylation; Epac: exchange protein directly activated by cAMP; ER stress: endoplasmic reticulum stress; FTase: farnesyltransferase; GAP: GTPase activating protein; GDI: GDP dissociation inhibitor; GEF: guanine nucleotide exchange factor; GGTase: geranylgeranyltransferase; GGpp: geranylgeranylpyrophosphate; GGPPS: geranylgeranyl pyrophosphate synthase; GSIS: glucose-stimulated insulin secretion; HGPRTase: hypoxanthine-guanine phosphoribosyltransferase; IMPDH: inosine monophosphate dehydrogenase; α-KIC: α-ketoisocaproic acid; MPA: mycophenolic acid; MVA: mevalonic acid; NDPK: nucleoside diphosphate kinase; NMPK: nucleoside monophosphate kinase; Nox2: phagocyte-like NADPH oxidase; PAK-I: p21-activated kinase-I; β-PIX: β-Pak-interacting exchange factor; PRMT: protein arginine methyltransferase; Rac1: ras-related C3 botulinum toxin substrate 1; Tiam1: T-cell lymphoma invasion and metastasis-inducing protein 1; Trx-1: thioredoxin-1; Vav2: vav guanine nucleotide exchange factor 2.

Megakaryocytes (MKs) are the bone marrow (BM) cells that generate blood platelets by a process that requires: i) polyploidization responsible for the increased MK size and ii) cytoplasmic organization leading to extension of long pseudopods, called proplatelets, through the endothelial barrier to allow platelet release into blood. Low level of localized RHOA activation prevents actomyosin accumulation at the cleavage furrow and participates in MK polyploidization. In the platelet production, RHOA and CDC42 play opposite, but complementary roles. RHOA inhibits both proplatelet formation and MK exit from BM, whereas CDC42 drives the development of the demarcation membranes and MK migration in BM. Moreover, the RhoA or Cdc42 MK specific knock-out in mice and the genetic alterations in their down-stream effectors in human induce a thrombocytopenia demonstrating their key roles in platelet production. A better knowledge of Rho-GTPase signalling is thus necessary to develop therapies for diseases associated with platelet production defects.Abbreviations: AKT: Protein Kinase BARHGEF2: Rho/Rac Guanine Nucleotide Exchange Factor 2ARP2/3: Actin related protein 2/3BM: Bone marrowCDC42: Cell division control protein 42 homologCFU-MK: Colony-forming-unit megakaryocyteCIP4: Cdc42-interacting protein 4mDIA: DiaphanousDIAPH1; Protein diaphanous homolog 1ECT2: Epithelial Cell Transforming Sequence 2FLNA: Filamin AGAP: GTPase-activating proteins or GTPase-accelerating proteinsGDI: GDP Dissociation InhibitorGEF: Guanine nucleotide exchange factorHDAC: Histone deacetylaseLIMK: LIM KinaseMAL: Megakaryoblastic leukaemiaMARCKS: Myristoylated alanine-rich C-kinase substrateMKL: Megakaryoblastic leukaemiaMLC: Myosin light chainMRTF: Myocardin Related Transcription FactorOTT: One-Twenty Two ProteinPACSIN2: Protein Kinase C And Casein Kinase Substrate In Neurons 2PAK: P21-Activated KinasePDK: Pyruvate Dehydrogenase kinasePI3K: Phosphoinositide 3-kinasePKC: Protein kinase CPTPRJ: Protein tyrosine phosphatase receptor type JRAC: Ras-related C3 botulinum toxin substrate 1RBM15: RNA Binding Motif Protein 15RHO: Ras homologousROCK: Rho-associated protein kinaseSCAR: Suppressor of cAMP receptorSRF: Serum response factorSRC: SarcTAZ: Transcriptional coactivator with PDZ motifTUBB1: Tubulin β1VEGF: Vascular endothelial growth factorWAS: Wiskott Aldrich syndromeWASP: Wiskott Aldrich syndrome proteinWAVE: WASP-family verprolin-homologous proteinWIP: WASP-interacting proteinYAP: Yes-associated protein.

Since the discovery by Madaule and Axel in 1985 of the first Ras homologue (Rho) protein in Aplysia and its human orthologue RhoB, membership in the Rho GTPase family has grown to 20 proteins, with representatives in all eukaryotic species. These GTPases are molecular switches that cycle between active (GTP bound) and inactivate (GDP bound) states. The exchange of GDP for GTP on Rho GTPases is facilitated by guanine exchange factors (GEFs). Approximately 80 Rho GEFs have been identified to date, and only a few GEFs associate with microtubules. The guanine nucleotide exchange factor H1, GEF-H1, is a unique GEF that associates with microtubules and is regulated by the polymerization state of microtubule networks. This review summarizes the regulation and functions of GEF-H1 and discusses the roles of GEF-H1 in human diseases.

Platelets are master regulators and effectors of haemostasis with increasingly recognized functions as mediators of inflammation and immune responses. The Rho family of GTPase members Rac1, Cdc42 and RhoA are known to be major components of the intracellular signalling network critical to platelet shape change and morphological dynamics, thus playing a major role in platelet spreading, secretion and thrombus formation. Initially linked to the regulation of actomyosin contraction and lamellipodia formation, recent reports have uncovered non-canonical functions of platelet RhoGTPases in the regulation of reactive oxygen species (ROS), where intrinsically generated ROS modulate platelet function and contribute to thrombus formation. Platelet RhoGTPases orchestrate oxidative processes and cytoskeletal rearrangement in an interconnected manner to regulate intracellular signalling networks underlying platelet activity and thrombus formation. Herein we review our current knowledge of the regulation of platelet ROS generation by RhoGTPases and their relationship with platelet cytoskeletal reorganization, activation and function.

While Rho-signalling controlling vascular contraction is a canonical mechanism, with the modern approaches used in research, we are advancing our understanding and details into this pathway are often uncovered. RhoA-mediated Rho-kinase is the major regulator of vascular smooth muscle cells and a key player manoeuvring other functions in these cells. The discovery of new interactions, such as oxidative stress and hydrogen sulphide with Rho signalling are emerging addition not only in the physiology of the smooth muscle, but especially in the pathophysiology of vascular diseases. Likewise, the interplay between ageing and Rho-kinase in the vasculature has been recently considered. Importantly, in smooth muscle contraction, this pathway may also be affected by sex hormones, and consequently, sex-differences. This review provides an overview of Rho signalling mediating vascular contraction and focuses on recent topics discussed in the literature affecting this pathway such as ageing, sex differences and oxidative stress.

Rho GTPases are known to play an essential role in fundamental processes such as defining cell shape, polarity and migration. As such, the majority of Rho GTPases localize and function at, or close to, the plasma membrane. However, it is becoming increasingly clear that a number of Rho family proteins are also associated with the Golgi complex, where they not only regulate events at this organelle but also more widely across the cell. Given the central location of this organelle, and the numerous membrane trafficking pathways that connect it to both the endocytic and secretory systems of cells, it is clear that the Golgi is fundamental for maintaining cellular homoeostasis. In this review, we describe these GTPases in the context of how they regulate Golgi architecture, membrane trafficking into and away from this organelle, and cell polarity and migration. We summarize the key findings that show the growing importance of the pool of Rho GTPases associated with Golgi function, namely Cdc42, RhoA, RhoD, RhoBTB1 and RhoBTB3, and we discuss how they act in concert with other key families of molecules associated with the Golgi, including Rab GTPases and matrix proteins.

Cell invasion is associated with numerous patho-physiologic states including cell development and metastatic dissemination. This process couples the activation of cell motility with the capacity to degrade the extracellular matrix, thereby permitting cells to pass through basal membranes. Invasion is sustained by the actions of invadosomes, an ensemble of subcellular structures with high functional homology. Invadosomes are 3D acto-adhesive structures that can also mediate local extracellular matrix degradation through the controlled delivery of proteases. Intracellular RHO GTPases play a central role in the regulation of invadosomes where their complex interplay regulates multiple invadosome functions. This review aims to provide an overview of the synergistic activities of the small GTPases in invadosome biology. This broad-based review also reinforces the importance of the spatiotemporal regulation of small GTPases and the impact of this process on invadosome dynamics.

Rnd proteins constitute a subfamily of Rho GTPases represented in mammals by Rnd1, Rnd2 and Rnd3. Despite their GTPase structure, their specific feature is the inability to hydrolyse GTP-bound nucleotide. This aspect makes them atypical among Rho GTPases. Rnds are regulated for their expression at the transcriptional or post-transcriptional levels and they are activated through post-translational modifications and interactions with other proteins. Rnd proteins are mainly involved in the regulation of the actin cytoskeleton and cell proliferation. Whereas Rnd3 is ubiquitously expressed, Rnd1 and 2 are tissue-specific. Increasing data has described their important role during development and diseases. Herein, we describe their involvement in physiological and pathological conditions with a focus on the neuronal and vascular systems, and summarize their implications in tumorigenesis.

Epithelial folding is a common means to execute morphogenetic movements. The gastrulating Drosophila embryo offers many examples of epithelial folding events, including the ventral, cephalic, and dorsal furrows. Each of these folding events is associated with changes in intracellular contractility and/or cytoskeleton structures that autonomously promote epithelial folding. Here, we review accumulating evidence that suggests the progression and final form of ventral, cephalic, and dorsal furrows are also influenced by the behaviour of cells neighbouring these folds. We further discuss the prevalence and importance of junctional rearrangements during epithelial folding events, suggesting adherens junction components are prime candidates to modulate the transmission of the intercellular forces that influence folding events. Finally, we discuss how recently developed methods that enable precise spatial and/or temporal control of protein activity allow direct testing of molecular models of morphogenesis in vivo.

Mitochondria and peroxisomes are highly dynamic, multifunctional organelles. Both perform key roles for cellular physiology and homoeostasis by mediating bioenergetics, biosynthesis, and/or signalling. To support cellular function, they must be properly distributed, of proper size, and be able to interact with other organelles. Accumulating evidence suggests that the small atypical GTPase Miro provides a central signalling node to coordinate mitochondrial as well as peroxisomal dynamics. In this review, I summarize our current understanding of Miro-dependent functions and molecular mechanisms underlying the proper distribution, size and function of mitochondria and peroxisomes.