Editorial

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4 pages, 202 KiB

Open AccessEditorial

Diverse Physiological Functions and Regulatory Mechanisms for Signal-Transducing Small GTPases

by Takaya Satoh

Int. J. Mol. Sci. 2020, 21(19), 7291; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197291 - 02 Oct 2020

Cited by 2 | Viewed by 1247

Abstract

Diverse GTPases act as signal transducing enzymes in a variety of organisms and cell types [...] Full article

(This article belongs to the Special Issue Small GTPases 2019)

Research

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18 pages, 1810 KiB

Open AccessArticle

Regulation of De Novo Lipid Synthesis by the Small GTPase Rac1 in the Adipogenic Differentiation of Progenitor Cells from Mouse White Adipose Tissue

by Kiko Hasegawa, Nobuyuki Takenaka, Maaya Yamamoto, Yoshiki Sakoda, Atsu Aiba and Takaya Satoh

Int. J. Mol. Sci. 2023, 24(5), 4608; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054608 - 27 Feb 2023

Cited by 1 | Viewed by 1335

Abstract

White adipocytes act as lipid storage, and play an important role in energy homeostasis. The small GTPase Rac1 has been implicated in the regulation of insulin-stimulated glucose uptake in white adipocytes. Adipocyte-specific rac1-knockout (adipo-rac1-KO) mice exhibit atrophy of subcutaneous and [...] Read more.

White adipocytes act as lipid storage, and play an important role in energy homeostasis. The small GTPase Rac1 has been implicated in the regulation of insulin-stimulated glucose uptake in white adipocytes. Adipocyte-specific rac1-knockout (adipo-rac1-KO) mice exhibit atrophy of subcutaneous and epididymal white adipose tissue (WAT); white adipocytes in these mice are significantly smaller than controls. Here, we aimed to investigate the mechanisms underlying the aberrations in the development of Rac1-deficient white adipocytes by employing in vitro differentiation systems. Cell fractions containing adipose progenitor cells were obtained from WAT and subjected to treatments that induced differentiation into adipocytes. In concordance with observations in vivo, the generation of lipid droplets was significantly attenuated in Rac1-deficient adipocytes. Notably, the induction of various enzymes responsible for de novo synthesis of fatty acids and triacylglycerol in the late stage of adipogenic differentiation was almost completely suppressed in Rac1-deficient adipocytes. Furthermore, the expression and activation of transcription factors, such as the CCAAT/enhancer-binding protein (C/EBP) β, which is required for the induction of lipogenic enzymes, were largely inhibited in Rac1-deficient cells in both early and late stages of differentiation. Altogether, Rac1 is responsible for adipogenic differentiation, including lipogenesis, through the regulation of differentiation-related transcription. Full article

(This article belongs to the Special Issue Small GTPases 2022)

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14 pages, 2240 KiB

Open AccessArticle

The Intracellular Distribution of the Small GTPase Rho5 and Its Dimeric Guanidine Nucleotide Exchange Factor Dck1/Lmo1 Determine Their Function in Oxidative Stress Response

by Linnet Bischof, Franziska Schweitzer, Carolin C. Sterk and Jürgen J. Heinisch

Int. J. Mol. Sci. 2022, 23(14), 7896; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147896 - 18 Jul 2022

Cited by 3 | Viewed by 1846

Abstract

Rho5, the yeast homolog of human Rac1, is a small GTPase which regulates the cell response to nutrient and oxidative stress by inducing mitophagy and apoptosis. It is activated by a dimeric GEF composed of the subunits Dck1 and Lmo1. Upon stress, all [...] Read more.

Rho5, the yeast homolog of human Rac1, is a small GTPase which regulates the cell response to nutrient and oxidative stress by inducing mitophagy and apoptosis. It is activated by a dimeric GEF composed of the subunits Dck1 and Lmo1. Upon stress, all three proteins rapidly translocate from the cell surface (Rho5) and a diffuse cytosolic distribution (Dck1 and Lmo1) to mitochondria, with translocation of the GTPase depending on both GEF subunits. We here show that the latter associate with mitochondria independent from each other and from Rho5. The trapping of Dck1-GFP or GFP-Lmo1 to the mitochondrial surface by a specific nanobody fused to the transmembrane domain (TMD) of Fis1 results in a loss of function, mimicking the phenotypes of the respective gene deletions, dck1 or lmo1. Direct fusion of Rho5 to Fis1^TMD, i.e., permanent attachment to the mitochondria, also mimics the phenotypes of an rho5 deletion. Together, these data suggest that the GTPase needs to be activated at the plasma membrane prior to its translocation in order to fulfill its function in the oxidative stress response. This notion is substantiated by the observation that strains carrying fusions of Rho5 to the cell wall integrity sensor Mid2, confining the GTPase to the plasma membrane, retained their function. We propose a model in which Rho5 activated at the plasma membrane represses the oxidative stress response under standard growth conditions. This repression is relieved upon its GEF-mediated translocation to mitochondria, thus triggering mitophagy and apoptosis. Full article

(This article belongs to the Special Issue Small GTPases 2022)

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15 pages, 8911 KiB

Open AccessArticle

Inhibition of Protein Prenylation of GTPases Alters Endothelial Barrier Function

by Muhammad Aslam, Christian Troidl, Christian Tanislav, Susanne Rohrbach, Dursun Gündüz and Christian W. Hamm

Int. J. Mol. Sci. 2020, 21(1), 2; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010002 - 18 Dec 2019

Cited by 8 | Viewed by 3764

Abstract

The members of Rho family of GTPases, RhoA and Rac1 regulate endothelial cytoskeleton dynamics and hence barrier integrity. The spatial activities of these GTPases are regulated by post-translational prenylation. In the present study, we investigated the effect of prenylation inhibition on the endothelial [...] Read more.

The members of Rho family of GTPases, RhoA and Rac1 regulate endothelial cytoskeleton dynamics and hence barrier integrity. The spatial activities of these GTPases are regulated by post-translational prenylation. In the present study, we investigated the effect of prenylation inhibition on the endothelial cytoskeleton and barrier properties. The study was carried out in human umbilical vein endothelial cells (HUVEC) and protein prenylation is manipulated with various pharmacological inhibitors. Inhibition of either complete prenylation using statins or specifically geranylgeranylation but not farnesylation has a biphasic effect on HUVEC cytoskeleton and permeability. Short-term treatment inhibits the spatial activity of RhoA/Rho kinase (Rock) to actin cytoskeleton resulting in adherens junctions (AJ) stabilization and ameliorates thrombin-induced barrier disruption whereas long-term inhibition results in collapse of endothelial cytoskeleton leading to increased basal permeability. These effects are reversed by supplementing the cells with geranylgeranyl but not farnesyl pyrophosphate. Moreover, long-term inhibition of protein prenylation results in basal hyper activation of RhoA/Rock signaling that is antagonized by a specific Rock inhibitor or an activation of cAMP signaling. In conclusion, inhibition of geranylgeranylation in endothelial cells (ECs) exerts biphasic effect on endothelial barrier properties. Short-term inhibition stabilizes AJs and hence barrier function whereas long-term treatment results in disruption of barrier properties. Full article

(This article belongs to the Special Issue Small GTPases 2019)

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21 pages, 5876 KiB

Open AccessArticle

Analysis of Functional Domains in Rho5, the Yeast Homolog of Human Rac1 GTPase, in Oxidative Stress Response

by Carolin Sterk, Lauren Gräber, Hans-Peter Schmitz and Jürgen J. Heinisch

Int. J. Mol. Sci. 2019, 20(22), 5550; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225550 - 07 Nov 2019

Cited by 8 | Viewed by 2825

Abstract

The small GTPase Rho5 of Saccharomyces cerevisiae is required for proper regulation of different signaling pathways, which includes the response to cell wall, osmotic, nutrient, and oxidative stress. We here show that proper in vivo function and intracellular distribution of Rho5 depends on [...] Read more.

The small GTPase Rho5 of Saccharomyces cerevisiae is required for proper regulation of different signaling pathways, which includes the response to cell wall, osmotic, nutrient, and oxidative stress. We here show that proper in vivo function and intracellular distribution of Rho5 depends on its hypervariable region at the carboxyterminal end, which includes the CAAX box for lipid modification, a preceding polybasic region (PBR) carrying a serine residue, and a 98 amino acid–specific insertion only present in Rho5 of S. cerevisiae but not in its human homolog Rac1. Results from trapping GFP-Rho5 variants to the mitochondrial surface suggest that the GTPase needs to be activated at the plasma membrane prior to its translocation to mitochondria in order to fulfil its role in oxidative stress response. These findings are supported by heterologous expression of a codon-optimized human RAC1 gene, which can only complement a yeast rho5 deletion in a chimeric fusion with RHO5 sequences that restore the correct spatiotemporal distribution of the encoded protein. Full article

(This article belongs to the Special Issue Small GTPases 2019)

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15 pages, 3016 KiB

Open AccessArticle

A Crucial Role for the Small GTPase Rac1 Downstream of the Protein Kinase Akt2 in Insulin Signaling that Regulates Glucose Uptake in Mouse Adipocytes

by Nobuyuki Takenaka, Mika Nakao, Sayaka Matsui and Takaya Satoh

Int. J. Mol. Sci. 2019, 20(21), 5443; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215443 - 31 Oct 2019

Cited by 16 | Viewed by 2815

Abstract

Insulin-stimulated glucose uptake is mediated by translocation of the glucose transporter GLUT4 to the plasma membrane in adipocytes and skeletal muscle cells. In both types of cells, phosphoinositide 3-kinase and the protein kinase Akt2 have been implicated as critical regulators. In skeletal muscle, [...] Read more.

Insulin-stimulated glucose uptake is mediated by translocation of the glucose transporter GLUT4 to the plasma membrane in adipocytes and skeletal muscle cells. In both types of cells, phosphoinositide 3-kinase and the protein kinase Akt2 have been implicated as critical regulators. In skeletal muscle, the small GTPase Rac1 plays an important role downstream of Akt2 in the regulation of insulin-stimulated glucose uptake. However, the role for Rac1 in adipocytes remains controversial. Here, we show that Rac1 is required for insulin-dependent GLUT4 translocation also in adipocytes. A Rac1-specific inhibitor almost completely suppressed GLUT4 translocation induced by insulin or a constitutively activated mutant of phosphoinositide 3-kinase or Akt2. Constitutively activated Rac1 also enhanced GLUT4 translocation. Insulin-induced, but not constitutively activated Rac1-induced, GLUT4 translocation was abrogated by inhibition of phosphoinositide 3-kinase or Akt2. On the other hand, constitutively activated Akt2 caused Rac1 activation, and insulin-induced Rac1 activation was suppressed by an Akt2-specific inhibitor. Moreover, GLUT4 translocation induced by a constitutively activated mutant of Akt2 or Rac1 was diminished by knockdown of another small GTPase RalA. RalA was activated by a constitutively activated mutant of Akt2 or Rac1, and insulin-induced RalA activation was suppressed by an Akt2- or Rac1-specific inhibitor. Collectively, these results suggest that Rac1 plays an important role in the regulation of insulin-dependent GLUT4 translocation downstream of Akt2, leading to RalA activation in adipocytes. Full article

(This article belongs to the Special Issue Small GTPases 2019)

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17 pages, 3182 KiB

Open AccessArticle

Rab39a and Rab39b Display Different Intracellular Distribution and Function in Sphingolipids and Phospholipids Transport

by Julián Gambarte Tudela, Julio Buonfigli, Agustín Luján, Mariano Alonso Bivou, Ignacio Cebrián, Anahí Capmany and María Teresa Damiani

Int. J. Mol. Sci. 2019, 20(7), 1688; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20071688 - 04 Apr 2019

Cited by 20 | Viewed by 4221

Abstract

Rab GTPases define the identity and destiny of vesicles. Some of these small GTPases present isoforms that are expressed differentially along developmental stages or in a tissue-specific manner, hence comparative analysis is difficult to achieve. Here, we describe the intracellular distribution and function [...] Read more.

Rab GTPases define the identity and destiny of vesicles. Some of these small GTPases present isoforms that are expressed differentially along developmental stages or in a tissue-specific manner, hence comparative analysis is difficult to achieve. Here, we describe the intracellular distribution and function in lipid transport of the poorly characterized Rab39 isoforms using typical cell biology experimental tools and new ones developed in our laboratory. We show that, despite their amino acid sequence similarity, Rab39a and Rab39b display non-overlapping intracellular distribution. Rab39a localizes in the late endocytic pathway, mainly at multivesicular bodies. In contrast, Rab39b distributes in the secretory network, at the endoplasmic reticulum/cis-Golgi interface. Therefore, Rab39a controls trafficking of lipids (sphingomyelin and phospholipids) segregated at multivesicular bodies, whereas Rab39b transports sphingolipids biosynthesized at the endoplasmic reticulum-Golgi factory. Interestingly, lyso bis-phosphatidic acid is exclusively transported by Rab39a, indicating that both isoforms do not exert identical functions in lipid transport. Conveniently, the requirement of eukaryotic lipids by the intracellular pathogen Chlamydia trachomatis rendered useful for dissecting and distinguishing Rab39a- and Rab39b-controlled trafficking pathways. Our findings provide comparative insights about the different subcellular distribution and function in lipid transport of the two Rab39 isoforms. Full article

(This article belongs to the Special Issue Small GTPases)

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16 pages, 2013 KiB

Open AccessArticle

Exploring Novel Functions of the Small GTPase Ypt1p under Heat-Shock by Characterizing a Temperature-Sensitive Mutant Yeast Strain, ypt1-G80D

by Chang Ho Kang, Joung Hun Park, Eun Seon Lee, Seol Ki Paeng, Ho Byoung Chae, Yong Hun Chi and Sang Yeol Lee

Int. J. Mol. Sci. 2019, 20(1), 132; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20010132 - 01 Jan 2019

Cited by 3 | Viewed by 3503

Abstract

In our previous study, we found that Ypt1p, a Rab family small GTPase protein, exhibits a stress-driven structural and functional switch from a GTPase to a molecular chaperone, and mediates thermo tolerance in Saccharomyces cerevisiae. In the current study, we focused on [...] Read more.

In our previous study, we found that Ypt1p, a Rab family small GTPase protein, exhibits a stress-driven structural and functional switch from a GTPase to a molecular chaperone, and mediates thermo tolerance in Saccharomyces cerevisiae. In the current study, we focused on the temperature-sensitive ypt1-G80D mutant, and found that the mutant cells are highly sensitive to heat-shock, due to a deficiency in the chaperone function of Ypt1p^G80D. This defect results from an inability of the protein to form high molecular weight polymers, even though it retains almost normal GTPase function. The heat-stress sensitivity of ypt1-G80D cells was partially recovered by treatment with 4-phenylbutyric acid, a chemical chaperone. These findings indicate that loss of the chaperone function of Ypt1p^G80D underlies the heat sensitivity of ypt1-G80D cells. We also compared the proteomes of YPT1 (wild-type) and ypt1-G80D cells to investigate Ypt1p-controlled proteins under heat-stress conditions. Our findings suggest that Ypt1p controls an abundance of proteins involved in metabolism, protein synthesis, cellular energy generation, stress response, and DNA regulation. Finally, we suggest that Ypt1p essentially regulates fundamental cellular processes under heat-stress conditions by acting as a molecular chaperone. Full article

(This article belongs to the Special Issue Small GTPases)

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16 pages, 7900 KiB

Open AccessArticle

Interaction of the GTPase Elongation Factor Like-1 with the Shwachman-Diamond Syndrome Protein and Its Missense Mutations

by Abril Gijsbers, Diana Carolina Montagut, Alfonso Méndez-Godoy, Davide Altamura, Michele Saviano, Dritan Siliqi and Nuria Sánchez-Puig

Int. J. Mol. Sci. 2018, 19(12), 4012; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19124012 - 12 Dec 2018

Cited by 10 | Viewed by 3184

Abstract

The Shwachman-Diamond Syndrome (SDS) is a disorder arising from mutations in the genes encoding for the Shwachman-Bodian-Diamond Syndrome (SBDS) protein and the GTPase known as Elongation Factor Like-1 (EFL1). Together, these proteins remove the anti-association factor eIF6 from the surface of the pre-60S [...] Read more.

The Shwachman-Diamond Syndrome (SDS) is a disorder arising from mutations in the genes encoding for the Shwachman-Bodian-Diamond Syndrome (SBDS) protein and the GTPase known as Elongation Factor Like-1 (EFL1). Together, these proteins remove the anti-association factor eIF6 from the surface of the pre-60S ribosomal subunit to promote the formation of mature ribosomes. SBDS missense mutations can either destabilize the protein fold or affect surface epitopes. The molecular alterations resulting from the latter remain largely unknown, although some evidence suggest that binding to EFL1 may be affected. We further explored the effect of these SBDS mutations on the interaction with EFL1, and showed that all tested mutations disrupted the binding to EFL1. Binding was either severely weakened or almost abolished, depending on the assessed mutation. In higher eukaryotes, SBDS is essential for development, and lack of the protein results in early lethality. The existence of patients whose only source of SBDS consists of that with surface missense mutations highlights the importance of the interaction with EFL1 for their function. Additionally, we studied the interaction mechanism of the proteins in solution and demonstrated that binding consists of two independent and cooperative events, with domains 2–3 of SBDS directing the initial interaction with EFL1, followed by docking of domain 1. In solution, both proteins exhibited large flexibility and consisted of an ensemble of conformations, as demonstrated by Small Angle X-ray Scattering (SAXS) experiments. Full article

(This article belongs to the Special Issue Small GTPases)

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19 pages, 4590 KiB

Open AccessArticle

Identification and Characterization of the Entamoeba Histolytica Rab8a Binding Protein: A Cdc50 Homolog

by Yuki Hanadate, Yumiko Saito-Nakano, Kumiko Nakada-Tsukui and Tomoyoshi Nozaki

Int. J. Mol. Sci. 2018, 19(12), 3831; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19123831 - 30 Nov 2018

Cited by 4 | Viewed by 3168

Abstract

Membrane traffic plays a pivotal role in virulence in the enteric protozoan parasite Entamoeba histolytica. EhRab8A small GTPase is a key regulator of membrane traffic at the endoplasmic reticulum (ER) of this protist and is involved in the transport of plasma membrane [...] Read more.

Membrane traffic plays a pivotal role in virulence in the enteric protozoan parasite Entamoeba histolytica. EhRab8A small GTPase is a key regulator of membrane traffic at the endoplasmic reticulum (ER) of this protist and is involved in the transport of plasma membrane proteins. Here we identified the binding proteins of EhRab8A. The Cdc50 homolog, a non-catalytic subunit of lipid flippase, was identified as an EhRab8A binding protein candidate by affinity coimmunoprecipitation. Binding of EhRab8A to EhCdc50 was also confirmed by reciprocal immunoprecipitation and blue-native polyacrylamide gel electrophoresis, the latter of which revealed an 87 kDa complex. Indirect immunofluorescence imaging with and without Triton X100 showed that endogenous EhCdc50 localized on the surface in the absence of permeabilizing agent but was observed on the intracellular structures and overlapped with the ER marker Bip when Triton X100 was used. Overexpression of N-terminal HA-tagged EhCdc50 impaired its translocation to the plasma membrane and caused its accumulation in the ER. As reported previously in other organisms, overexpression and accumulation of Cdc50 in the ER likely inhibited surface transport and function of the plasma membrane lipid flippase P4-ATPase. Interestingly, HA-EhCdc50-expressing trophozoites gained resistance to miltefosine, which is consistent with the prediction that HA-EhCdc50 overexpression caused its accumulation in the ER and mislocalization of the unidentified lipid flippase. Similarly, EhRab8A gene silenced trophozoites showed increased resistance to miltefosine, supporting EhRab8A-dependent transport of EhCdc50. This study demonstrated for the first time that EhRab8A mediates the transport of EhCdc50 and lipid flippase P4-ATPase from the ER to the plasma membrane. Full article

(This article belongs to the Special Issue Small GTPases)

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10 pages, 2318 KiB

Open AccessArticle

TBC1D21 Potentially Interacts with and Regulates Rap1 during Murine Spermatogenesis

by Chih-Chun Ke, Ying-Hung Lin, Ya-Yun Wang, Ying-Yu Wu, Mei-Feng Chen, Wei-Chi Ku, Han-Sun Chiang and Tsung-Hsuan Lai

Int. J. Mol. Sci. 2018, 19(11), 3292; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19113292 - 23 Oct 2018

Cited by 11 | Viewed by 2926

Abstract

Few papers have focused on small guanosine triphosphate (GTP)-binding proteins and their regulation during spermatogenesis. TBC1D21 genes (also known as male germ cell RAB GTPase-activating protein MGCRABGAP) are related to sterility, as determined through cDNA microarray testing of human testicular tissues exhibiting spermatogenic [...] Read more.

Few papers have focused on small guanosine triphosphate (GTP)-binding proteins and their regulation during spermatogenesis. TBC1D21 genes (also known as male germ cell RAB GTPase-activating protein MGCRABGAP) are related to sterility, as determined through cDNA microarray testing of human testicular tissues exhibiting spermatogenic defects. TBC1D21 is a protein specifically expressed in the testes that exhibits specific localizations of elongating and elongated spermatids during mammalian spermiogenesis. Furthermore, through co-immunoprecipitation (co-IP) and nano liquid chromatography–tandem mass spectrometry (nano LC–MS/MS), Rap1 has been recognized as a potential TBC1D21 interactor. This study determined the possible roles of Rap1 and TBC1D21 during mammalian spermiogenesis. First, the binding ability between Rap1 and TBC1D21 was verified using co-IP. Second, the stronger signals of Rap1 expressed in elongating and elongated murine spermatids extracted from testicular sections, namely spermatogonia, spermatocytes, and round spermatids, were compared. Third, Rap1 and TBC1D21 exhibited similar localizations at postacrosomal regions of spermatids and at the midpieces of mature sperms, through isolated male germ cells. Fourth, the results of an activating Rap1 pull-down assay indicated that TBC1D21 overexpression inactivates Rap1 activity in cell models. In conclusion, TBC1D21 may interact with and potentially regulate Rap1 during murine spermatogenesis. Full article

(This article belongs to the Special Issue Small GTPases)

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11 pages, 2419 KiB

Open AccessArticle

CDC42 Negatively Regulates Testis-Specific SEPT12 Polymerization

by Chia-Yen Huang, Ya-Yun Wang, Ying-Liang Chen, Mei-Feng Chen, Han-Sun Chiang, Pao-Lin Kuo and Ying-Hung Lin

Int. J. Mol. Sci. 2018, 19(9), 2627; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092627 - 05 Sep 2018

Cited by 10 | Viewed by 3581

Abstract

Septin (SEPT) genes encode well-preserved polymerizing GTP-binding cytoskeletal proteins. The cellular functions of SEPTs consist of mitosis, cytoskeletal remodeling, cell polarity, and vesicle trafficking through interactions with various types of cytoskeletons. We discovered that mutated SEPTIN12 in different codons resulted in [...] Read more.

Septin (SEPT) genes encode well-preserved polymerizing GTP-binding cytoskeletal proteins. The cellular functions of SEPTs consist of mitosis, cytoskeletal remodeling, cell polarity, and vesicle trafficking through interactions with various types of cytoskeletons. We discovered that mutated SEPTIN12 in different codons resulted in teratozoospermia or oligozoospermia. In mouse models with a defective Septin12 allele, sperm morphology was abnormal, sperm count decreased, and sperms were immotile. However, the regulators of SEPT12 are completely unknown. Some studies have indicated that CDC42 negatively regulates the polymerization of SEPT2/6/7 complexes in mammalian cell lines. In this study, we investigated whether CDC42 modulates SEPT12 polymerization and is involved in the terminal differentiation of male germ cells. First, through scanning electron microscopy analysis, we determined that the loss of Septin12 caused defective sperm heads. This indicated that Septin12 is critical for the formation of sperm heads. Second, CDC42 and SEPT12 were similarly localized in the perinuclear regions of the manchette at the head of elongating spermatids, neck region of elongated spermatids, and midpiece of mature spermatozoa. Third, wild-type CDC42 and CDC42Q61L (a constitutive-acting-mutant) substantially repressed SEPT12 polymerization, but CDC42T17N (a dominant-negative-acting mutant) did not, as evident through ectopic expression analysis. We concluded that CDC42 negatively regulates SEPT12 polymerization and is involved in terminal structure formation of sperm heads. Full article

(This article belongs to the Special Issue Small GTPases)

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15 pages, 7959 KiB

Open AccessArticle

Kinesin-2 Controls the Motility of RAB5 Endosomes and Their Association with the Spindle in Mitosis

by Emanuela Pupo, Daniele Avanzato, Marco Scianna, Amanda Oldani, Guido Serini and Letizia Lanzetti

Int. J. Mol. Sci. 2018, 19(9), 2575; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092575 - 30 Aug 2018

Cited by 3 | Viewed by 3941

Abstract

RAB5 is a small GTPase that belongs to the wide family of Rab proteins and localizes on early endosomes. In its active GTP-bound form, RAB5 recruits downstream effectors that, in turn, are responsible for distinct aspects of early endosome function, including their movement [...] Read more.

RAB5 is a small GTPase that belongs to the wide family of Rab proteins and localizes on early endosomes. In its active GTP-bound form, RAB5 recruits downstream effectors that, in turn, are responsible for distinct aspects of early endosome function, including their movement along microtubules. We previously reported that, at the onset of mitosis, RAB5positive vesicles cluster around the spindle poles and, during metaphase, move along spindle microtubules. RNAi-mediated depletion of the three RAB5 isoforms delays nuclear envelope breakdown at prophase and severely affects chromosome alignment and segregation. Here we show that depletion of the Kinesin-2 motor complex impairs long-range movement of RAB5 endosomes in interphase cells and prevents localization of these vesicles at the spindle during metaphase. Similarly to the effect caused by RAB5 depletion, functional ablation of Kinesin-2 delays nuclear envelope breakdown resulting in prolonged prophase. Altogether these findings suggest that endosomal transport at the onset of mitosis is required to control timing of nuclear envelope breakdown. Full article

(This article belongs to the Special Issue Small GTPases)

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17 pages, 13092 KiB

Open AccessArticle

The Small Yeast GTPase Rho5 and Its Dimeric GEF Dck1/Lmo1 Respond to Glucose Starvation

by Hans-Peter Schmitz, Arne Jendretzki, Carolin Sterk and Jürgen J. Heinisch

Int. J. Mol. Sci. 2018, 19(8), 2186; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19082186 - 26 Jul 2018

Cited by 15 | Viewed by 4382

Abstract

Rho5 is a small GTPase of Saccharomyces cerevisiae and a homolog of mammalian Rac1. The latter regulates glucose metabolism and actin cytoskeleton dynamics, and its misregulation causes cancer and a variety of other diseases. In yeast, Rho5 has been implicated in different signal [...] Read more.

Rho5 is a small GTPase of Saccharomyces cerevisiae and a homolog of mammalian Rac1. The latter regulates glucose metabolism and actin cytoskeleton dynamics, and its misregulation causes cancer and a variety of other diseases. In yeast, Rho5 has been implicated in different signal transduction pathways, governing cell wall integrity and the responses to high medium osmolarity and oxidative stress. It has also been proposed to affect mitophagy and apoptosis. Here, we demonstrate that Rho5 rapidly relocates from the plasma membrane to mitochondria upon glucose starvation, mediated by its dimeric GDP/GTP exchange factor (GEF) Dck1/Lmo1. A function in response to glucose availability is also suggested by synthetic genetic phenotypes of a rho5 deletion with gpr1, gpa2, and sch9 null mutants. On the other hand, the role of mammalian Rac1 in regulating the action cytoskeleton does not seem to be strongly conserved in S. cerevisiae Rho5. We propose that Rho5 serves as a central hub in integrating various stress conditions, including a crosstalk with the cAMP/PKA (cyclic AMP activating protein kinase A) and Sch9 branches of glucose signaling pathways. Full article

(This article belongs to the Special Issue Small GTPases)

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20 pages, 5326 KiB

Open AccessArticle

The Role of Trio, a Rho Guanine Nucleotide Exchange Factor, in Glomerular Podocytes

by Mirela Maier, Cindy Baldwin, Lamine Aoudjit and Tomoko Takano

Int. J. Mol. Sci. 2018, 19(2), 479; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020479 - 06 Feb 2018

Cited by 12 | Viewed by 6276

Abstract

Nephrotic syndrome is a kidney disease featured by heavy proteinuria. It is caused by injury to the specialized epithelial cells called “podocytes” within the filtration unit of the kidney, glomerulus. Previous studies showed that hyperactivation of the RhoGTPase, Rac1, in podocytes causes podocyte [...] Read more.

Nephrotic syndrome is a kidney disease featured by heavy proteinuria. It is caused by injury to the specialized epithelial cells called “podocytes” within the filtration unit of the kidney, glomerulus. Previous studies showed that hyperactivation of the RhoGTPase, Rac1, in podocytes causes podocyte injury and glomerulosclerosis (accumulation of extracellular matrix in the glomerulus). However, the mechanism by which Rac1 is activated during podocyte injury is unknown. Trio is a guanine nucleotide exchange factor (GEF) known to activate Rac1. By RNA-sequencing, we found that Trio mRNA is abundantly expressed in cultured human podocytes. Trio mRNA was also significantly upregulated in humans with minimal change disease and focal segmental glomerulosclerosis, two representative causes of nephrotic syndrome. Reduced expression of Trio in cultured human podocytes decreased basal Rac1 activity, cell size, attachment to laminin, and motility. Furthermore, while the pro-fibrotic cytokine, transforming growth factor β1 increased Rac1 activity in control cells, it decreases Rac1 activity in cells with reduced Trio expression. This was likely due to simultaneous activation of the Rac1-GTPase activation protein, CdGAP. Thus, Trio is important in the basal functions of podocytes and may also contribute to glomerular pathology, such as sclerosis, via Rac1 activation. Full article

(This article belongs to the Special Issue Small GTPases)

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Review

Jump to: Editorial, Research

26 pages, 427 KiB

Open AccessReview

Physiological and Pathological Roles of the Cytohesin Family in Neurons

by Akiko Ito, Masahiro Fukaya, Hirotsugu Okamoto and Hiroyuki Sakagami

Int. J. Mol. Sci. 2022, 23(9), 5087; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095087 - 03 May 2022

Cited by 3 | Viewed by 2561

Abstract

The cytohesin proteins, consisting of four closely related members (cytohesins-1, -2, -3, and -4), are a subfamily of the Sec7 domain-containing guanine nucleotide exchange factors for ADP ribosylation factors (Arfs), which are critical regulators of membrane trafficking and actin cytoskeleton remodeling. Recent advances [...] Read more.

The cytohesin proteins, consisting of four closely related members (cytohesins-1, -2, -3, and -4), are a subfamily of the Sec7 domain-containing guanine nucleotide exchange factors for ADP ribosylation factors (Arfs), which are critical regulators of membrane trafficking and actin cytoskeleton remodeling. Recent advances in molecular biological techniques and the development of a specific pharmacological inhibitor for cytohesins, SecinH3, have revealed the functional involvement of the cytohesin–Arf pathway in diverse neuronal functions from the formation of axons and dendrites, axonal pathfinding, and synaptic vesicle recycling, to pathophysiological processes including chronic pain and neurotoxicity induced by proteins related to neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer’s disease. Here, we review the physiological and pathological roles of the cytohesin–Arf pathway in neurons and discuss the future directions of this research field. Full article

(This article belongs to the Special Issue Small GTPases 2022)

21 pages, 4476 KiB

Open AccessReview

Integration of Rap1 and Calcium Signaling

by Ramoji Kosuru and Magdalena Chrzanowska

Int. J. Mol. Sci. 2020, 21(5), 1616; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051616 - 27 Feb 2020

Cited by 29 | Viewed by 7528

Abstract

Ca²⁺ is a universal intracellular signal. The modulation of cytoplasmic Ca²⁺ concentration regulates a plethora of cellular processes, such as: synaptic plasticity, neuronal survival, chemotaxis of immune cells, platelet aggregation, vasodilation, and cardiac excitation–contraction coupling. Rap1 GTPases are ubiquitously expressed binary [...] Read more.

Ca²⁺ is a universal intracellular signal. The modulation of cytoplasmic Ca²⁺ concentration regulates a plethora of cellular processes, such as: synaptic plasticity, neuronal survival, chemotaxis of immune cells, platelet aggregation, vasodilation, and cardiac excitation–contraction coupling. Rap1 GTPases are ubiquitously expressed binary switches that alternate between active and inactive states and are regulated by diverse families of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Active Rap1 couples extracellular stimulation with intracellular signaling through secondary messengers—cyclic adenosine monophosphate (cAMP), Ca²⁺, and diacylglycerol (DAG). Much evidence indicates that Rap1 signaling intersects with Ca²⁺ signaling pathways to control the important cellular functions of platelet activation or neuronal plasticity. Rap1 acts as an effector of Ca²⁺ signaling when activated by mechanisms involving Ca²⁺ and DAG-activated (CalDAG-) GEFs. Conversely, activated by other GEFs, such as cAMP-dependent GEF Epac, Rap1 controls cytoplasmic Ca²⁺ levels. It does so by regulating the activity of Ca²⁺ signaling proteins such as sarcoendoplasmic reticulum Ca²⁺-ATPase (SERCA). In this review, we focus on the physiological significance of the links between Rap1 and Ca²⁺ signaling and emphasize the molecular interactions that may offer new targets for the therapy of Alzheimer’s disease, hypertension, and atherosclerosis, among other diseases. Full article

(This article belongs to the Special Issue Small GTPases 2022)

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19 pages, 6480 KiB

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Rabs in Signaling and Embryonic Development

by Sonya Nassari, Tomas Del Olmo and Steve Jean

Int. J. Mol. Sci. 2020, 21(3), 1064; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21031064 - 05 Feb 2020

Cited by 13 | Viewed by 7644

Abstract

Rab GTPases play key roles in various cellular processes. They are essential, among other roles, to membrane trafficking and intracellular signaling events. Both trafficking and signaling events are crucial for proper embryonic development. Indeed, embryogenesis is a complex process in which cells respond [...] Read more.

Rab GTPases play key roles in various cellular processes. They are essential, among other roles, to membrane trafficking and intracellular signaling events. Both trafficking and signaling events are crucial for proper embryonic development. Indeed, embryogenesis is a complex process in which cells respond to various signals and undergo dramatic changes in their shape, position, and function. Over the last few decades, cellular studies have highlighted the novel signaling roles played by Rab GTPases, while numerous studies have shed light on the important requirements of Rab proteins at various steps of embryonic development. In this review, we aimed to generate an overview of Rab contributions during animal embryogenesis. We first briefly summarize the involvement of Rabs in signaling events. We then extensively highlight the contribution of Rabs in shaping metazoan development and conclude with new approaches that will allow investigation of Rab functions in vivo. Full article

(This article belongs to the Special Issue Small GTPases 2022)

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16 pages, 1716 KiB

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The Hypervariable Region of K-Ras4B Governs Molecular Recognition and Function

by Hazem Abdelkarim, Avik Banerjee, Patrick Grudzien, Nicholas Leschinsky, Mahmoud Abushaer and Vadim Gaponenko

Int. J. Mol. Sci. 2019, 20(22), 5718; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225718 - 14 Nov 2019

Cited by 10 | Viewed by 3377

Abstract

The flexible C-terminal hypervariable region distinguishes K-Ras4B, an important proto-oncogenic GTPase, from other Ras GTPases. This unique lysine-rich portion of the protein harbors sites for post-translational modification, including cysteine prenylation, carboxymethylation, phosphorylation, and likely many others. The functions of the hypervariable region are [...] Read more.

The flexible C-terminal hypervariable region distinguishes K-Ras4B, an important proto-oncogenic GTPase, from other Ras GTPases. This unique lysine-rich portion of the protein harbors sites for post-translational modification, including cysteine prenylation, carboxymethylation, phosphorylation, and likely many others. The functions of the hypervariable region are diverse, ranging from anchoring K-Ras4B at the plasma membrane to sampling potentially auto-inhibitory binding sites in its GTPase domain and participating in isoform-specific protein–protein interactions and signaling. Despite much research, there are still many questions about the hypervariable region of K-Ras4B. For example, mechanistic details of its interaction with plasma membrane lipids and with the GTPase domain require further clarification. The roles of the hypervariable region in K-Ras4B-specific protein–protein interactions and signaling are incompletely defined. It is also unclear why post-translational modifications frequently found in protein polylysine domains, such as acetylation, glycation, and carbamoylation, have not been observed in K-Ras4B. Expanding knowledge of the hypervariable region will likely drive the development of novel highly-efficient and selective inhibitors of K-Ras4B that are urgently needed by cancer patients. Full article

(This article belongs to the Special Issue Small GTPases 2019)

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23 pages, 1961 KiB

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The Small GTPase Arf6: An Overview of Its Mechanisms of Action and of Its Role in Host–Pathogen Interactions and Innate Immunity

by Tim Van Acker, Jan Tavernier and Frank Peelman

Int. J. Mol. Sci. 2019, 20(9), 2209; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092209 - 05 May 2019

Cited by 54 | Viewed by 7377

Abstract

The small GTase Arf6 has several important functions in intracellular vesicular trafficking and regulates the recycling of different types of cargo internalized via clathrin-dependent or -independent endocytosis. It activates the lipid modifying enzymes PIP 5-kinase and phospholipase D, promotes actin polymerization, and affects [...] Read more.

The small GTase Arf6 has several important functions in intracellular vesicular trafficking and regulates the recycling of different types of cargo internalized via clathrin-dependent or -independent endocytosis. It activates the lipid modifying enzymes PIP 5-kinase and phospholipase D, promotes actin polymerization, and affects several functionally distinct processes in the cell. Arf6 is used for the phagocytosis of pathogens and can be directly or indirectly targeted by various pathogens to block phagocytosis or induce the uptake of intracellular pathogens. Arf6 is also used in the signaling of Toll-like receptors and in the activation of NADPH oxidases. In this review, we first give an overview of the different roles and mechanisms of action of Arf6 and then focus on its role in innate immunity and host–pathogen interactions. Full article

(This article belongs to the Special Issue Small GTPases 2019)

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31 pages, 903 KiB

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Regulators of Rho GTPases in the Nervous System: Molecular Implication in Axon Guidance and Neurological Disorders

by Sadig Niftullayev and Nathalie Lamarche-Vane

Int. J. Mol. Sci. 2019, 20(6), 1497; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20061497 - 25 Mar 2019

Cited by 27 | Viewed by 6968

Abstract

One of the fundamental steps during development of the nervous system is the formation of proper connections between neurons and their target cells—a process called neural wiring, failure of which causes neurological disorders ranging from autism to Down’s syndrome. Axons navigate through the [...] Read more.

One of the fundamental steps during development of the nervous system is the formation of proper connections between neurons and their target cells—a process called neural wiring, failure of which causes neurological disorders ranging from autism to Down’s syndrome. Axons navigate through the complex environment of a developing embryo toward their targets, which can be far away from their cell bodies. Successful implementation of neuronal wiring, which is crucial for fulfillment of all behavioral functions, is achieved through an intimate interplay between axon guidance and neural activity. In this review, our focus will be on axon pathfinding and the implication of some of its downstream molecular components in neurological disorders. More precisely, we will talk about axon guidance and the molecules implicated in this process. After, we will briefly review the Rho family of small GTPases, their regulators, and their involvement in downstream signaling pathways of the axon guidance cues/receptor complexes. We will then proceed to the final and main part of this review, where we will thoroughly comment on the implication of the regulators for Rho GTPases—GEFs (Guanine nucleotide Exchange Factors) and GAPs (GTPase-activating Proteins)—in neurological diseases and disorders. Full article

(This article belongs to the Special Issue Small GTPases 2019)

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16 pages, 1323 KiB

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Small GTPases and Their Role in Vascular Disease

by Alison Flentje, Richa Kalsi and Thomas S. Monahan

Int. J. Mol. Sci. 2019, 20(4), 917; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20040917 - 20 Feb 2019

Cited by 36 | Viewed by 3655

Abstract

Over eighty million people in the United States have cardiovascular disease that can affect the heart causing myocardial infarction; the carotid arteries causing stroke; and the lower extremities leading to amputation. The treatment for end-stage cardiovascular disease is surgical—either endovascular therapy with balloons [...] Read more.

Over eighty million people in the United States have cardiovascular disease that can affect the heart causing myocardial infarction; the carotid arteries causing stroke; and the lower extremities leading to amputation. The treatment for end-stage cardiovascular disease is surgical—either endovascular therapy with balloons and stents—or open reconstruction to reestablish blood flow. All interventions damage or destroy the protective inner lining of the blood vessel—the endothelium. An intact endothelium is essential to provide a protective; antithrombotic lining of a blood vessel. Currently; there are no agents used in the clinical setting that promote reendothelialization. This process requires migration of endothelial cells to the denuded vessel; proliferation of endothelial cells on the denuded vessel surface; and the reconstitution of the tight adherence junctions responsible for the formation of an impermeable surface. These processes are all regulated in part and are dependent on small GTPases. As important as the small GTPases are for reendothelialization, dysregulation of these molecules can result in various vascular pathologies including aneurysm formation, atherosclerosis, diabetes, angiogenesis, and hypertension. A better understanding of the role of small GTPases in endothelial cell migration is essential to the development for novel agents to treat vascular disease. Full article

(This article belongs to the Special Issue Small GTPases)

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23 pages, 958 KiB

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Arf GAPs as Regulators of the Actin Cytoskeleton—An Update

by Christine E. Tanna, Louisa B. Goss, Calvin G. Ludwig and Pei-Wen Chen

Int. J. Mol. Sci. 2019, 20(2), 442; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20020442 - 21 Jan 2019

Cited by 30 | Viewed by 7112

Abstract

Arf GTPase-activating proteins (Arf GAPs) control the activity of ADP-ribosylation factors (Arfs) by inducing GTP hydrolysis and participate in a diverse array of cellular functions both through mechanisms that are dependent on and independent of their Arf GAP activity. A number of these [...] Read more.

Arf GTPase-activating proteins (Arf GAPs) control the activity of ADP-ribosylation factors (Arfs) by inducing GTP hydrolysis and participate in a diverse array of cellular functions both through mechanisms that are dependent on and independent of their Arf GAP activity. A number of these functions hinge on the remodeling of actin filaments. Accordingly, some of the effects exerted by Arf GAPs involve proteins known to engage in regulation of the actin dynamics and architecture, such as Rho family proteins and nonmuscle myosin 2. Circular dorsal ruffles (CDRs), podosomes, invadopodia, lamellipodia, stress fibers and focal adhesions are among the actin-based structures regulated by Arf GAPs. Arf GAPs are thus important actors in broad functions like adhesion and motility, as well as the specialized functions of bone resorption, neurite outgrowth, and pathogen internalization by immune cells. Arf GAPs, with their multiple protein-protein interactions, membrane-binding domains and sites for post-translational modification, are good candidates for linking the changes in actin to the membrane. The findings discussed depict a family of proteins with a critical role in regulating actin dynamics to enable proper cell function. Full article

(This article belongs to the Special Issue Small GTPases)

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21 pages, 2971 KiB

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Roco Proteins: GTPases with a Baroque Structure and Mechanism

by Lina Wauters, Wim Versées and Arjan Kortholt

Int. J. Mol. Sci. 2019, 20(1), 147; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20010147 - 03 Jan 2019

Cited by 24 | Viewed by 5064

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of genetically inherited Parkinson’s Disease (PD). LRRK2 is a large, multi-domain protein belonging to the Roco protein family, a family of GTPases characterized by a central RocCOR (Ras of complex proteins/C-terminal of [...] Read more.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of genetically inherited Parkinson’s Disease (PD). LRRK2 is a large, multi-domain protein belonging to the Roco protein family, a family of GTPases characterized by a central RocCOR (Ras of complex proteins/C-terminal of Roc) domain tandem. Despite the progress in characterizing the GTPase function of Roco proteins, there is still an ongoing debate concerning the working mechanism of Roco proteins in general, and LRRK2 in particular. This review consists of two parts. First, an overview is given of the wide evolutionary range of Roco proteins, leading to a variety of physiological functions. The second part focusses on the GTPase function of the RocCOR domain tandem central to the action of all Roco proteins, and progress in the understanding of its structure and biochemistry is discussed and reviewed. Finally, based on the recent work of our and other labs, a new working hypothesis for the mechanism of Roco proteins is proposed. Full article

(This article belongs to the Special Issue Small GTPases)

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21 pages, 693 KiB

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Druggable Targets in Cyclic Nucleotide Signaling Pathways in Apicomplexan Parasites and Kinetoplastids against Disabling Protozoan Diseases in Humans

by Annette Kaiser

Int. J. Mol. Sci. 2019, 20(1), 138; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20010138 - 02 Jan 2019

Cited by 10 | Viewed by 4714

Abstract

Cell signaling in eukaryotes is an evolutionarily conserved mechanism to respond and adapt to various environmental changes. In general, signal sensation is mediated by a receptor which transfers the signal to a cascade of effector proteins. The cyclic nucleotides 3′,5′-cyclic adenosine monophosphate (cAMP) [...] Read more.

Cell signaling in eukaryotes is an evolutionarily conserved mechanism to respond and adapt to various environmental changes. In general, signal sensation is mediated by a receptor which transfers the signal to a cascade of effector proteins. The cyclic nucleotides 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) are intracellular messengers mediating an extracellular stimulus to cyclic nucleotide-dependent kinases driving a change in cell function. In apicomplexan parasites and kinetoplastids, which are responsible for a variety of neglected, tropical diseases, unique mechanisms of cyclic nucleotide signaling are currently identified. Collectively, cyclic nucleotides seem to be essential for parasitic proliferation and differentiation. However, there is no a genomic evidence for canonical G-proteins in these parasites while small GTPases and secondary effector proteins with structural differences to host orthologues occur. Database entries encoding G-protein-coupled receptors (GPCRs) are still without functional proof. Instead, signals from the parasite trigger GPCR-mediated signaling in the host during parasite invasion and egress. The role of cyclic nucleotide signaling in the absence of G-proteins and GPCRs, with a particular focus on small GTPases in pathogenesis, is reviewed here. Due to the absence of G-proteins, apicomplexan parasites and kinetoplastids may use small GTPases or their secondary effector proteins and host canonical G-proteins during infection. Thus, the feasibility of targeting cyclic nucleotide signaling pathways in these parasites, will be an enormous challenge for the identification of selective, pharmacological inhibitors since canonical host proteins also contribute to pathogenesis. Full article

(This article belongs to the Special Issue Small GTPases)

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15 pages, 1068 KiB

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Roco Proteins and the Parkinson’s Disease-Associated LRRK2

by Jingling Liao and Quyen Q. Hoang

Int. J. Mol. Sci. 2018, 19(12), 4074; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19124074 - 17 Dec 2018

Cited by 5 | Viewed by 3635

Abstract

Small G-proteins are structurally-conserved modules that function as molecular on-off switches. They function in many different cellular processes with differential specificity determined by the unique effector-binding surfaces, which undergo conformational changes during the switching action. These switches are typically standalone monomeric modules that [...] Read more.

Small G-proteins are structurally-conserved modules that function as molecular on-off switches. They function in many different cellular processes with differential specificity determined by the unique effector-binding surfaces, which undergo conformational changes during the switching action. These switches are typically standalone monomeric modules that form transient heterodimers with specific effector proteins in the ‘on’ state, and cycle to back to the monomeric conformation in the ‘off’ state. A new class of small G-proteins called “Roco” was discovered about a decade ago; this class is distinct from the typical G-proteins in several intriguing ways. Their switch module resides within a polypeptide chain of a large multi-domain protein, always adjacent to a unique domain called COR, and its effector kinase often resides within the same polypeptide. As such, the mechanisms of action of the Roco G-proteins are likely to differ from those of the typical G-proteins. Understanding these mechanisms is important because aberrant activity in the human Roco protein LRRK2 is associated with the pathogenesis of Parkinson’s disease. This review provides an update on the current state of our understanding of the Roco G-proteins and the prospects of targeting them for therapeutic purposes. Full article

(This article belongs to the Special Issue Small GTPases)

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37 pages, 2340 KiB

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Perspectives of RAS and RHEB GTPase Signaling Pathways in Regenerating Brain Neurons

by Hendrik Schöneborn, Fabian Raudzus, Mathieu Coppey, Sebastian Neumann and Rolf Heumann

Int. J. Mol. Sci. 2018, 19(12), 4052; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19124052 - 14 Dec 2018

Cited by 19 | Viewed by 11250

Abstract

Cellular activation of RAS GTPases into the GTP-binding “ON” state is a key switch for regulating brain functions. Molecular protein structural elements of rat sarcoma (RAS) and RAS homolog protein enriched in brain (RHEB) GTPases involved in this switch are discussed including their [...] Read more.

Cellular activation of RAS GTPases into the GTP-binding “ON” state is a key switch for regulating brain functions. Molecular protein structural elements of rat sarcoma (RAS) and RAS homolog protein enriched in brain (RHEB) GTPases involved in this switch are discussed including their subcellular membrane localization for triggering specific signaling pathways resulting in regulation of synaptic connectivity, axonal growth, differentiation, migration, cytoskeletal dynamics, neural protection, and apoptosis. A beneficial role of neuronal H-RAS activity is suggested from cellular and animal models of neurodegenerative diseases. Recent experiments on optogenetic regulation offer insights into the spatiotemporal aspects controlling RAS/mitogen activated protein kinase (MAPK) or phosphoinositide-3 kinase (PI3K) pathways. As optogenetic manipulation of cellular signaling in deep brain regions critically requires penetration of light through large distances of absorbing tissue, we discuss magnetic guidance of re-growing axons as a complementary approach. In Parkinson’s disease, dopaminergic neuronal cell bodies degenerate in the substantia nigra. Current human trials of stem cell-derived dopaminergic neurons must take into account the inability of neuronal axons navigating over a large distance from the grafted site into striatal target regions. Grafting dopaminergic precursor neurons directly into the degenerating substantia nigra is discussed as a novel concept aiming to guide axonal growth by activating GTPase signaling through protein-functionalized intracellular magnetic nanoparticles responding to external magnets. Full article

(This article belongs to the Special Issue Small GTPases)

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24 pages, 716 KiB

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Rac GTPases in Hematological Malignancies

by Valerie Durand-Onaylı, Theresa Haslauer, Andrea Härzschel and Tanja Nicole Hartmann

Int. J. Mol. Sci. 2018, 19(12), 4041; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19124041 - 14 Dec 2018

Cited by 14 | Viewed by 4478

Abstract

Emerging evidence suggests that crosstalk between hematologic tumor cells and the tumor microenvironment contributes to leukemia and lymphoma cell migration, survival, and proliferation. The supportive tumor cell-microenvironment interactions and the resulting cellular processes require adaptations and modulations of the cytoskeleton. The Rac subfamily [...] Read more.

Emerging evidence suggests that crosstalk between hematologic tumor cells and the tumor microenvironment contributes to leukemia and lymphoma cell migration, survival, and proliferation. The supportive tumor cell-microenvironment interactions and the resulting cellular processes require adaptations and modulations of the cytoskeleton. The Rac subfamily of the Rho family GTPases includes key regulators of the cytoskeleton, with essential functions in both normal and transformed leukocytes. Rac proteins function downstream of receptor tyrosine kinases, chemokine receptors, and integrins, orchestrating a multitude of signals arising from the microenvironment. As such, it is not surprising that deregulation of Rac expression and activation plays a role in the development and progression of hematological malignancies. In this review, we will give an overview of the specific contribution of the deregulation of Rac GTPases in hematologic malignancies. Full article

(This article belongs to the Special Issue Small GTPases)

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14 pages, 856 KiB

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Activated Rho GTPases in Cancer—The Beginning of a New Paradigm

by Pontus Aspenström

Int. J. Mol. Sci. 2018, 19(12), 3949; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19123949 - 08 Dec 2018

Cited by 55 | Viewed by 7188

Abstract

Involvement of Rho GTPases in cancer has been a matter of debate since the identification of the first members of this branch of the Ras superfamily of small GTPases. The Rho GTPases were ascribed important roles in the cell, although these were restricted [...] Read more.

Involvement of Rho GTPases in cancer has been a matter of debate since the identification of the first members of this branch of the Ras superfamily of small GTPases. The Rho GTPases were ascribed important roles in the cell, although these were restricted to regulation of cytoskeletal dynamics, cell morphogenesis, and cell locomotion, with initially no clear indications of direct involvement in cancer progression. This paradigm has been challenged by numerous observations that Rho-regulated pathways are often dysregulated in cancers. More recently, identification of point mutants in the Rho GTPases Rac1, RhoA, and Cdc42 in human tumors has finally given rise to a new paradigm, and we can now state with confidence that Rho GTPases serve as oncogenes in several human cancers. This article provides an exposé of current knowledge of the roles of activated Rho GTPases in cancers. Full article

(This article belongs to the Special Issue Small GTPases)

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20 pages, 1613 KiB

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The Many Faces of Rap1 GTPase

by Anna Jaśkiewicz, Beata Pająk and Arkadiusz Orzechowski

Int. J. Mol. Sci. 2018, 19(10), 2848; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19102848 - 20 Sep 2018

Cited by 57 | Viewed by 7261

Abstract

This review addresses the issue of the numerous roles played by Rap1 GTPase (guanosine triphosphatase) in different cell types, in terms of both physiology and pathology. It is one among a myriad of small G proteins with endogenous GTP-hydrolyzing activity that is considerably [...] Read more.

This review addresses the issue of the numerous roles played by Rap1 GTPase (guanosine triphosphatase) in different cell types, in terms of both physiology and pathology. It is one among a myriad of small G proteins with endogenous GTP-hydrolyzing activity that is considerably stimulated by posttranslational modifications (geranylgeranylation) or guanine nucleotide exchange factors (GEFs), and inhibited by GTPase-activating proteins (GAPs). Rap1 is a ubiquitous protein that plays an essential role in the control of metabolic processes, such as signal transduction from plasma membrane receptors, cytoskeleton rearrangements necessary for cell division, intracellular and substratum adhesion, as well as cell motility, which is needed for extravasation or fusion. We present several examples of how Rap1 affects cells and organs, pointing to possible molecular manipulations that could have application in the therapy of several diseases. Full article

(This article belongs to the Special Issue Small GTPases)

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18 pages, 1559 KiB

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Rab38 Mutation and the Lung Phenotype

by Kazuhiro Osanai

Int. J. Mol. Sci. 2018, 19(8), 2203; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19082203 - 27 Jul 2018

Cited by 13 | Viewed by 5239

Abstract

Rab38 is highly expressed in alveolar type II cells, melanocytes, and platelets. These cells are specifically-differentiated cells and contain characteristic intracellular organelles called lysosome-related organelles, i.e., lamellar bodies in alveolar type II cells, melanosomes in melanocytes, and dense granules in platelets. There are [...] Read more.

Rab38 is highly expressed in alveolar type II cells, melanocytes, and platelets. These cells are specifically-differentiated cells and contain characteristic intracellular organelles called lysosome-related organelles, i.e., lamellar bodies in alveolar type II cells, melanosomes in melanocytes, and dense granules in platelets. There are Rab38-mutant rodents, i.e., chocolate mice and Ruby rats. While chocolate mice only show oculocutaneous albinism, Ruby rats show oculocutaneous albinism and prolonged bleeding time and, hence, are a rat model of Hermansky-Pudlak syndrome (HPS). Most patients with HPS suffer from fatal interstitial pneumonia by middle age. The lungs of both chocolate mice and Ruby rats show remarkably increased amounts of lung surfactant and conspicuously enlarged lysosome-related organelles, i.e., lamellar bodies, which are also characteristic of the lungs in human HPS. There are 16 mutant HPS-mouse strains, of which ten mutant genes have been identified to be causative in patients with HPS thus far. The gene products of eight of the ten genes constitute one of the three protein complexes, i.e., biogenesis of lysosome-related organelle complex-1, -2, -3 (BLOC-1, -2, -3). Patients with HPS of the mutant BLOC-3 genotype develop interstitial pneumonia. Recently, BLOC-3 has been elucidated to be a guanine nucleotide exchange factor for Rab38. Growing evidence suggests that Rab38 is an additional candidate gene of human HPS that displays the lung phenotype. Full article

(This article belongs to the Special Issue Small GTPases)

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14 pages, 2087 KiB

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Functions of Rhotekin, an Effector of Rho GTPase, and Its Binding Partners in Mammals

by Hidenori Ito, Rika Morishita and Koh-ichi Nagata

Int. J. Mol. Sci. 2018, 19(7), 2121; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19072121 - 20 Jul 2018

Cited by 18 | Viewed by 6375

Abstract

Rhotekin is an effector protein for small GTPase Rho. This protein consists of a Rho binding domain (RBD), a pleckstrin homology (PH) domain, two proline-rich regions and a C-terminal PDZ (PSD-95, Discs-large, and ZO-1)-binding motif. We, and other groups, have identified various binding [...] Read more.

Rhotekin is an effector protein for small GTPase Rho. This protein consists of a Rho binding domain (RBD), a pleckstrin homology (PH) domain, two proline-rich regions and a C-terminal PDZ (PSD-95, Discs-large, and ZO-1)-binding motif. We, and other groups, have identified various binding partners for Rhotekin and carried out biochemical and cell biological characterization. However, the physiological functions of Rhotekin, per se, are as of yet largely unknown. In this review, we summarize known features of Rhotekin and its binding partners in neuronal tissues and cancer cells. Full article

(This article belongs to the Special Issue Small GTPases)

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35 pages, 2440 KiB

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Rho GTPases in Intellectual Disability: From Genetics to Therapeutic Opportunities

by Valentina Zamboni, Rebecca Jones, Alessandro Umbach, Alessandra Ammoni, Maria Passafaro, Emilio Hirsch and Giorgio R. Merlo

Int. J. Mol. Sci. 2018, 19(6), 1821; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19061821 - 20 Jun 2018

Cited by 55 | Viewed by 8474

Abstract

Rho-class small GTPases are implicated in basic cellular processes at nearly all brain developmental steps, from neurogenesis and migration to axon guidance and synaptic plasticity. GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction [...] Read more.

Rho-class small GTPases are implicated in basic cellular processes at nearly all brain developmental steps, from neurogenesis and migration to axon guidance and synaptic plasticity. GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction of neuronal networks, as well as for synaptic function and plasticity. Rho GTPases are highly regulated by a complex set of activating (GEFs) and inactivating (GAPs) partners, via protein:protein interactions (PPI). Misregulated RhoA, Rac1/Rac3 and cdc42 activity has been linked with intellectual disability (ID) and other neurodevelopmental conditions that comprise ID. All genetic evidences indicate that in these disorders the RhoA pathway is hyperactive while the Rac1 and cdc42 pathways are consistently hypoactive. Adopting cultured neurons for in vitro testing and specific animal models of ID for in vivo examination, the endophenotypes associated with these conditions are emerging and include altered neuronal networking, unbalanced excitation/inhibition and altered synaptic activity and plasticity. As we approach a clearer definition of these phenotype(s) and the role of hyper- and hypo-active GTPases in the construction of neuronal networks, there is an increasing possibility that selective inhibitors and activators might be designed via PPI, or identified by screening, that counteract the misregulation of small GTPases and result in alleviation of the cognitive condition. Here we review all knowledge in support of this possibility. Full article

(This article belongs to the Special Issue Small GTPases)

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