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Small GTPases

Yong Zhou, John F Hancock
Ras proteins must localize to the plasma membrane (PM) for biological function. The membrane anchor of the K-Ras4B isoform comprises a farnesylated and methylated C-terminal cysteine together with an adjacent hexa-lysine polybasic domain (PBD). Traditionally, polybasic sequences have been thought to interact electrostatically with negatively charged membranes showing no specificity for anionic lipid head groups. By contrast we recently showed that the K-Ras membrane anchor actually exhibits a very high degree of specificity for phosphatidylserine (PtdSer)...
December 14, 2017: Small GTPases
Marcellus J Banworth, Guangpu Li
Rab GTPases are important regulators of intracellular membrane trafficking in eukaryotes. Both activating and inactivating mutations in Rab genes have been identified and implicated in human diseases ranging from neurological disorders to cancer. In addition, altered Rab expression is often associated with disease prognosis. As such, the study of diseases associated with Rabs or Rab-interacting proteins has shed light on the important role of intracellular membrane trafficking in disease etiology. In this review, we cover recent advances in the field with an emphasis on cellular mechanisms...
December 14, 2017: Small GTPases
Eun-Kyoung Choi, Jae-Gyu Kim, Hee-Jun Kim, Jung-Yoon Cho, Hwalrim Jeong, Yohan Park, Rokibul Islam, Cuong Kim Cap, Jae-Bong Park
Rho GTPases play significant roles in cellular function and their activity is regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), providing activation and inactivation of these GTPases, respectively. Active GTP-bound form of RhoA activates its effector proteins while the inactive GDP-bound form of RhoA exists in a RhoA-RhoGDI (guanine nucleotide dissociation inhibitor) complex in the cytosol. In particular, IκB kinase γ IKKγ/NF-κB essential modulator (NEMO) plays a role as a GDI displacement factor (GDF) for RhoA activation through binding to RhoA-RhoGDI complex...
December 3, 2017: Small GTPases
Richard G Hodge, Anne J Ridley
Rho GTPases play central roles in a wide variety of cellular processes, including cytoskeletal dynamics, cell adhesion and cell polarity. RhoU and RhoV are Rho GTPases that have some atypical properties compared with classical Rho family members, such as the presence of N- and C-terminal extension regions, unusual GDP/GTP cycling and post-translational modification by palmitoylation but not prenylation. Their activity and localization is regulated by the N-terminal and C-terminal regions, and so far no GEFs or GAPs have been identified for them...
November 30, 2017: Small GTPases
Noah Fine, Ioannis D Dimitriou, Robert Rottapel
Neutrophils in circulation experience significant shear forces due to blood flow when they tether to the vascular endothelium. Biochemical and biophysical responses of neutrophils to the physical force of flowing blood modulate their behavior and promote tissue recruitment under pro-inflammatory conditions. Neutrophil mechanotransduction responses occur through mechanisms that are not yet fully understood. In our recent work, we showed that GEF-H1, a RhoA specific guanine nucleotide exchange factor (GEF), is required to maintain neutrophil motility and migration in response to shear stress...
November 30, 2017: Small GTPases
Federico T Bianchi, Marta Gai, Gaia E Berto, Ferdinando Di Cunto
The Citron protein was originally identified for its capability to specifically bind the active form of RhoA small GTPase, leading to the simplistic hypothesis that it may work as a RhoA downstream effector in actin remodeling. More than two decades later, a much more complex picture has emerged. In particular, it has become clear that in animals, and especially in mammals, the functions of the Citron gene (CIT) are intimately linked to many aspects of central nervous system (CNS) development and function, although the gene is broadly expressed...
November 29, 2017: Small GTPases
Ryan Thurman, Edhriz Siraliev-Perez, Sharon L Campbell
RAS proteins function as molecular switches that regulate cellular growth by cycling between active GTP- and inactive GDP bound states. While RAS activity is modulated by factors (guanine nucleotide exchange and GTPase activating proteins) that control levels of active Ras-GTP, RAS proteins also undergo a number of post-translational modifications that regulate their function. One such modification is ubiquitylation. Monoubiquitylation of KRAS at lysine 147 (mUbRAS) enhances Ras activation and promotes signaling through the RAF and Phosphoinositide 3-Kinase (PI3K) signaling pathways...
November 29, 2017: Small GTPases
Abdullah Al Mosabbir, Kevin Truong
Protein-based systems for light directed migration of cells have been demonstrated up to distances of several hundred microns, but larger distances in the centimeter scale would allow new possible applications. Light activated migration in mammalian cells can be achieved by cells expressing channelrhodopsin-2 and an engineered Ca2+ sensitive Rac1 protein called RACer. In this study, light was used to induce wound healing, localize cells into a region of interest, and move cells over centimeter scale distances...
November 26, 2017: Small GTPases
Yan Zuo, John d'Aigle, Anjali Chauhan, Jeffrey A Frost
Macrophages are innate immune cells that constantly patrol an organism to fulfill protective and homeostatic roles. Previous studies have shown that Rho GTPase activity is required for macrophage mobility, yet the roles of upstream regulatory proteins controlling Rho GTPase function in these cells are not well defined. Previously we have shown that the RhoA GEF Net1 is required for human breast cancer cell motility and extracellular matrix invasion. To assess the role of Net1 in macrophage motility, we isolated bone marrow macrophage (BMM) precursors from wild type and Net1 knockout mice...
November 26, 2017: Small GTPases
Ana Herrero, Mariana Reis-Cardoso, Iñaki Jiménez-Gómez, Carolanne Doherty, Lorena Agudo-Ibañez, Adán Pinto, Fernando Calvo, Walter Kolch, Piero Crespo, David Matallanas
Ras GTPases convey signals from different types of membranes. At these locations, different Ras isoforms, interactors and regulators generate different biochemical signals and biological outputs. The study of Ras localisation-specific signal transduction networks has been hampered by our inability to specifically activate each of these Ras pools. Here, we describe a new set of site-specific tethered exchange factors, engineered by fusing the RasGRF1 CDC25 domain to sub-localisation-defining cues, whereby Ras pools at specific locations can be precisely activated...
November 26, 2017: Small GTPases
Pauline Jeannot, Arnaud Besson
Actin remodeling plays an essential role in diverse cellular processes such as cell motility, vesicle trafficking or cytokinesis. The scaffold protein and actin nucleation promoting factor Cortactin is present in virtually all actin-based structures, participating in the formation of branched actin networks. It has been involved in the control of endocytosis, and vesicle trafficking, axon guidance and organization, as well as adhesion, migration and invasion. To migrate and invade through three-dimensional environments, cells have developed specialized actin-based structures called invadosomes, a generic term to designate invadopodia and podosomes...
November 26, 2017: Small GTPases
Inés M Antón, Carla Gómez-Oro, Sergio Rivas, Francisco Wandosell
Through actin-binding proteins such as the neural Wiskott-Aldrich syndrome protein (N-WASP) and WASP-interacting protein (WIP), the Rho family GTPases RhoA, Rac1 and Cdc42 are major modulators of the cytoskeleton. (N-)WASP and WIP control Rho GTPase activity in various cell types, either by direct WIP/(N-)WASP/Cdc42 or potential WIP/RhoA binding, or through secondary links that regulate GTPase distribution and/or transcription levels. WIP helps to regulate filopodium generation and participates in the Rac1-mediated ruffle formation that determines cell motility...
November 26, 2017: Small GTPases
Niranjan Venkateswaran, Maralice Conacci-Sorrell
Members of the MYC family of proto-oncogenes are the most commonly deregulated genes in all human cancers. MYC proteins drive an increase in cellular proliferation and facilitate multiple aspects of tumor initiation and progression, thereby controlling all hallmarks of cancer. MYC's ability to drive metabolic reprogramming of tumor cells leading to biomass accumulation and cellular proliferation is the most studied function of these oncogenes. MYC also regulates tumor progression and is often implicated in resistance to chemotherapy and in metastasis...
November 25, 2017: Small GTPases
Emmanuel Martin, Grégoire Bonnamour, Sarah Jenna
Autophagy is the process where cytosolic components are digested by the cell. This process is required for cell survival in stressful conditions. It was also shown to control cell division and more recently, cell morphology and migration. We characterized signalling pathways enabling embryonic epidermal cells of the nematode Caenorhabditis elegans to elongate along their antero-posterior axis. Previous studies revealed that epidermal cells can adopt either a RhoA-like or a Rac1-like morphogenic program. We show here that the AMP-activated protein kinase (AMPK) and genes controlling autophagy are required for proper elongation of epidermal cells following the RhoA-like program and are dispensable for other cells...
November 25, 2017: Small GTPases
Pontus Aspenström
The Rho GTPases were discovered more than 30 years ago, and they were for a long time considered to follow simple cycling between GDP-bound and GTP-bound conformations, as for the Ras subfamily of small GTPases. The Rho GTPases consist of 20 members, but at least 10 of these do not follow this classical GTPase cycle. Thus, based on their kinetic properties, these Rho GTPases can instead be classified as atypical. Some of these atypical Rho GTPases do not hydrolyze GTP, and some have significantly increased intrinsic GDP/GTP exchange activity...
November 20, 2017: Small GTPases
Xue Bai, Kevin Mangum, Masao Kakoki, Oliver Smithies, Christopher P Mack, Joan M Taylor
Vascular resistance is a major determinant of BP and is controlled, in large part, by RhoA-dependent smooth muscle cell (SMC) contraction within small peripheral arterioles and previous studies from our lab indicate that GRAF3 is a critical regulator of RhoA in vascular SMC. The elevated contractile responses we observed in GRAF3 deficient vessels coupled with the hypertensive phenotype provided a mechanistic link for the hypertensive locus recently identified within the GRAF3 gene. On the basis of our previous findings that the RhoA signaling axis also controls SMC contractile gene expression and that GRAF3 expression was itself controlled by this pathway, we postulated that GRAF3 serves as an important counter-regulator of SMC phenotype...
November 3, 2017: Small GTPases
Bruno Goud, Shijie Liu, Brian Storrie
GTP-ases of the Rab family (about 70 in human) are key regulators of intracellular transport and membrane trafficking in eukaryotic cells. Remarkably, almost one third associate with membranes of the Golgi complex and TGN (trans-Golgi network). Through interactions with a variety of effectors that include molecular motors, tethering complexes, scaffolding proteins and lipid kinases, they play an important role in maintaining Golgi architecture.
November 3, 2017: Small GTPases
Graziana Modica, Stephane Lefrancois
The small GTPase Rab7 is the main regulator of membrane trafficking at late endosomes. This small GTPase regulates endosome-to-trans Golgi Network trafficking of sorting receptors, membrane fusion of late endosomes to lysosomes, and autophagosomes to lysosomes during autophagy. Rab7, like all Rab GTPases, binds downstream effectors coordinating several divergent pathways. How cells regulate these interactions and downstream functions is not well understood. Recent evidence suggests that Rab7 function can be modulated by the combination of several post-translational modifications that facilitate interactions with one effector while preventing binding to another one...
November 3, 2017: Small GTPases
Gaofeng Fan, Nicholas Nicholas
Uncontrolled metastasis significantly contributes to high lethality of patients suffering from ovarian cancer. To date, the detailed molecular mechanisms which account for ovarian tumor cell spreading and metastasis remain largely unknown. In a recent study, we have demonstrated that aberrantly high expression of the non-receptor tyrosine kinase FER is responsible for ovarian tumor cell metastasis both in vitro and in vivo. Mechanistically, we indentified Hepatocyte Growth Factor Receptor HGFR/MET as a novel substrate of FER, and through which the kinase FER modulates ovarian cancer cell motility and invasiveness in a ligand-independent manner...
November 3, 2017: Small GTPases
Oliver E Blacque, Noemie Scheidel, Stefanie Kuhns
Cilia are microtubule-based organelles extending from a basal body at the surface of eukaryotic cells. Cilia regulate cell and fluid motility, sensation and developmental signaling, and ciliary defects cause human diseases (ciliopathies) affecting the formation and function of many tissues and organs. Over the past decade, various Rab and Rab-like membrane trafficking proteins have been shown to regulate cilia-related processes such as basal body maturation, ciliary axoneme extension, intraflagellar transport and ciliary signaling...
October 26, 2017: Small GTPases
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