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Small GTPases

Ryan S D'Souza, James E Casanova
The IQsec/BRAG proteins are a subfamily of Arf-nucleotide exchange factors. Since their discovery almost 15 years ago, the BRAGs have been reported to be involved in diverse physiological processes from myoblast fusion, neuronal pathfinding and angiogenesis, to pathophysiological processes including X-linked intellectual disability and tumor metastasis. In this review we will address how, in each of these situations, the BRAGs are thought to regulate the surface levels of adhesive and signaling receptors. While in most cases BRAGs are thought to enhance the endocytosis of these receptors, how they achieve this remains unclear...
October 14, 2016: Small GTPases
Youtao Liu, Jesus Lacal, Richard A Firtel, Arjan Kortholt
The directional movement towards extracellular chemical gradients, a process called chemotaxis, is an important property of cells. Central to eukaryotic chemotaxis is the molecular mechanism by which chemoattractant-mediated activation of G-protein coupled receptors (GPCRs) induces symmetry breaking in the activated downstream signaling pathways. Studies with mainly Dictyostelium and mammalian neutrophils as experimental systems have shown that chemotaxis is mediated by a complex network of signaling pathways...
October 7, 2016: Small GTPases
Anna Bagnato, Laura Rosanò
Metastatization is a complex multistep process requiring fine-tuned regulated cytoskeleton re-modeling, mediated by the cross-talk of actin with interacting partners, such as the Rho GTPases. Our expanding knowledge of invadopodia, small invasive membrane protrusions composed of a core of F-actin, actin regulators and actin-binding proteins, and hotspots for secretion of extracellular matrix (ECM) proteinases, contributes to clarify critical steps of the metastatic program. Growth factor receptors and their intermediate signaling molecules, along with matrix adhesion and rigidity, pH and hypoxia, act as drivers of cytoskeleton changes and invadopodia formation...
October 3, 2016: Small GTPases
Francisco J Calero-Cuenca, Sol Sotillos
A tight relationship between apico-basal polarity and trafficking is essential for epithelial physiology and tissue homeostasis. Recent studies have described how some Rab GTPases, key components of the intracellular traffic machinery, contribute to the establishment of cell polarity in vertebrates. We have demonstrated a novel connection between cell polarity and trafficking: in Drosophila epithelia, the apical determinant aPKC is recycled via Rab11-Nuf-recycling endosomes to maintain cell polarity. Furthermore, the phosphorylation of Nuf by aPKC allows aPKC to control the sub-cellular localization of Nuf and its own membrane accumulation...
September 29, 2016: Small GTPases
Otilia V Vieira
Disruption of the cell plasma membrane can occur due to mechanical damage, pore forming toxins, etc. Resealing or plasma membrane repair (PMR) is the emergency response required for cell survival. It is triggered by Ca(2+) entering through the disruption, causing organelles such as lysosomes located underneath the plasma membrane to fuse rapidly with the adjacent plasma membrane. We have recently identified some of the molecular traffic machinery that is involved in this vital process. Specifically, we showed that 2 members of the Rab family of small GTPases, Rab3a and Rab10, are essential for lysosome exocytosis and PMR in cells challenged with a bacterial toxin, streptolysin-O (SLO)...
September 29, 2016: Small GTPases
Olivier Calvayrac, Anne Pradines, Gilles Favre
Metastatic dissemination is the cause of death in the vast majority of cancers, including lung cancers. In order to metastasize, tumor cells must undergo a well-known series of changes, however the molecular details of how they manage to overcome the barriers at each stage remain incomplete. One critical step is acquiring the ability to migrate through the extracellular matrix. Loss of expression of the RAS-related small GTPase RHOB is a common feature of lung cancer progression, and we recently reported that this induces an epithelial-to-mesenchymal transition (EMT) that is dependent on SLUG overexpression and E-Cadherin inhibition and is characterized by 3-dimensional cell shape reorganization and the increased invasiveness of bronchial cells...
September 27, 2016: Small GTPases
Christopher A Lamb, Andrea Longatti, Sharon A Tooze
Formation of autophagosomes requires vesicular trafficking from virtually every subcellular compartment to the formation site. This traffic must be tightly regulated but also adaptable as different membrane compartments will contribute varying amounts of membrane, lipids and proteins to the forming autophagosome depending on the stimulus. In mammalian cells, efforts to understand how autophagosomes form have been focused on the role of Rab proteins in autophagy. Rab proteins provide specificity through their interaction with coat proteins, vesicle tethers and SNAREs...
September 26, 2016: Small GTPases
Liang Zhang, Jeffrey L Wrana
Migratory polarity and epithelial polarity share many common regulatory mechanisms. Rho GTPases play a key role in modulating cell polarity, which in migrating cells has been conventionally studied along the solitary front-rear axis. In recent work, we discovered that Prickle1 (Pk1), a core com-ponent of planar cell polarity (PCP) signaling, mediates a novel lateral signaling pathway that coordinates multi-axial protrusive activities from the lateral cortex of migrating cancer cells. We identified that Arhgap21 and 23 are essential effectors of Pk1, and that lateral signaling regulates RhoA, actomyosin and focal adhesion dynamics...
September 22, 2016: Small GTPases
Campbell D Lawson, Channing J Der
Like RAS proteins, the aberrant function of RHO family small GTPases has been implicated in driving cancer development and growth. However, unlike the RAS family, where gain-of-function missense mutations are found in ∼25% of all human cancers, missense mutations are relatively rare in RHO proteins. Instead, altered RHO activity in cancer more commonly arises through the aberrant functions of RHO GTPase regulators. In many cancer types, altered expression and/or mutation of RHO-selective guanine nucleotide exchange factors (RHOGEFs) or GTPase-activating proteins (RHOGAPs), which activate or inactivate RHO GTPases, respectively, is observed...
September 22, 2016: Small GTPases
Shuting Xia, Zikai Zhou, Zhengping Jia
The Rho family small GTPases and their effectors, including PAKs, are extensively studied in the context of the actin cytoskeleton, excitatory synaptic function, spine morphology and memory formation. However, their roles in inhibitory synaptic function remain poorly understood. We have recently shown that PAK1 is a potent regulator of GABAergic synaptic transmission. Thus, disruption of PAK1 leads to significant impairments in inhibitory postsynaptic currents which are manifested as reduced GABA presynaptic releases...
September 20, 2016: Small GTPases
Virtu Solano-Collado, Adam Rofe, Stefania Spanò
Our immune system is engaged in a continuous battle against invading pathogens, many of which have evolved to survive in intracellular niches of mammalian hosts. A variety of cellular processes are involved in preventing bacterial invasion or in killing bacteria that successfully invade host cells. Recently, the Rab GTPase Rab32 emerged as critical regulator of a host defense pathway that can eliminate bacterial pathogens. Salmonella enterica is an intracellular bacterium and a major cause of infections and deaths in humans...
September 20, 2016: Small GTPases
Raquel B Haga, Anne J Ridley
Rho GTPases are well known for their roles in regulating cell migration, and also contribute to a variety of other cellular responses. They are subdivided into two groups: typical and atypical. The typical Rho family members, including RhoA, Rac1 and Cdc42, cycle between an active GTP-bound and inactive GDP-bound conformation, and are regulated by GEFs, GAPs and GDIs, whereas atypical Rho family members have amino acid substitutions that alter their ability to interact with GTP/GDP and hence are regulated by different mechanisms...
September 14, 2016: Small GTPases
Diego García-Weber, Jaime Millán
The appearance of multicellularity implied the adaptation of signaling networks required for unicellular life to new functions arising in this remarkable evolutionary transition. A hallmark of multicellular organisms is the formation of cellular barriers that compartmentalize spaces and functions. Here we discuss recent findings concerning the role of RhoB in the negative control of Rac1 trafficking from endosomes to the cell border in order to induce membrane extensions to restore endothelial barrier function after acute contraction...
September 6, 2016: Small GTPases
Cristina Casalou, Alexandra Faustino, Duarte C Barral
Members of the ADP-ribosylation factor (Arf) family of small GTP-binding (G) proteins regulate several aspects of membrane trafficking, such as vesicle budding, tethering and cytoskeleton organization. Arf family members, including Arf-like (Arl) proteins have been implicated in several essential cellular functions, like cell spreading and migration. These functions are used by cancer cells to disseminate and invade the tissues surrounding the primary tumor, leading to the formation of metastases. Indeed, Arf and Arl proteins, as well as their guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) have been found to be abnormally expressed in different cancer cell types and human cancers...
September 2, 2016: Small GTPases
Marcelo G Kazanietz, Laura Barrio-Real, Victoria Casado-Medrano, Martin J Baker, Cynthia Lopez-Haber
Guanine nucleotide Exchange Factors (GEFs) are responsible for mediating GDP/GTP exchange for specific small G proteins, such as Rac. There has been substantial evidence for the involvement of Rac-GEFs in the control of cancer cell migration and metastatic progression. We have previously established that the Rac-GEF P-Rex1 is a mediator of actin cytoskeleton rearrangements and cell motility in breast cancer cells downstream of HER/ErbB receptors and the G-Protein Coupled Receptor (GPCR) CXCR4. P-Rex1 is highly expressed in luminal A and B breast cancer compared to normal mammary tissue, whereas expression is very low in basal breast cancer, and its expression correlates with the appearance of metastasis in patients...
September 2, 2016: Small GTPases
Owen A Brady, Heba I Diab, Rosa Puertollano
The Rags represent a unique family of evolutionarily conserved, heterodimeric, lysosome-localized small GTPases that play an indispensible role in regulating cellular metabolism in response to various amino acid signaling mechanisms. Rapid progress in the field has begun to unveil a picture in which Rags act as central players in translating information regarding cellular amino acid levels by modulating their nucleotide binding status through an ensemble of support proteins localized in and around the lysosomes...
August 31, 2016: Small GTPases
Akihisa Mino, Anja Troeger, Christian Brendel, Alan Cantor, Chad Harris, Marioara F Ciuculescu, David A Williams
RhoH is a haematopoietic -specific, GTPase-deficient Rho GTPase that plays an essential role in T lymphocyte development and haematopoietic cell migration. RhoH is known to interact with ZAP70 in T cell receptor (TCR) signaling and antagonize Rac GTPase activity. To further elucidate the molecular mechanisms of RhoH in T cell function, we carried out in vivo biotinylation and mass spectrometry analysis to identify new RhoH-interacting proteins in Jurkat T cells. We indentified Kaiso by streptavidin capture and confirmed the interaction with RhoH by co-immunoprecipitation...
August 30, 2016: Small GTPases
Joseph H R Hetmanski, Jean-Marc Schwartz, Patrick T Caswell
Precise spatiotemporal dynamics of Rho GTPases are essential for efficient cell migration. Manipulating Rac1 and RhoA signaling is thus a potential intervention strategy to abrogate harmful cell invasion and subsequent metastasis; however GTPase signaling can be extremely complicated due to crosstalk and the multitude of upstream regulators and downstream effectors. Studying Rho GTPase networks in a formal mathematical setting can therefore be of great use. We recently built a predictive model based on Boolean logic which identified a negative feedback loop critical for RhoA and Rac1 activity...
August 30, 2016: Small GTPases
Daniela Araiza-Olivera, Jonathan Chernoff
Ras oncoproteins can promote or suppress cellular apoptosis, but the mechanisms underlying these varied responses remain incompletely understood. Ras is linked to the Hippo tumor suppressor pathway, a highly conserved signaling cassette that regulates organ size in animals ranging from flies to humans. The proximal members of this pathway, Mammalian Ste20-like kinases (Msts) -1 and -2, self-associate in homodimers and also form heterodimers with other proteins. Formation of such complexes is known to regulate Mst kinase activity and thus, the Hippo pathway...
August 25, 2016: Small GTPases
Lan K Nguyen, Boris N Kholodenko, Alex von Kriegsheim
Cell migration requires a precise temporal and spatial coordination of several processes which allow the cell to efficiently move. The extension and retraction of membrane protrusion, as well as adhesion are controlled by the Rho-family small GTPases. Two members of the family, Rac1 and RhoA, can show opposite behaviors and spatial localisations, with RhoA being active toward the rear of the cell and regulating its retraction during migration, whereas Rac1 is active toward the front of the cell. In addition to the spatial segregation, RhoA and Rac1 activity at the leading edge of the cells has an element of temporal segregation, with RhoA and Rac1 activities peaking at separate points during the migratory cycle of protrusion and retraction...
August 17, 2016: Small GTPases
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