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Small GTPases

Hanh My Hoang, Hope Gloria Umutesi, Jongyun Heo
Son of Sevenless (SOS), one of guanine nucleotide exchange factors (GEFs), activates Ras. We discovered that the allosteric domain of SOS yields SOS to proceed a previously unrecognized autoactivation kinetics. Its essential feature is a time-dependent acceleration of SOS feedback activation with a reaction initiator or with the priming of active Ras. Thus, this mechanistic autoactivation feature explains the notion, previously only conjectured, of accelerative SOS activation followed by the priming of active Ras, an action produced by another GEF Ras guanyl nucleotide-releasing protein (RasGRP)...
April 13, 2019: Small GTPases
Samuel J Tong, Adam A Wall, Yu Hung, Lin Luo, Jennifer L Stow
Macrophages are important immune sentinels that detect and clear pathogens and initiate inflammatory responses through the activation of surface receptors, including Toll-like receptors (TLRs). Activated TLRs employ complex cellular trafficking and signalling pathways to initiate transcription for inflammatory cytokine programs. We have previously shown that Rab8a is activated by multiple TLRs and regulates downstream Akt/mTOR signalling by recruiting the effector PI3Kγ, but the guanine nucleotide exchange factors (GEF) canonically required for Rab8a activation in TLR pathways is not known...
March 7, 2019: Small GTPases
Mathieu Unbekandt, Sergio Lilla, Sara Zanivan, Michael F Olson
The CDC42 small GTPase is a major influence on actin-myosin cytoskeleton organization and dynamics, signalling via effector proteins including the Myotonic dystrophy related CDC42-binding protein kinases (MRCK) α and β. We previously identified Serine 1003 of MRCKα as a site of autophosphorylation, and showed that a phosphorylation-sensitive antibody raised against this site could be used as a surrogate indicator of kinase activity. In this study, a kinase-dead version of MRCKβ was established by mutation of the conserved Lysine 105 to Methionine (K105M), which was then used for mass spectrometry analysis to identify phosphorylation events that occurred in catalytically-competent MRCKβ but not in the kinase-dead form...
January 22, 2019: Small GTPases
Luciana Bueno De Paiva, Vanessa Aline Bernusso, João Agostinho Machado-Neto, Fabiola Traina, Anne J Ridley, Sara Teresinha Olalla-Saad, Mariana Lazarini
RhoA and RhoC contribute to the regulation of glutamine metabolism, which is a crucial determinant of cell growth in some types of cancer. Here we investigated the participation of RhoA and RhoC in the response of prostate cancer cells to glutamine deprivation. We found that RhoA and RhoC activities were up- or downregulated by glutamine reduction in PC3 and LNCaP cell lines, which was concomitant to a reduction in cell number and proliferation. Stable overexpression of wild type RhoA or RhoC did not alter the sensitivity to glutamine deprivation...
November 18, 2018: Small GTPases
Yoshihiro Adachi, Miho Iijima, Hiromi Sesaki
Dynamin-related protein 1 (Drp1) is a dynamin superfamily GTPase, which drives membrane constriction during mitochondrial division. To mediate mitochondrial division, Drp1 is recruited to the mitochondrial outer membrane and is assembled into the division machinery. We previously showed that Drp1 interacts with phosphatidic acid (PA) and saturated phospholipids in the mitochondrial membrane, and this interaction restrains Drp1 in initiating the constriction of mitochondria. Here, we show that the role of saturated acyl chains of phospholipids is independent of their contribution to the membrane curvature or lipid packing suggesting their direct interaction with Drp1...
November 2, 2018: Small GTPases
Szabolcs Takáts, Attila Boda, Tamás Csizmadia, Gábor Juhász
During macroautophagy, the phagophore-mediated formation of autophagosomes and their subsequent fusion with lysosomes requires extensive transformation of the endomembrane system. Membrane dynamics in eukaryotic cells is regulated by small GTPase proteins including Arfs and Rabs. The small GTPase proteins that regulate autophagic membrane traffic are mostly conserved in yeast and metazoans, but there are also several differences. In this mini-review, we compare the small GTPase network of yeast and metazoan cells that regulates autophagy, and point out the similarities and differences in these organisms...
November 2, 2018: Small GTPases
Po-Chen Chu, Samuel K Kulp, Tanios Bekaii-Saab, Ching-Shih Chen
Although oncogenic KRAS represents a therapeutically relevant target in pancreatic cancer, it is deemed "non-druggable" because of the intrinsic difficulty in designing direct inhibitors of KRAS. Our recent work demonstrated a KRAS-integrin-linked kinase (ILK) regulatory feedback loop that allows pancreatic cancer cells to regulate KRAS expression and to interact with the tumor microenvironment to promote aggressive phenotype. KRAS induces E2F1-mediated transcriptional activation of ILK expression, and ILK, in turn, controls KRAS expression via hnRNPA1, which binds and destabilizes the G-quadruplex in the KRAS promoter...
November 2, 2018: Small GTPases
Christian Schneeweis, Matthias Wirth, Dieter Saur, Maximilian Reichert, Günter Schneider
EGFR signaling has a critical role in oncogenic KRAS-driven tumorigenesis of the pancreas, whereas it is dispensable in other organs. The complex signaling network engaged by oncogenic KRAS and its modulation by EGFR signaling, remains incompletely understood. In order to study early signaling events activated by oncogenic KRAS in the pancreas, we recently developed a novel model system based on murine primary pancreatic epithelial cells enabling the time-specific expression of mutant KrasG12D from its endogenous promoter...
November 2, 2018: Small GTPases
Vincent Hyenne, Michel Labouesse, Jacky G Goetz
Extracellular vesicles are novel mediators of cell-cell communication. They are present in all species and involved in physiological and pathological processes. One class of extracellular vesicles, the exosomes, originate from an endosomal compartment, the MultiVesicular Body (MVB), and are released from the cell upon fusion of the MVB with the plasma membrane. Although different molecular mechanisms have been associated with MVB biogenesis and exosome secretion, how they coordinate remains poorly documented...
November 2, 2018: Small GTPases
Arzu Ulu, Jeffrey A Frost
Jnks are mitogen activated protein kinases that are best known for regulating transcription and apoptotic signaling. However, they also play important roles in controlling cell motility and invasion by phosphorylating many actin and microtubule regulatory proteins. These mechanisms have important implications for normal cell motility as well as cancer metastasis. Jnks are activated by growth factors and cytokines that stimulate cell motility, and this often requires upstream activation of Rho GTPases. Our recent work indicates that Jnks may also regulate Rho GTPase activation...
October 17, 2018: Small GTPases
Kuldeep Verma, Vijay Kumar Srivastava, Sunando Datta
Rab GTPases constitute the largest subgroup in the Ras superfamily of GTPases. It is well established that different Rab GTPases are localized in discrete subcellular localization and regulate the membrane trafficking in nearly all eukaryotic cells. Rab GTPase diversity is often regarded as an expression of vesicular trafficking complexity. The pathogenic amoeba Entamoeba histolytica harbours 91 Rab GTPases which is the highest among the currently available genome sequences from the eukaryotic kingdom. Here, we review the current status of amoebic Rab GTPases diversity, unique biochemical and structural features and summarise their predicted regulators...
October 13, 2018: Small GTPases
Samantha Messina
RAS signaling is involved in the development of autoimmunity in general. Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system. It is widely recognized that a reduction of Foxp3+ regulatory T (Treg) cells is an immunological hallmark of MS, but the underlying mechanisms are unclear. In experimental autoimmune models, N-Ras and K-Ras inhibition triggers an anti-inflammatory effect up-regulating, via foxp3 elevation, the numbers and the functional suppressive properties of Tregs...
September 18, 2018: Small GTPases
Orry Van Geel, Roland Hartsuiker, Theodorus W J Gadella
Light-induced dimerizing systems, e.g. iLID, are an increasingly utilized optogenetics tool to perturb cellular signaling. The major benefit of this technique is that it allows external spatiotemporal control over protein localization with sub-cellular specificity. However, when it comes to local recruitment of signaling components to the plasmamembrane, this precision in localization is easily lost due to rapid diffusion of the membrane anchor. In this study, we explore different approaches of countering the diffusion of peripheral membrane anchors, to the point where we detect immobilized fractions with iFRAP on a timescale of several minutes...
September 5, 2018: Small GTPases
Barbara E Tanos, Charles Yeaman, Enrique Rodriguez-Boulan
IQGAP1 is a scaffold protein involved in the assembly of adherens junctions. Our work has recently revealed a novel role for IQGAP1 in the regulation of tight junctions (TJ) through differential recruitment of claudins to the nascent TJ. Here, we discuss the potential mechanisms of this regulation, including IQGAP1 effects on CDC42, and IQGAP1 interactions with sorting/trafficking molecules (e.g. Exo70). Given the many roles of IQGAP1 and the large number of interacting partners, we focus our discussion of these functions in the context of junction formation, trafficking, growth factor signaling and cancer...
September 3, 2018: Small GTPases
Francisco M Vega, Anne J Ridley
RhoB is a Rho family GTPase that is highly similar to RhoA and RhoC, yet has distinct functions in cells. Its unique C-terminal region is subject to specific post-translational modifications that confer different localization and functions to RhoB. Apart from the common role with RhoA and RhoC in actin organization and cell migration, RhoB is also implicated in a variety of other cellular processes including membrane trafficking, cell proliferation, DNA-repair and apoptosis. RhoB is not an essential gene in mice, but it is implicated in several physiological and pathological processes...
September 3, 2018: Small GTPases
Daniel Z Bar, Chayki Charar, Yosef Gruenbaum
The mechanistic target of rapamycin (mTOR) is an evolutionary conserved protein with a serine/threonine kinase activity that regulates cell growth, proliferation, motility, survival, protein synthesis, autophagy and transcription. It is embedded in 2 large protein complexes: mTORC1 and mTORC2. Regulation of specific mTOR pathway functions depends on multiple GTPases, that act either as regulators of mTOR protein complexes, coupling energy availability with mTORC1 activity, or as downstream effectors of both mTORC1 and mTORC2...
September 3, 2018: Small GTPases
Christopher P Webster, Emma F Smith, Andrew J Grierson, Kurt J De Vos
A GGGGCC hexanucleotide repeat expansion in the first intron of the C9orf72 gene is the most common genetic defect associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Haploinsufficiency and a resulting loss of C9orf72 protein function has been suggested as a possible pathogenic mechanism in C9ALS/FTD. C9ALS/FTD patients exhibit specific ubiquitin and p62/sequestosome-1 positive but TDP-43 negative inclusions in the cerebellum and hippocampus, indicating possible autophagy deficits in these patients...
September 3, 2018: Small GTPases
Noelia López-Montero, Jost Enninga
Small GTPases of the Rab protein family control intracellular vesicular trafficking to allow their communication and maintenance. It is a common strategy for intracellular bacteria to exploit these pathways to shape their respective niches for survival. The subversion of Rabs for the generation of an intracellular environment favoring the pathogen has been described almost exclusively for intracellular bacteria that reside within bacterial containing vacuoles (BCVs). However, less is known about Rab subversion for bacteria that rupture the BCV to reach the host cytoplasm...
September 3, 2018: Small GTPases
Shu Yang, Anne Rosenwald
Macroautophagy, a highly conserved process in eukaryotic cells, is initiated in response to stress, especially nutrient starvation. Macroautophagy helps cells survive by engulfing proteins and organelles into an unusual double-membraned structure called the autophagosome, which then fuses with the lysosome. Upon degradation of the engulfed contents, the building blocks are recycled for synthesis of new macromolecules. Recent work has demonstrated that construction of the autophagosome requires a variety of small GTPases in variations of their normal roles in membrane traffic...
September 3, 2018: Small GTPases
Alberto García-Mariscal, Karine Peyrollier, Astrid Basse, Esben Pedersen, Ralph Rühl, Jolanda van Hengel, Cord Brakebusch
The ubiquitously expressed small GTPase RhoA is essential for embryonic development and mutated in different cancers. Functionally, it is well described as a regulator of the actin cytoskeleton, but its role in gene regulation is less understood. Using primary mouse keratinocytes with a deletion of the RhoA gene, we have now been exploring how the loss of RhoA affects gene expression. Performing transcription factor reporter assays, we found a significantly decreased activity of a RAR luciferase reporter in RhoA-null keratinocytes...
September 3, 2018: Small GTPases
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