scholarly journals Chemotactic Signaling Pathways in Neutrophils: from Receptor to Actin Assembly

2002 ◽  
Vol 13 (3) ◽  
pp. 220-228 ◽  
Author(s):  
Gregor Cicchetti ◽  
Philip G. Allen ◽  
Michael Glogauer
Keyword(s):  
G Proteins ◽  
Neutrophil Function ◽  
Small Gtpases ◽  
Regulatory Proteins ◽  
Heterotrimeric G Proteins ◽  
Actin Assembly ◽  
Receptor Ligand ◽  
Downstream Effectors ◽  
Ligand Interactions ◽  
Rho Family

In this review, we present an overview of the signaling elements between neutrophil chemotactic receptors and the actin cytoskeleton that drives cell motility. From receptor-ligand interactions, activation of heterotrimeric G-proteins, their downstream effectors PLC and PI-3 kinase, the activation of small GTPases of the Rho family, and their regulation of particular cytoskeletal regulatory proteins, we describe pathways specific to the chemotaxing neutrophil and elements documented to be important for neutrophil function.

Inhibition of neutrophil function by aspirin-like drugs (NSAIDS): Requirement for assembly of heterotrimeric G proteins in bilayer phospholipid

1994 ◽  
Vol 47 (3) ◽  
pp. 563-572 ◽  
Author(s):  
Steven B. Abramson ◽  
Joanna Leszczynska-Piziak ◽  
Robert M. Clancy ◽  
Mark Philips ◽  
Gerald Weissmann
Keyword(s):  
G Proteins ◽  
Neutrophil Function ◽  
Heterotrimeric G Proteins

scholarly journals Identification of Tetratricopeptide Repeat 1 as an Adaptor Protein That Interacts with Heterotrimeric G Proteins and the Small GTPase Ras

2003 ◽  
Vol 23 (11) ◽  
pp. 3847-3858 ◽  
Author(s):  
Caroline Marty ◽  
Darren D. Browning ◽  
Richard D. Ye
Keyword(s):  
G Proteins ◽  
Mammalian Cells ◽  
Active Form ◽  
Adaptor Protein ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Tetratricopeptide Repeat ◽  
Heterotrimeric G Proteins ◽  
Interacting Protein

ABSTRACT The biological functions of heterotrimeric G proteins and small GTPases are modulated by both extracellular stimuli and intracellular regulatory proteins. Using Saccharomyces cerevisiae two-hybrid screening, we identified tetratricopeptide repeat 1 (TPR1), a 292-amino-acid protein with three TPR motifs, as a Gα16-binding protein. The interaction was confirmed both in vitro and in transfected mammalian cells, where TPR1 also binds to several other Gα proteins. TPR1 was found to interact with Ha-Ras preferentially in its active form. Overexpression of TPR1 promotes accumulation of active Ras. TPR1 was found to compete with the Ras-binding domain (RBD) of Raf-1 for binding to the active Ras, suggesting that it may also compete with Ras GTPase-activating protein, thus contributing to the accumulation of GTP-bound Ras. Expression of Gα16 strongly enhances the interaction between TPR1 and Ras. Removal of the TPR1 N-terminal 112 residues abolishes potentiation by Gα16 while maintaining the interaction with Gα16 and the ability to discriminate active Ras from wild-type Ras. We have also observed that LGN, a Gαi-interacting protein with seven TPR motifs, binds Ha-Ras. Thus, TPR1 is a novel adaptor protein for Ras and selected Gα proteins that may be involved in protein-protein interaction relating to G-protein signaling.

scholarly journals Activation of STAT transcription factors by the Rho-family GTPases

2020 ◽  
Vol 48 (5) ◽  
pp. 2213-2227
Author(s):  
Jessica Corry ◽  
Helen R. Mott ◽  
Darerca Owen
Keyword(s):  
Transcription Factors ◽  
Rho Gtpase ◽  
Therapeutic Potential ◽  
Small Gtpases ◽  
Cellular Morphology ◽  
Invasion And Metastasis ◽  
Family Control ◽  
Signal Transducers ◽  
Downstream Effectors ◽  
Rho Family

The Rho-family of small GTPases are biological molecular switches that are best known for their regulation of the actin cytoskeleton. Through their activation and stimulation of downstream effectors, the Rho-family control pathways involved in cellular morphology, which are commonly activated in cancer cell invasion and metastasis. While this makes them excellent potential therapeutic targets, a deeper understanding of the downstream signalling pathways they influence will be required for successful drug targeting. Signal transducers and activators of transcription (STATs) are a family of transcription factors that are hyper-activated in most cancer types and while STATs are widely understood to be activated by the JAK family of kinases, many additional activators have been discovered. A growing number of examples of Rho-family driven STAT activation, largely of the oncogenic family members, STAT3 and STAT5, are being identified. Cdc42, Rac1, RhoA, RhoC and RhoH have all been implicated in STAT activation, contributing to Rho GTPase-driven changes in cellular morphology that lead to cell proliferation, invasion and metastasis. This highlights the importance and therapeutic potential of the Rho-family as regulators of non-canonical activation of STAT signalling.

scholarly journals Plant receptor-like kinase signaling through heterotrimeric G-proteins

2020 ◽  
Vol 71 (5) ◽  
pp. 1742-1751 ◽  
Author(s):  
Sona Pandey
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Current Knowledge ◽  
Regulatory Mechanisms ◽  
Protein Signaling ◽  
Heterotrimeric G Proteins ◽  
Signal Perception ◽  
Downstream Effectors ◽  
Activation Mechanisms ◽  
Dependent Signal

Abstract Heterotrimeric G-proteins regulate multiple aspects of plant growth, development, and response to biotic and abiotic stresses. While the core components of heterotrimeric G-proteins and their basic biochemistry are similar in plants and metazoans, key differences exist in their regulatory mechanisms. In particular, the activation mechanisms of plant G-proteins appear diverse and may include both canonical and novel modes. Classical G-protein-coupled receptor-like proteins exist in plants and interact with Gα proteins, but their ability to activate Gα by facilitating GDP to GTP exchange has not been demonstrated. Conversely, there is genetic and functional evidence that plant G-proteins interact with the highly prevalent receptor-like kinases (RLKs) and are phosphorylated by them. This suggests the exciting scenario that in plants the G-proteins integrate RLK-dependent signal perception at the plasma membrane with downstream effectors. Because RLKs are active kinases, it is also likely that the activity of plant G-proteins is regulated via phosphorylation/dephosphorylation rather than GTP–GDP exchange as in metazoans. This review discusses our current knowledge of the possible RLK-dependent regulatory mechanisms of plant G-protein signaling in the context of several biological systems and outlines the diversity that might exist in such regulation.

Role of G proteins in agonist-induced Ca2+ sensitization of tracheal smooth muscle

1998 ◽  
Vol 275 (4) ◽  
pp. L748-L755 ◽  
Author(s):  
Thomas L. Croxton ◽  
Boris Lande ◽  
Carol A. Hirshman
Keyword(s):  
Smooth Muscle ◽  
G Proteins ◽  
Airway Smooth Muscle ◽  
Tracheal Smooth Muscle ◽  
Heterotrimeric G Proteins ◽  
Contractile Responses ◽  
Intracellular Ca ◽  
Increased Sensitivity ◽  
Rho Family

Increased sensitivity to intracellular Ca2+ concentration ([Ca2+]) is an important mechanism for agonist-induced contraction of airway smooth muscle, but the signal transduction pathways involved are uncertain. We studied Ca2+ sensitization with acetylcholine (ACh) and endothelin (ET)-1 in porcine tracheal smooth muscle by measuring contractions at a constant [Ca2+] in strips permeabilized with α-toxin or β-escin. The peptide inhibitor G protein antagonist 2A (GP Ant-2A), which has selectivity for Gq over Gi, inhibited contractile responses to ET-1, ACh, and guanosine 5′- O-(3-thiotriphosphate) (GTPγS), but the proportional inhibition of ACh responses was less than that of ET-1. Pretreatment with pertussis toxin reduced ACh contractions but had no effect on those of ET-1 or GTPγS. Clostridium botulinum C3 exoenzyme, which inactivates Rho family monomeric G proteins, caused similar reductions in contractile responses to ACh, ET-1, and GTPγS. Farnesyltransferase inhibition, which inhibits Ras G proteins, reduced responses to ET-1. We conclude that the heterotrimeric G proteins Gq and Gi both contribute to Ca2+ sensitization by ACh, whereas ET-1 responses involve Gq but not Gi. Both Gq and Gi pathways likely involve Rho family small G proteins. A Ras-mediated pathway also contributes to Ca2+ sensitization by ET-1 in airway smooth muscle.

1,25-Dihydroxyvitamin D3 but not TPA activates PLD in Caco-2 cells via pp60c-src and RhoA

1999 ◽  
Vol 276 (4) ◽  
pp. G1005-G1015 ◽  
Author(s):  
Sharad Khare ◽  
Marc Bissonnette ◽  
Ramesh Wali ◽  
Susan Skarosi ◽  
Gerry R. Boss ◽  
...  
Keyword(s):  
Signal Transduction ◽  
G Proteins ◽  
Specific Inhibitor ◽  
Brefeldin A ◽  
Heterotrimeric G Proteins ◽  
Dihydroxyvitamin D3 ◽  
Dihydroxyvitamin D ◽  
Rho Family ◽  
Adp Ribosylation Factor ◽  
Stimulation Of

In the accompanying paper [Khare et al., Am. J. Physiol. 276 ( Gastrointest. Liver Physiol. 39): G993–G1004, 1999], activation of protein kinase C-α (PKC-α) was shown to be involved in the stimulation of phospholipase D (PLD) by 1,25-dihydroxyvitamin D3[1,25(OH)2D3] and 12- O-tetradecanoylphorbol 13-acetate (TPA) in Caco-2 cells. Monomeric or heterotrimeric G proteins, as well as pp60c- src have been implicated in PLD activation. We therefore determined whether these signal transduction elements were involved in PLD stimulation by 1,25(OH)2D3or TPA. Treatment with C3 transferase, which inhibits members of the Rho family of monomeric G proteins, markedly diminished the ability of 1,25(OH)2D3, but not TPA, to stimulate PLD. Brefeldin A, an inhibitor of ADP-ribosylation factor proteins, did not, however, significantly reduce the stimulation of PLD by either of these agents. Moreover, 1,25(OH)2D3, but not TPA, activated pp60c- src and treatment with PP1, a specific inhibitor of the pp60c- src family, blocked the ability of 1,25(OH)2D3to activate PLD. Pretreatment of cells with pertussis toxin (PTx) markedly reduced the stimulation of PLD by either agonist. PTx, moreover, inhibited the stimulation of pp60c- src and PKC-α by 1,25(OH)2D3. PTx did not, however, block the membrane translocation of RhoA induced by 1,25(OH)2D3or inhibit the stimulation of PKC-α by TPA. These findings, taken together with those of the accompanying paper, indicate that although 1,25(OH)2D3and TPA each activate PLD in Caco-2 cells in part via PKC-α, their stimulation of PLD differs in a number of important aspects, including the requirement for pp60c- src and RhoA in the activation of PLD by 1,25(OH)2D3, but not TPA. Moreover, the requirement for different signal transduction elements by 1,25(OH)2D3and TPA to induce the stimulation of PLD may potentially underlie differences in the physiological effects of these agents in Caco-2 cells.

scholarly journals Function of small GTPases in Dictyostelium macropinocytosis

2018 ◽  
Vol 374 (1765) ◽  
pp. 20180150 ◽  
Author(s):  
Thomas D. Williams ◽  
Peggy I. Paschke ◽  
Robert R. Kay
Keyword(s):  
G Proteins ◽  
Large Scale ◽  
Small Gtpases ◽  
Ras Proteins ◽  
Cell Interior ◽  
Ras Activation ◽  
Specific Uptake ◽  
Rho Family ◽  
The Individual ◽  
Small G Proteins

Macropinocytosis—the large-scale, non-specific uptake of fluid by cells—is used by Dictyostelium discoideum amoebae to obtain nutrients. These cells form circular ruffles around regions of membrane defined by a patch of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and the activated forms of the small G-proteins Ras and Rac. When this ruffle closes, a vesicle of the medium is delivered to the cell interior for further processing. It is accepted that PIP3 is required for efficient macropinocytosis. Here, we assess the roles of Ras and Rac in Dictyostelium macropinocytosis. Gain-of-function experiments show that macropinocytosis is stimulated by persistent Ras activation and genetic analysis suggests that RasG and RasS are the key Ras proteins involved. Among the activating guanine exchange factors (GEFs), GefF is implicated in macropinocytosis by an insertional mutant. The individual roles of Rho family proteins are little understood but activation of at least some may be independent of PIP3. This article is part of the Theo Murphy meeting issue ‘Macropinocytosis’.

Mammalian G Proteins and Their Cell Type Specific Functions

2005 ◽  
Vol 85 (4) ◽  
pp. 1159-1204 ◽  
Author(s):  
Nina Wettschureck ◽  
Stefan Offermanns
Keyword(s):  
G Proteins ◽  
Sensory Information ◽  
Regulatory Proteins ◽  
Hormone Release ◽  
Heterotrimeric G Proteins ◽  
Signal Transduction System ◽  
Cell Growth And Differentiation ◽  
Cell Type Specific ◽  
And Migration ◽  
Huge Variety

Heterotrimeric G proteins are key players in transmembrane signaling by coupling a huge variety of receptors to channel proteins, enzymes, and other effector molecules. Multiple subforms of G proteins together with receptors, effectors, and various regulatory proteins represent the components of a highly versatile signal transduction system. G protein-mediated signaling is employed by virtually all cells in the mammalian organism and is centrally involved in diverse physiological functions such as perception of sensory information, modulation of synaptic transmission, hormone release and actions, regulation of cell contraction and migration, or cell growth and differentiation. In this review, some of the functions of heterotrimeric G proteins in defined cells and tissues are described.

scholarly journals Corequirement of Specific Phosphoinositides and Small GTP-binding Protein Cdc42 in Inducing Actin Assembly in Xenopus Egg Extracts

1998 ◽  
Vol 140 (5) ◽  
pp. 1125-1136 ◽  
Author(s):  
Le Ma ◽  
Lewis C. Cantley ◽  
Paul A. Janmey ◽  
Marc W. Kirschner
Keyword(s):  
G Proteins ◽  
Membrane Vesicles ◽  
Lipid Vesicles ◽  
Actin Assembly ◽  
Free System ◽  
Gtp Binding ◽  
Guanine Nucleotide Dissociation Inhibitor ◽  
Egg Extracts ◽  
Rho Family ◽  
Xenopus Egg Extracts

Both phosphoinositides and small GTP-binding proteins of the Rho family have been postulated to regulate actin assembly in cells. We have reconstituted actin assembly in response to these signals in Xenopus extracts and examined the relationship of these pathways. We have found that GTPγS stimulates actin assembly in the presence of endogenous membrane vesicles in low speed extracts. These membrane vesicles are required, but can be replaced by lipid vesicles prepared from purified phospholipids containing phosphoinositides. Vesicles containing phosphatidylinositol (4,5) bisphosphate or phosphatidylinositol (3,4,5) trisphosphate can induce actin assembly even in the absence of GTPγS. RhoGDI, a guanine-nucleotide dissociation inhibitor for the Rho family, inhibits phosphoinositide-induced actin assembly, suggesting the involvement of the Rho family small G proteins. Using various dominant mutants of these G proteins, we demonstrate the requirement of Cdc42 for phosphoinositide-induced actin assembly. Our results suggest that phosphoinositides may act to facilitate GTP exchange on Cdc42, as well as to anchor Cdc42 and actin nucleation activities. Hence, both phosphoinositides and Cdc42 are required to induce actin assembly in this cell-free system.

Structure and function of RLIP76 (RalBP1): an intersection point between Ras and Rho signalling

2014 ◽  
Vol 42 (1) ◽  
pp. 52-58 ◽  
Author(s):  
Helen R. Mott ◽  
Darerca Owen
Keyword(s):  
G Proteins ◽  
Coiled Coil ◽  
Intersection Point ◽  
Small Gtpases ◽  
Protein Domain ◽  
Atp Binding ◽  
Interacting Protein ◽  
Switch Regions ◽  
Ras Family ◽  
Rho Family

RLIP76 (Ral-interacting protein of 76 kDa) [also known as RalBP1 (Ral-binding protein 1)] is an effector for the Ral family small GTPases. RLIP76 has been implicated in a number of cell processes, including receptor-mediated endocytosis, cell migration, mitochondrial division and metabolite transport. RLIP76 has two recognizable domains in the centre of the protein sequence: a GAP (GTPase-activating protein) domain for the Rho family G-proteins and an RBD (Ral-binding domain). The remainder of RLIP76 has no discernable homology with other proteins. The RBD forms a simple coiled-coil of two α-helices, which interacts with RalB by binding to both of the nucleotide-sensitive ‘switch’ regions. Both of these RLIP76 helices are involved in the interaction with Ral, but the interhelix loop is left free. This is the location of one of the two ATP-binding sites that have been identified in RLIP76 and suggests that Ral interaction would not prevent ATP binding. The structure of the RhoGAP–RBD dyad shows that the two domains are fixed in their orientation by a relatively rigid linker. This domain arrangement allows the two domains to engage Rho family and Ral small G-proteins simultaneously at the membrane. This suggests that RLIP76 is a node for Rho and Ras family signalling.

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