C-Terminal motifs found in Ras-superfamily G-proteins: CAAX and C-seven motifs

Villar, Keith Del; Dorin, Dominique; Sattler, Isabel; Urano, Jun; Poullet, Patrick; Robinson, Nicole; Mitsuzawa, H.; Tamanoi, Fuyuhiko

doi:10.1042/bst0240709

Cited by 33 publications

(27 citation statements)

References 9 publications

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“…Thus, although we cannot exclude the possibility that the lipidation of ANXA1 is a transient event, perhaps essential for the passage of ANXA1 across the plasma membrane (Fig. 10); it seems more likely that the targets are signaling intermediates, for example RAS and PKC, which are substrates for farnesylation and myristoylation, respectively (42,43).…”

Section: Discussionmentioning

confidence: 99%

Post‐translational modification plays an essential role in the translocation of annexin A1 from the cytoplasm to the cell surface

et al. 2006

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Annexin A1 (ANXA1) has an important role in cell-cell communication in the host defense and neuroendocrine systems. In both systems, its actions are exerted extracellularly via membrane-bound receptors on adjacent sites after translocation of the protein from the cytoplasm to the cell surface of adjacent cells. This study used molecular, microscopic, and pharmacological approaches to explore the mechanisms underlying the cellular exportation of ANXA1 in TtT/GF (pituitary folliculo-stellate) cells. LPS caused serine-phosphorylation of ANXA1 (ANXA1-S 27 -PO 4 ) and translocation of the phosphorylated protein to the cell membrane. The fundamental requirement of phosphorylation for membrane translocation was confirmed by immunofluorescence microscopy on cells transfected with wild-type or mutated (S 27 /A) ANXA1 constructs tagged with enhanced green fluorescence protein.The trafficking of ANXA1-S 27 -PO 4 to the cell surface was dependent on PI3-kinase and MAPkinase. It also required HMG-coenzyme A and myristoylation. The effects of HMG-coenzyme A blockade were overcome by mevalonic acid (the product of HMG-coenzyme A) and farnesylpyrophosphate but not by geranyl-geranylpyrophosphate or cholesterol. Together, these results suggest that serine-27 phosphorylation is essential for the translocation of ANXA1 across the cell membrane and also identify a role for isoprenyl lipids. Such lipids could target consensus sequences in ANXA1. Alternatively, they may target other proteins in the signal transduction cascade (e.g., transporters). Keywordsphosphorylation; green fluorescence protein; lipidation; signaling Annexin A1 (ANXA1) is a Ca 2+ -and phospholipids-binding protein that acts both intracellularly and extracellularly to modulate cell signaling. Data from our laboratory have shown that it has a particularly important role in the regulation of the host defense and neuroendocrine systems and that ANXA1 mimetics may provide a novel therapeutic approach to the control of inflammatory disease (reviewed in ref 1). The regulatory actions of ANXA1 in both systems appear to be exerted mainly extracellularly, via membrane-bound cell surface receptors (2-4). Access of endogenous ANXA1 to these receptors is thus dependent on the translocation of the protein from its cytoplasmic stores to the cell surface (1). These conclusions are supported by evidence that within the neuroendocrine system ANXA1 is expressed in cells adjacent to its target cells (5), and it is concentrated at sites where the cells make contact with UKPMC Funders Group Author ManuscriptUKPMC Funders Group Author Manuscript endocrine cells (6) and translocated to the cell surface in response to appropriate stimuli (7,8). Further evidence of the paracrine/juxtacrine mode of ANXA1 action is provided by evidence that drugs that prevent the cellular exportation of the protein ablate the regulatory actions of endogenous ANXA1 within the neuroendocrine system (6,7,9,10) as also do compounds that destroy the cell surface ANXA1 receptors (2). Substantial evidence...

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Section: Discussionmentioning

confidence: 99%

Post‐translational modification plays an essential role in the translocation of annexin A1 from the cytoplasm to the cell surface

et al. 2006

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“…RhoA is an essential host cell protein with GTPase activity and is known to influence a variety of signaling pathways and basic cell functions (11,20). One of the steps in RhoA activation is geranylgeranylation at its carboxy terminus, which allows RhoA to be attached to the plasma membrane (1,6,13,19). We have shown that activated RhoA and subsequent signaling events are required for RSV syncytium formation and viral filament formation (Gower et al, unpublished observation).…”

Section: Discussionmentioning

confidence: 99%

“…This is of particular interest because of the association of RSV with childhood asthma (32,33). Cytoplasmic RhoA is activated by an exchange of GTP for GDP and by attachment to the intracellular side of the plasma membrane after isoprenylation by geranylgeranyltransferase at the carboxy-terminal cysteine of the protein (1,6,13,19,23). Activation of RhoA in a cell affects production of several cytokines, such as interleukin-1-beta (IL-1␤), IL-6, and IL-8, which are produced by RSVinfected cells (4), and alters cytoskeletal structure by inducing organization of actin stress fibers and formation of focal adhesion plaques (11,20,28,34).…”

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confidence: 99%

Antiviral Activity of Lovastatin against Respiratory Syncytial Virus In Vivo and In Vitro

Gower

Graham

2001

Antimicrob Agents Chemother

114

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Respiratory syncytial virus (RSV) is an important human pathogen that can cause severe and life-threatening respiratory infections in infants and immunocompromised adults. We have recently shown that the RSV F glycoprotein, which mediates viral fusion, binds to RhoA. One of the steps in RhoA activation involves isoprenylation at the carboxy terminus of the protein by geranylgeranyltransferase. This modification allows RhoA to be attached to phosphatidyl serine on the inner leaflet of the plasma membrane. Treatment of mice with lovastatin, a drug that inhibits prenylation pathways in the cell by directly inhibiting hydroxymethylglutaryl coenzyme A reductase, diminishes RSV but not vaccinia virus replication when administered up to 24 h after RSV infection and decreases virus-induced weight loss and illness in mice. The inhibition of replication is not likely due to the inhibition of cholesterol biosynthesis, since gemfibrozil, another cholesterol-lowering agent, did not affect virus replication and serum cholesterol levels were not significantly lowered by lovastatin within the time frame of the experiment. Lovastatin also reduces cell-to-cell fusion in cell culture and eliminates RSV replication in HEp-2 cells. These data indicate that lovastatin, more specific isoprenylation inhibitors, or other pharmacological approaches for preventing RhoA membrane localization should be considered for evaluation as a preventive antiviral therapy for selected groups of patients at high risk for severe RSV disease, such as the institutionalized elderly and bone marrow or lung transplant recipients.

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“…The motif regions G-1 through G-5, characteristic of GTPases (9), are present in Dexras1. In addition, the C terminus has a typical CAAX motif (9,11,12). In Ras family members, this C-terminal region characteristically undergoes prenylation (in this case, farnesylation), involving addition of a hydrophobic farnesyl group to the cysteine and removal of the three C-terminal amino acids (11,12).…”

Section: Novel Ras-related Gene Induced By Glucocorticoids 3130mentioning

confidence: 99%

Dexamethasone Rapidly Induces a Novel Ras Superfamily Member-related Gene in AtT-20 Cells

Kemppainen

Behrend

1998

Journal of Biological Chemistry

165

138

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Differential display was used to identify a newThe gene was also identified in mouse heart, brain, liver, and kidney and furthermore was induced in these tissues after Dex treatment. The deduced protein shows regions of homology characteristic of members of the Ras superfamily of small GTPases. Highest homology (36% identity, 57% positives) was found with human Rap-2b, followed closely by a number of other Ras subfamily members, suggesting that Dexras1 is probably a member of the Ras subfamily of GTPases (members include Ras and Rap). Dexras1 is the first Ras superfamily member identified that is induced in response to steroids. The function of this gene is unknown; however, its wide distribution and rapid induction by Dex suggests the possibility of a role in glucocorticoid action in a variety of tissues.The intracellular mechanism mediating glucocorticoid inhibition of stimulated corticotropin (ACTH) 1 release from the corticotrophs in the anterior pituitary gland in the early time domain is unknown. Exposure of corticotrophs to glucocorticoids for periods ranging from approximately 10 min to 3 h (early time domain) inhibits ACTH secretion induced by a variety of secretagogues, including corticotropin-releasing hormone and arginine vasopressin (1). Results of several studies indicate that the inhibitory effect in this time domain is mediated through induction of new protein synthesis, because this suppression can be blocked by inhibitors of transcription and translation (1, 2). Several proteins have been proposed as mediating feedback (1); however, it is presently unclear if they are involved in the process.Differential display is a method for identifying and cloning induced genes (3). The method involves synthesis of cDNA from mRNA by reverse transcription followed by PCR amplification of 3Ј-termini of the cDNA fragments using combinations of downstream (oligo(dT)) and upstream arbitrary primers. The labeled, amplified fragments are separated on polyacrylamide gels, and induced fragments are identified by comparison with bands originating from RNA isolated from noninduced cells or tissues.In an attempt to identify the gene(s) and protein(s) mediating early feedback, we used differential display to isolate dexamethasone (Dex)-induced genes in AtT-20 cells. These mousederived corticotroph tumor cells have been shown to be an appropriate model for study of feedback regulation of ACTH secretion (2, 4). EXPERIMENTAL PROCEDURESDifferential Display-Total RNA was collected from AtT-20/D16 -16 cells cultured using standard methods (4). Cells were cultured in 75-cm 2 flasks and treated either with Dex at 100 nM for 2-24 h or with an equivalent volume of ethanol (vehicle). RNA was collected using phenol/ guanidine isothiocyanate (TRIzol, Life Technologies, Inc.) and was treated with DNase I to remove chromosomal DNA. Differential display was performed using the RNAimage system (GenHunter, Nashville, TN) using combinations of three one-base-anchored oligo(dT) primers (-G, -A, and -C) and 80 upstream primers for PCR.33 P-...

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C-Terminal motifs found in Ras-superfamily G-proteins: CAAX and C-seven motifs

Cited by 33 publications

References 9 publications

Post‐translational modification plays an essential role in the translocation of annexin A1 from the cytoplasm to the cell surface

Post‐translational modification plays an essential role in the translocation of annexin A1 from the cytoplasm to the cell surface

Antiviral Activity of Lovastatin against Respiratory Syncytial Virus In Vivo and In Vitro

Dexamethasone Rapidly Induces a Novel Ras Superfamily Member-related Gene in AtT-20 Cells

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