Cytotoxic Necrotizing Factor 1 from Escherichia coli and Dermonecrotic Toxin from Bordetella bronchiseptica Induce p21 -dependent Tyrosine Phosphorylation of Focal Adhesion Kinase and Paxillin in Swiss 3T3 Cells

Lacerda, Hadriano M.; Pullinger, Gill D.; Lax, Alistair J.; Rozengurt, Enrique

doi:10.1074/jbc.272.14.9587

Cited by 91 publications

(93 citation statements)

References 76 publications

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Section: Introductionmentioning

confidence: 99%

“…Although Rho, Rac and Cdc42 are mainly involved in the actin cytoskeleton organization (Hall, 1998), it is known that these proteins are also involved in a huge number of other cellular processes, such as gene transcription, cell proliferation, and survival. Thus, the consequence of CNF1-induced Rho activation is the induction of a number of actin-dependent phenomena, such as contractility, cell spreading (Fiorentini et al, 1988), assembly of focal adhesion plaques (Lacerda et al, 1997), and the induction of macropinocytosis (Falzano et al, 1993;Fiorentini et al, 2001), as well as the stimulation of new activities in cells, including the ability to counteract apoptosis (Fiorentini et al, 1998).It is well known that, among the several molecules implied in the regulation of apoptotic cell death, an important role is played by the transcription factor nuclear factor-B (NF-B), whose activation has been reported to protect from various apoptotic stimuli in different cellular systems (for review, see Shishodia and Aggarwal, 2002). In this context, we recently demonstrated the ability of CNF1 to induce the activation of NF-B , highlighting a possible involvement of this transcription factor in the toxininduced cell survival.…”

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confidence: 99%

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Cytotoxic Necrotizing Factor 1 Prevents Apoptosis via the Akt/IκB Kinase Pathway: Role of Nuclear Factor-κB and Bcl-2

Miraglia

Travaglione²,

Meschini

et al. 2007

MBoC

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Cytotoxic necrotizing factor 1 (CNF1) is a protein toxin produced by some pathogenic strains of Escherichia coli that specifically activates Rho, Rac, and Cdc42 GTPases. We previously reported that this toxin prevents the ultraviolet-Binduced apoptosis in epithelial cells, with a mechanism that remained to be defined. In this work, we show that the proteasomal degradation of the Rho GTPase is necessary to achieve cell death protection, because inhibition of Rho degradation abolishes the prosurvival activity of CNF1. We hypothesize that Rho inactivation allows the activity of Rac to become dominant. This in turn leads to stimulation of the phosphoinositide 3-kinase/Akt/I B kinase/nuclear factor-B prosurvival pathway and to a remarkable modification in the architecture of the mitochondrial network, mainly consisting in the appearance of elongated and interconnected mitochondria. Importantly, we found that Bcl-2 silencing reduces the ability of CNF1 to protect cells against apoptosis and that it also prevents the CNF1-induced mitochondrial changes. It is worth noting that the ability of a bacterial toxin to induce such a remodeling of the mitochondrial network is herein reported for the first time. The possible pathophysiological relevance of this finding is discussed. INTRODUCTIONToday, it is largely acknowledged that apoptosis, besides being an evolutionary conserved form of cell death that plays a pivotal role during development, morphogenesis, and cell homeostasis, is also critically implied in a constantly growing number of diseases (Fadeel and Orrenius, 2005). In fact, apoptosis can be regarded as a widespread strategy exploited by pathogenic bacteria to favor their own survival or spreading in the host , often by producing protein toxins that mediate their long-range cross-talk with host cells. In this context, we have previously reported the ability of a protein toxin from Escherichia coli, namely the cytotoxic necrotizing factor 1 (CNF1), to prevent the ultraviolet-B (UVB)-induced apoptosis and to increase the expression of antiapoptotic Bcl-2 family proteins (Fiorentini et al., 1998). The precise mechanism by which CNF1 allows cells to survive, however, is not yet defined.CNF1 is a protein toxin produced by some pathogenic strains of E. coli mainly involved in extraintestinal infections (Landraud et al., 2000). In eukaryotic cells, CNF1 binds to its receptor, reported to be the receptor of laminin , and it is endocytosed and released into the cytoplasm by an acidic-dependent mechanism (Contamin et al., 2000). Once in the cytoplasm, CNF1 exerts its enzymatic activity that is represented by deamidation of a pivotal glutamine residue of the guanosine triphosphate (GTP)-binding proteins Rho, Rac, and Cdc42 (glutamine 63 of Rho or glutamine 61 of Rac and Cdc42), giving rise to a glutamic acid (Flatau et al., 1997;Schmidt et al., 1997;Lerm et al., 1999). The glutamine residue modified by CNF1 lies in the switch 2 domain of Rho proteins, which is involved in GTP hydrolysis; thus, the modification exerted by CNF1...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Cytotoxic Necrotizing Factor 1 Prevents Apoptosis via the Akt/IκB Kinase Pathway: Role of Nuclear Factor-κB and Bcl-2

Miraglia

Travaglione²,

Meschini

et al. 2007

MBoC

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“…We and others have shown that the cellular effects of CNF1 can be antagonized by weak bases such as ammonium chloride (Falzano et al, 1993) and methylamine (Lacerda et al, 1997), suggesting that a low pH step is necessary for the toxin to penetrate into the cytosol. As shown in Figure 6, bafilomycin A1 and monensin, which block acidification of endosomal and lysosomal compartments, are strong inhibitors of CNF1 cellular activity.…”

Section: Cnf1 Requires An Acidic Ph-dependent Mechanism To Translocatmentioning

confidence: 90%

“…It is well established that the cellular effects of CNF1 can be antagonized by agents that increase endosomal pH such as ammonium chloride (Falzano et al, 1993) and methylamine (Lacerda et al, 1997). By analogy with DT (Sandvig and Olsnes, 1991), it has been assumed that CNF1 must reach an acidic cell compartment to translocate its deamidase activity into the cytosol.…”

Section: Introductionmentioning

confidence: 99%

“…The enzymatic domain of CNF1 lies within a 300-amino-acid domain located at the carboxyl terminus of the toxin (Lemichez et al, 1997b;Schmidt et al, 1998), and the cell-receptor binding domain is located within amino acids 53-190 (Fabbri et al, 1999). Figure 1 depicts the molecular organization of CNF1.It is well established that the cellular effects of CNF1 can be antagonized by agents that increase endosomal pH such as ammonium chloride (Falzano et al, 1993) and methylamine (Lacerda et al, 1997). By analogy with DT (Sandvig and Olsnes, 1991), it has been assumed that CNF1 must reach an acidic cell compartment to translocate its deamidase activity into the cytosol.…”

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The p21 Rho-activating Toxin Cytotoxic Necrotizing Factor 1 Is Endocytosed by a Clathrin-independent Mechanism and Enters the Cytosol by an Acidic-dependent Membrane Translocation Step

Contamin

Galmiche

Doye

et al. 2000

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100

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Cytotoxic necrotizing factor 1 (CNF1), a protein produced by pathogenic strains of Escherichia coli, activates the p21 Rho-GTP-binding protein, inducing a profound reorganization of the actin cytoskeleton. CNF1 binds to its cell surface receptor on HEp-2 cells with high affinity (K d ϭ 20 pM). In HEp-2 cells the action of CNF1 is not blocked in the presence of filipin, a drug described to reduce cholera toxin internalization by the caveolae-like mechanism. Moreover, HEp-2 cells, which express a dominant negative form of proteins that impair the formation of clathrin coated-vesicles and internalization of transferrin (Eps15, dynamin or intersectin-Src homology 3), are still sensitive to CNF1. In this respect, the endocytosis of CNF1 is similar to the plant toxin ricin. However, unlike ricin toxin, CNF1 does not cross the Golgi apparatus and requires an acidic cell compartment to transfer its enzymatic activity into the cytosol in a manner similar to that required by diphtheria toxin. As shown for diphtheria toxin, the pH-dependent membrane translocation step of CNF1 could be mimicked at the level of the plasma membrane by a brief exposure to a pH of Յ5.2. CNF1 is the first bacterial toxin described that uses both a clathrinindependent endocytic mechanism and an acidic-dependent membrane translocation step in its delivery of the catalytic domain to the cell cytosol. INTRODUCTIONBacterial protein toxins are among the most powerful virulence factors produced by pathogenic microorganisms. In general, these toxins are divided into three groups according to their mechanism of action (Boquet and Gill, 1991). Group I toxins such as the heat-stable Escherichia coli enterotoxin (reviewed by Sears and Kaper, 1996) act on cell surface where they induce transmembrane signaling. Group II toxins or "pore-forming toxins" (e.g., perfringolysin O, Staphylococcus aureus alpha toxin, and aerolysin [reviewed by Bhakdi et al., 1996]) act by disrupting the integrity of the plasma membrane. Finally, group III toxins, such as diphtheria, cholera, or tetanus toxins, transfer an enzymatically active domain into the cytosol and modify a eukaryotic target, which gives rise to toxicity (reviewed by Montecucco et al., 1994). The latter group is clearly the most potent, because it is believed that one or a few copies of the toxin enzymatic domain, for instance of the diphtheria toxin (DT) fragment A, introduced into the cytosol can kill a cell within 2 d (Yamaizumi et al., 1978). Group III toxins are also known as A-B toxins on the basis of their structure-function relationships, which involve a catalytic domain (the A subunit) and cell binding and membrane translocation domains (the B subunit).Translocation of the catalytic domain of the type III toxins into the eukaryotic cytosol appears to be accomplished by either one or two mechanisms (reviewed by Johannes and Goud, 1998;Lord and Roberts, 1998;Montecucco, 1998). In the first instance, for which the paradigm is DT (Sandvig and Olsnes, 1991), the toxin first binds to its cell surface and is ...

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Signal transduction pathways in the mitogenic response to G protein-coupled neuropeptide receptor agonists

Rozengurt

1998

J. Cell. Phys.

Self Cite

158

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Neuropeptides, including mammalian bombesin-like peptides, act as potent cellular growth factors and have been implicated in a variety of normal and abnormal processes, including development, inflammation, and malignant transformation. These signaling peptides exert their characteristic effects on cellular processes by binding to specific G protein-coupled receptors (GPCR) on the surface of their target cells. Typically, the binding of a neuropeptide to its cognate GPCR triggers the activation of multiple signal transduction pathways that act in a synergistic and combinatorial fashion to relay the mitogenic signal to the nucleus and promote cell proliferation. A rapid increase in the synthesis of lipid-derived second messengers with subsequent activation of protein phosphorylation cascades is an important early response to neuropeptides. An emerging theme in signal transduction is that these agonists also induce rapid and coordinate tyrosine phosphorylation of cellular proteins including the nonreceptor tyrosine kinase p125fak and the adaptor proteins p130cas and paxillin. This tyrosine phosphorylation pathway depends on the integrity of the actin cytoskeleton and requires functional Rho. The purpose of this article is to review recent advances in unraveling the pathways that play a role in transducing mitogenic and migratory responses induced by G protein-coupled neuropeptide receptor agonists.

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Cytotoxic Necrotizing Factor 1 from Escherichia coli and Dermonecrotic Toxin from Bordetella bronchiseptica Induce p21 -dependent Tyrosine Phosphorylation of Focal Adhesion Kinase and Paxillin in Swiss 3T3 Cells

Cited by 91 publications

References 76 publications

Cytotoxic Necrotizing Factor 1 Prevents Apoptosis via the Akt/IκB Kinase Pathway: Role of Nuclear Factor-κB and Bcl-2

Cytotoxic Necrotizing Factor 1 Prevents Apoptosis via the Akt/IκB Kinase Pathway: Role of Nuclear Factor-κB and Bcl-2

The p21 Rho-activating Toxin Cytotoxic Necrotizing Factor 1 Is Endocytosed by a Clathrin-independent Mechanism and Enters the Cytosol by an Acidic-dependent Membrane Translocation Step

Signal transduction pathways in the mitogenic response to G protein-coupled neuropeptide receptor agonists

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