Skip to main content Accessibility help
×
Hostname: page-component-cd9895bd7-jkksz Total loading time: 0 Render date: 2024-12-22T18:48:20.393Z Has data issue: false hasContentIssue false

2 - The mitogenic Pasteurella multocida toxin and cellular signalling

Published online by Cambridge University Press:  15 September 2009

Gillian D Pullinger
Affiliation:
Institute for Animal Health
Alistair J. Lax
Affiliation:
King's College London
Get access

Summary

The Pasteurella multocida toxin (PMT) is produced by some type A and D strains of the Gram-negative bacterium Pasteurella multocida. These bacteria cause several animal infections and can occasionally cause human disease. PMT is the major virulence factor associated with porcine atrophic rhinitis, a non-fatal respiratory infection characterised by loss of the nasal turbinate bones and a twisting or shortening of the snout. However, PMT is highly toxic to animals, being lethal to mice at similar concentrations to diphtheria toxin. Despite these toxic properties, it turns out that PMT has unexpected effects on cells in culture leading to perturbation of several signalling pathways. The consequence of this action is that PMT can affect the regulation of cell growth and differentiation.

PMT IS A MITOGEN

The cellular effects of PMT have been most widely studied on Swiss 3T3 cells, a mouse fibroblast cell line. These cells are useful for studying growth factors since they are contact-inhibited and are readily quiesced by growing to confluence and allowing the cells to deplete the medium of growth factors. Rozengurt et al. (1990) first showed that PMT caused quiescent Swiss 3T3 cells to recommence DNA synthesis. The toxin is highly potent, inducing maximal DNA synthesis at only 1.25 ng/ml (or about 2 pM). This is equivalent to the DNA synthesis induced by 10% foetal bovine serum. Thus, PMT is more mitogenic for this cell type than any known growth factor (Figure 2.1, top panel).

Type
Chapter
Information
Bacterial Protein Toxins
Role in the Interference with Cell Growth Regulation
, pp. 7 - 32
Publisher: Cambridge University Press
Print publication year: 2005

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Adams, J W, Sakata, Y, Davis, M G, Sah, V P, Wang, Y, Liggett, S B, Chien, K R, Brown, J H, and Dorn, G W (1998). Enhanced Gαq signalling: A common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proc. Natl. Acad. Sci. USA, 95, 10140–10145CrossRefGoogle Scholar
Baldwin M R, Lakey J H, and Lax A J (2004). Identification and characterisation of the Pasteurella multocida toxin translocation domain. Mol. Microbiol (in press)
Baldwin, M R, Pullinger, G D, and Lax, A J (2003). Pasteurella multocida toxin facilitates inositol phosphate formation by bombesin through tyrosine phosphorylation of Gαq. J. Biol. Chem., 278, 32719–32725CrossRefGoogle Scholar
Busch, C, Orth, J, and Aktories, K (2001). Biological activity of a C-terminal fragment of Pasteurella multocida toxin. Infect. Immun., 69, 3628–3634CrossRefGoogle ScholarPubMed
Buys, W E C M, Smith, H E, Kamps, A M I E, Kamp, E M, and Smits, M A (1990). Sequence of the dermonecrotic toxin of Pasteurella multocida ssp. multocida. Nucleic. Acids Res., 18, 2815–2816CrossRefGoogle ScholarPubMed
Chanter, N, Rutter, J M, and Mackenzie, A (1986). Partial purification of an osteolytic toxin from Pasteurella multocida. J. Gen. Microbiol., 132, 1089–1097Google ScholarPubMed
Chardin, P, Boquet, P, Modaule, P, Popoff, M R, Rubin, E J, and Gill, D M (1989). The mammalian G protein RhoC is ADP-ribosylated by Clostridium botulinum exoenzyme C3 and affects actin microfilaments in Vero cells. EMBO J., 8, 1087–1092Google ScholarPubMed
Donnio, P Y, Avril, J L, Andre, P M, and Vaucel, J (1991). Dermonecrotic toxin production by strains of Pasteurella multocida isolated from man. J. Med. Microbiol., 34, 333–337CrossRefGoogle ScholarPubMed
Dudet, L I, Chailler, P, Dubreuil, J D, and Martineau-Doize, B (1996). Pasteurella multocida toxin stimulates mitogenesis and cytoskeleton reorganization in Swiss 3T3 fibroblasts. J. Cell Physiol., 168, 173–1823.0.CO;2-7>CrossRefGoogle ScholarPubMed
Dyer, N W, Haynes, J S, Ackermann, M R, and Rimler, R (1998). Morphological effects of Pasteurella multocida type-D dermonecrotoxin on rat osteosarcoma cells in a nude mouse model. J. Comp. Pathol., 119, 149–158CrossRefGoogle Scholar
Essler, M, Hermann, K, Amano, M, Kaibuchi, K, Heesemann, J, Weber, P C, and Aepfelbacher, M (1998). Pasteurella multocida toxin increases endothelial permeability via Rho kinase and myosin light chain phosphatase. J. Immunol., 161, 5640–5646Google ScholarPubMed
Fukuhara, S, Murga, C, Zohar, M, Igishi, T, and Gutkind, J S (1999). A novel PDZ domain containing guanine nucleotide exchange factor links heterotrimeric G proteins to Rho. J. Biol. Chem., 274, 5868–5879CrossRefGoogle ScholarPubMed
Gilman, A G (1987). G proteins: Transducers of receptor-generated signals. Annu. Rev. Biochem., 56, 615–649CrossRefGoogle ScholarPubMed
Gutkind, J S (1998). The pathways connecting G protein-coupled receptors to the nucleus through divergent mitogen-activated protein kinase cascades. J. Biol. Chem., 273, 1839–1842CrossRefGoogle ScholarPubMed
Hart, M J, Jiang, X, Kozasa, T, Roscoe, W, Singer, W D, Gilman, A G, Sternweis, P C, and Bollag, G (1998). Direct stimulation of the guanine nucleotide exchange activity of p115 RhoGEF by Gα13. Science, 280, 2112–2114CrossRefGoogle ScholarPubMed
Higgins, T E, Murphy, A C, Staddon, J M, Lax, A J, and Rozengurt, E (1992). Pasteurella multocida toxin is a potent inducer of anchorage-independent cell growth. Proc. Natl. Acad. Sci. USA, 89, 4240–4244CrossRefGoogle ScholarPubMed
Hoskins, I C, Thomas, L H, and Lax, A J (1997). Nasal infection with Pasteurella multocida causes proliferation of bladder epithelium in gnotobiotic pigs. Vet. Rec., 140, 22CrossRefGoogle ScholarPubMed
James, S R and Downes, C P (1997). Structural and mechanistic features of phospholipases C: Effectors of inositol phospholipid-mediated signal transduction. Cell. Signal., 5, 329–336CrossRefGoogle Scholar
Kamps, A M I E, Kamp, E M, and Smits, M A (1990). Cloning and expression of the dermonecrotic toxin gene of Pasteurella multocida ssp. multocida in Escherichia coli. FEMS Microbiol. Lett., 67, 187–190CrossRefGoogle Scholar
Kimura, K, Ito, M, Amano, M, Chihara, K, Fukata, Y, Nakafuku, M, Yamamori, B, Feng, J, Nakano, T, Okawa, K, Iwamatsu, A, and Kaibuchi, K (1996). Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science, 273, 245–248CrossRefGoogle Scholar
Kozasa, T, Jiang, X, Hart, M J, Sternweis, P M, Singer, W D, Gilman, A G, Bollag, G, and Sternweis, P C (1998). p115 RhoGEF, a GTPase activating protein for Gα12 and Gα13. Science, 280, 2109–2111CrossRefGoogle ScholarPubMed
Lacerda, H M, Lax, A J, and Rozengurt, E (1996). Pasteurella multocida toxin, a potent intracellularly acting mitogen, induces p125FAK and paxillin tyrosine phosphorylation, actin stress fiber formation, and focal contact assembly in Swiss 3T3 cells. J. Biol. Chem., 271, 439–445CrossRefGoogle ScholarPubMed
Lacerda, H M, Pullinger, G D, Lax, A J, and Rozengurt, E. (1997). Cytotoxic necrotizing factor 1 from Escherichia coli and dermonecrotic toxin from Bordetella bronchiseptica induce p21rho-dependent tyrosine phosphorylation of focal adhesion kinase and paxillin in Swiss 3T3 cells. J. Biol. Chem., 272, 9587–9596CrossRefGoogle ScholarPubMed
Lax, A J and Chanter, N (1990). Cloning of the toxin gene from Pasteurella multocida and its role in atrophic rhinitis. J. Gen. Microbiol., 136, 81–87CrossRefGoogle ScholarPubMed
Lax, A J, Chanter, N, Pullinger, G D, Higgins, T, Staddon, J M, and Rozengurt, E (1990). Sequence analysis of the potent mitogenic toxin of Pasteurella multocida. FEBS Lett., 277, 59–64CrossRefGoogle ScholarPubMed
Lemichez, E, Flatau, G, Bruzzone, M, Boquet, P, and Gauthier, M (1997). Molecular localization of the Escherichia coli cytotoxic necrotizing factor CNF1 cell-binding and catalytic domains. Mol. Microbiol., 24, 1061–1070CrossRefGoogle ScholarPubMed
Mullan, P B and Lax, A J (1996). Pasteurella multocida toxin is a mitogen for bone cells in primary culture. Infect. Immun., 64, 959–965Google ScholarPubMed
Murphy, A C and Rozengurt, E (1992). Pasteurella multocida toxin selectively facilitates phosphatidylinositol 4,5-bisphosphate hydrolysis by bombesin, vasopressin and endothelin. Requirement for a functional G protein. J. Biol. Chem., 267, 25296–25303Google ScholarPubMed
Nakai, T, Sawata, A, Tsuji, M, Samejima, Y, and Kume, K (1984). Purification of dermonecrotic toxin from a sonic extract of Pasteurella multocida SP-72 serotype D. Infect. Immun., 46, 429–434Google ScholarPubMed
Neer, E J (1995). Heterotrimeric G proteins: Organizers of transmembrane signals. Cell, 80, 249–257CrossRefGoogle ScholarPubMed
Olsnes, S, Deurs, B, and Sandvig, K (1993). Protein toxins acting on intracellular targets: Cellular uptake and translocation to the cytosol. Med. Microbiol. Immun., 182, 51–61CrossRefGoogle ScholarPubMed
Orth, J H C, Blocker, D, and Aktories, K (2003). His1205 and His1223 are essential for the activity of the mitogenic Pasteurella multocida toxin. Biochemistry, 42, 4971–4977CrossRefGoogle ScholarPubMed
Parsons, J T and Parsons, S J (1997). Src family protein tyrosine kinases: Cooperating with growth factor and adhesion signalling pathways. Curr. Opin. Cell Biol., 9, 187–192CrossRefGoogle Scholar
Pedersen, K B and Barfod, K (1981). The aetiological significance of Bordetella bronchiseptica and Pasteurella multocida in atrophic rhinitis of swine. Nord. Vet. Med., 33, 513–522Google ScholarPubMed
Petersen, S K (1990). The complete nucleotide sequence of the Pasteurella multocida toxin gene and evidence for a transcriptional repressor, TxaR. Mol. Microbiol., 4, 821–830CrossRefGoogle ScholarPubMed
Petersen, S K and Foged, N T (1989). Cloning and expression of the Pasteurella multocida toxin gene, toxA, in Escherichia coli. Infect. Immun., 57, 3907–3913Google ScholarPubMed
Petersen, S K, Foged, N T, Bording, A, Nielsen, J P, Riemann, H K, and Frandsen, P L (1991). Recombinant derivatives of Pasteurella multocida toxin: Candidates for a vaccine against progressive atrophic rhinitis. Infect. Immun., 59, 1387–1393Google ScholarPubMed
Pettit, R K, Ackermann, M R, and Rimler, R B (1993). Receptor-mediated binding of Pasteurella multocida dermonecrotic toxin to canine osteosarcoma and monkey kidney (vero) cells. Lab. Invest., 69, 94–100Google ScholarPubMed
Pullinger, G D, Bevir, T, and Lax, A J (2004). The Pasteurella multocida toxin is encoded within a lysogenic bacteriophage. Mol. Microbiol., 51, 255–269CrossRefGoogle ScholarPubMed
Pullinger, G D, Sowdhamini, R, and Lax, A J (2001). Localization of functional domains of the mitogenic toxin of Pasteurella multocida. Infect. Immun., 69, 7839–7850CrossRefGoogle ScholarPubMed
Rhee, S G (2001). Regulation of phosphoinositide-specific phospholipase C. Annu. Rev. Biochem., 70, 281–312CrossRefGoogle ScholarPubMed
Ridley, A J and Hall, A (1992). The small GTP-binding protein Rho regulates the assembly of focal adhesions and actin stress fibres in response to growth factors. Cell, 70, 389–399CrossRefGoogle ScholarPubMed
Rozengurt, E, Higgins, T, Chanter, N, Lax, A J, and Staddon, J M (1990). Pasteurella multocida toxin: Potent mitogen for cultured fibroblasts. Proc. Natl. Acad. Sci. USA, 87, 123–127CrossRefGoogle ScholarPubMed
Rutter, J M, Francis, L M A, and Sansom, B F (1982). Virulence of Bordetella bronchiseptica from pigs with or without atrophic rhinitis. J. Med. Microbiol., 15, 105–116CrossRefGoogle ScholarPubMed
Rutter, J M and Luther, P D (1984). Cell culture assay for toxigenic Pasteurella multocida from atrophic rhinitis of pigs. Vet. Rec., 114, 393–396CrossRefGoogle ScholarPubMed
Rutter, J M and Mackenzie, A (1984). Pathogenesis of atrophic rhinitis in pigs: A new perspective. Vet. Rec., 114, 89–90CrossRefGoogle ScholarPubMed
Rutter, J M and Rojas, X (1982). Atrophic rhinitis in gnotobiotic piglets: Differences in the pathogenicity of Pasteurella multocida in combined infections with Bordetella bronchiseptica. Vet. Rec., 110, 531–535Google Scholar
Sabri, A, Wilson, B A, and Steinberg, S F (2002). Dual actions of the Gαq agonist Pasteurella multocida toxin to promote cardiomyocyte hypertrophy and enhance apoptosis susceptibility. Circ. Res., 90, 850–857CrossRefGoogle Scholar
Sasaki, T and Takai, Y (1998). The Rho small G protein family-RhoGDI system as a temporal and spatial determinant for cytoskeletal control. Biochem. Biophys. Res. Commun., 245, 641–645CrossRefGoogle ScholarPubMed
Seo, B, Choy, E W, Maudsley, S, Miller, W E, Wilson, B A, and Luttrell, L M (2000). Pasteurella multocida toxin stimulates mitogen-activated protein kinase via Gq/11-dependent transactivation of the epidermal growth factor receptor. J. Biol. Chem., 275, 2239–2245CrossRefGoogle Scholar
Smyth, M G, Pickersgill, R W, and Lax, A J (1995). The potent mitogen Pasteurella multocida toxin is highly resistant to proteolysis but becomes susceptible at lysosomal pH. FEBS Lett., 360, 62–66CrossRefGoogle ScholarPubMed
Smyth, M G, Sumner, I G, and Lax, A J (1999). Reduced pH causes structural changes in the potent mitogenic toxin of Pasteurella multocida. FEMS Microbiol. Lett., 180, 15–20CrossRefGoogle ScholarPubMed
Sprang, S R (1997). G protein mechanisms: Insights from structural analysis. Annu. Rev. Biochem., 66, 639–678CrossRefGoogle ScholarPubMed
Staddon, J M, Barker, C J, Murphy, A C, Chanter, N, Lax, A J, Michell, R H, and Rozengurt, E (1991a). Pasteurella multocida toxin, a potent mitogen, increases inositol 1,4,5-trisphosphate and mobilizes Ca2+ in Swiss 3T3 cells. J. Biol. Chem., 266, 4840–4847Google Scholar
Staddon, J M, Bouzyk, M M, and Rozengurt, E (1991b). A novel approach to detect toxin-catalyzed ADP-ribosylation in intact cells: Its use to study the action of Pasteurella multocida toxin. J. Cell Biol., 115, 949–958CrossRefGoogle Scholar
Staddon, J M, Chanter, N, Lax, A J, Higgins, T E, and Rozengurt, E (1990). Pasteurella multocida toxin, a potent mitogen, stimulates protein kinase C-dependent and -independent protein phosphorylation in Swiss 3T3 cells. J. Biol. Chem., 265, 11841–11848Google ScholarPubMed
Switzer W P and Farrington D O (1975). Infectious atrophic rhinitis. In Diseases of Swine, ed H. W. Dunne and A D. Leman, 4th edn, pp. 687–711. Ames: Iowa State University Press
Thomas, W, Pullinger, G D, Lax, A J, and Rozengurt, E (2001). Escherichia coli cytotoxic necrotizing factor and Pasteurella multocida toxin induce focal adhesion kinase autophosphorylation and Src association. Infect. Immun., 69, 5931–5935CrossRefGoogle ScholarPubMed
Varmus, H E (1984). The molecular genetics of cellular oncogenes. Annu. Rev. Genet., 18, 553–612CrossRefGoogle ScholarPubMed
Ward, P N, Higgins, T E, Murphy, A C, Mullan, P B, Rozengurt, E, and Lax, A J (1994). Mutation of a putative ADP-ribosylation motif in the Pasteurella multocida toxin does not affect mitogenic activity. FEBS Lett., 342, 81–84CrossRefGoogle Scholar
Ward, P N, Miles, A J, Sumner, I G, Thomas, L H, and Lax, A J (1998). Activity of the mitogenic Pasteurella multocida toxin requires an essential C-terminal residue. Infect. Immun., 66, 5636–5642Google ScholarPubMed
Wilson, B A, Aminova, L R, Ponferrada, V G, and Ho, M (2000). Differential modulation and subsequent blockade of mitogenic signalling and cell cycle progression by Pasteurella multocida toxin. Infect. Immun., 68, 4531–4538CrossRefGoogle Scholar
Wilson, B A, Ponferrada, V G, Vallance, J E, and Ho, M (1999). Localization of the intracellular activity domain of Pasteurella multocida toxin to the N terminus. Infect. Immun., 67, 80–87Google ScholarPubMed
Wilson, B A, Zhu, X, Ho, M, and Lu, L (1997). Pasteurella multocida toxin activates the inositol trisphosphate signaling pathway in Xenopus oocytes via Gqα-coupled phospholipase C-β1. J. Biol. Chem., 272, 1268–1275CrossRefGoogle Scholar
Zywietz, A, Gohla, A, Schmelz, M, Schultz, G, and Offermanns, S (2001). Pleiotropic effects of Pasteurella multocida toxin are mediated by Gq-dependent and -independent mechanisms. Involvement of Gq but not G11. J. Biol. Chem., 276, 3840–3845CrossRefGoogle Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×