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Pasteurella multocida toxin: the mitogenic toxin that stimulates signalling cascades to regulate growth and
1Department of Oral Microbiology, Guy's King's and St Thomas' Dental Institute, King's College London, UK. alistair.lax@kcl.ac.uk
Abstract:
Pasteurella multocida toxin (PMT) is an unusual toxin that acts as a mitogen by stimulating various intracellular signalling cascades. Pathways downstream of the G-protein Gq and also downstream of the Rho proteins are activated. Thus PMT action stimulates phospholipase C leading to activation of protein kinase C, an increase in inositol phosphates, and a rise in intracellular calcium. Rho activation of the Rho kinase leads to cytoskeletal reorganisation, tyrosine phosphorylation of the focal adhesion kinase, and activation of the Src proto-oncogene. In addition, signalling through the Ras-MAP kinase signalling pathway is also initiated. PMT is an intracellularly acting toxin, and functional domains that carry out different aspects of its function have been described. The intracellular target of the toxin is currently not known. PMT also acts to inhibit differentiation, in particular of bone cells, where it prevents the formation of mineralised bone nodules in vitro. The toxin is the causative agent of a porcine disease that is characterised by bone resorption. Injection of very low doses of toxin leads to proliferative effects, but at higher doses is lethal. The possible effect of PMT-induced perturbation of signal transduction pathways is discussed.
Insights
Pasteurella multocida toxin (PMT) activates multiple cell signaling pathways, impacting cell growth and differentiation. This toxin inhibits bone cell differentiation, contributing to bone resorption in porcine diseases.
Area of Science:
- Microbiology
- Cell Biology
- Toxicology
Background:
- Pasteurella multocida toxin (PMT) is a potent mitogen.
- PMT activates intracellular signaling cascades, including Gq and Rho pathways.
- The toxin's precise intracellular target remains unidentified.
Purpose of the Study:
- To elucidate the signaling pathways affected by PMT.
- To investigate PMT's role in cellular differentiation, particularly in bone cells.
- To understand the mechanisms underlying PMT-induced porcine diseases.
Main Methods:
- Analysis of intracellular signaling pathways (Gq, Rho, Ras-MAP kinase).
- Assessment of phospholipase C, protein kinase C, and intracellular calcium levels.
- In vitro studies on bone cell differentiation and mineralized nodule formation.
Main Results:
- PMT activates Gq and Rho proteins, leading to increased phospholipase C, protein kinase C, and intracellular calcium.
- Rho activation results in cytoskeletal reorganisation and focal adhesion kinase phosphorylation.
- PMT inhibits bone cell differentiation, preventing mineralized bone nodule formation.
Conclusions:
- PMT profoundly perturbs host cell signal transduction pathways.
- The toxin's effects on cell signaling contribute to its mitogenic and differentiation-inhibiting activities.
- PMT is implicated in bone resorption observed in porcine diseases.