Pasteurella Multocida Toxin: the Mitogenic Toxin That Stimulates Signalling Cascades to Regulate Growth and Differentiation

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.