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 mitoge n by stimulating various intracellular signalling cascades. Pathways downst ream of the G-protein Ga and also downstream of the Rho proteins are activa ted. Thus PMT action stimulates phospholipase C leading to activation of pr otein kinase C, an increase in inositol phosphates, and a rise in intracell ular calcium. Rho activation of the Rho kinase leads to cytoskeletal reorga nisation, tyrosine phosphorylation of the focal adhesion kinase, and activa tion of the Src proto-oncogene. In addition signalling through the Ras-MAP kinase signalling pathway is also initiated. PMT is an intracellularly acti ng toxin, and functional domains that carry out different aspects of its fu nction have been described. The intracellular target of the toxin is curren tly not known. PMT also acts to inhibit differentiation, in particular of b one cells, where it prevents the formation of mineralised bone nodules in v itro. The toxin is the causative agent of a porcine disease that is charact erised by bone resorption. Injection of very low doses of toxin leads to pr oliferative effects, but at higher doses is lethal. The possible effect of PMT induced perturbation of signal transduction pathways is discussed.