Pasteurella multocida toxin activates Gbetagamma dimers of heterotrimeric G proteins.
The mitogenic Pasteurella multocida toxin (PMT) is a major virulence factor of P. multocida, which causes Pasteurellosis in man and animals. The toxin activates the small GTPase RhoA, the MAP kinase ERK and STAT proteins via the stimulation of members of two G protein families, G(q) and G(12/13). PMT action also results in an increase in inositol phosphates, which is due to the stimulation of PLCbeta via Galpha(q). Recent studies indicate that PMT additionally activates Galpha(i) to inhibit adenylyl cyclase. Here we show that PMT acts not only via Galpha but also through Gbetagamma signaling. Activation of Gbetagamma by PMT causes stimulation of phosphoinositide 3-kinase (PI3K) gamma and formation of phosphatidylinositol-3,4,5-trisphosphate (PIP(3)) as indicated by the recruitment of a PIP(3)-binding pleckstrin homology (PH) domain-containing protein to the plasma membrane. Moreover, it is demonstrated that Gbetagamma is necessary for PMT-induced signaling via Galpha. Mutants of Galpha(q) incapable of binding or releasing Gbetagamma are not activated by PMT. Similarly, sequestration of Gbetagamma inhibits PMT-induced Galpha-signaling.
Preuss
Inga
I
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität Freiburg, Germany.
Kurig
Barbara
B
Nürnberg
Bernd
B
Orth
Joachim H C
JH
Aktories
Klaus
K
D019943:Amino Acid Substitution; D001426:Bacterial Proteins / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005136:Eye Proteins / Q000494:pharmacology; D020555:GTP-Binding Protein Regulators / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D010456:Peptides, Cyclic / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis; D010750:Phosphoproteins / Q000494:pharmacology; D017354:Point Mutation; D021381:Protein Transport / Q000187:drug effects; D043587:Receptor, Muscarinic M3 / Q000187:drug effects / Q000378:metabolism; D026362:Serum Response Factor / Q000187:drug effects
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D005136:Eye Proteins; D020555:GTP-Binding Protein Regulators; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; C062258:Pasteurella multocida toxin; D010456:Peptides, Cyclic; D018129:Phosphatidylinositol Phosphates; D010750:Phosphoproteins; D043587:Receptor, Muscarinic M3; D026362:Serum Response Factor; C475455:YM-254890; C065631:phosducin; C060974:phosphatidylinositol 3,4,5-triphosphate; D002217:Carbachol; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins