Abstract
The intracellularly acting Pasteurella multocida toxin (PMT) is a potent mitogen that stimulates Gq-dependent formation of inositol trisphosphate. We show that PMT, a nontoxic mutant of PMT (PMTC1165S), and bombesin each stimulate time-dependent phosphorylation of G alpha q at tyrosine 349. Although PMT and PMTC1165S each cause phosphorylation of G alpha q, only the wild-type toxin activates Gq. Pretreatment of cells with wild-type or mutant PMT potentiated the formation of inositol phosphates stimulated by bombesin equally. These data show that PMT potentiates bombesin receptor signaling through tyrosine phosphorylation of Gq and distinguishes between the two proposed models of Gq activation, showing that tyrosine phosphorylation is not linked to receptor uncoupling.
Highlights
The Pasteurella multocida toxin (PMT)1 is a highly potent mitogen for mesenchymal cells, including Swiss 3T3 fibroblasts [1]
These data show that PMT potentiates bombesin receptor signaling through tyrosine phosphorylation of Gq and distinguishes between the two proposed models of Gq activation, showing that tyrosine phosphorylation is not linked to receptor uncoupling
Recent studies have indicated that G␣q phosphorylation forms part of a novel cycle in which tyrosine kinases and phosphatases regulate Gq activation [11,12,13]
Summary
The Pasteurella multocida toxin (PMT) is a highly potent mitogen for mesenchymal cells, including Swiss 3T3 fibroblasts [1]. The G␣q class are widely expressed and regulate various effector proteins including phospholipase C and Bruton’s tyrosine kinase [10]. GTP binding results in the dissociation of G␣-GTP and ␥ complexes, each of which can modulate effector proteins. The regulation of these processes in vivo has yet to be fully elucidated. Transient expression of a dominant active mutant of the Fyn tyrosine kinase elevated the phosphorylation of G␣q but blocked receptor-stimulated IP3 production [12]. Taken together, these results implied that cellular kinases and phosphatases coordinately regulate the activity of G␣q. Using wildtype and mutant forms of PMT, we show that tyrosine phosphorylation of G␣q can potentiate signaling through the Gqcoupled bombesin receptor
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