Pasteurella multocida Toxin, a Potent Intracellularly Acting Mitogen, Induces p125FAK@ and Paxillin Tyrosine Phosphorylation, Actin Stress Fiber Formation, and Focal Contact Assembly in Swiss 3T3 Cells

Lacerda, Hadriano M.; Lax, Alistair J.; Rozengurt, Enrique

doi:10.1074/jbc.271.1.439

Cited by 81 publications

(91 citation statements)

References 66 publications

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“…TGF-␤ and activin A, which stimulate receptor serine/threonine kinase activity, also indirectly trigger paxillin tyrosine phosphorylation (212). Similarly, agonists of many 7-pass transmembrane serpentine family receptors induce paxillin tyrosine phosphorylation including acetylcholine (298), epineph- (3,288) and exposure to their toxins including Pasteurella multocida toxin, cytotoxic necrotizing factor 1, dermonecrotic toxin, and lipopolysaccharide (136,137) can also induce paxillin tyrosine phosphorylation. In each of these scenarios, profound alterations in the cytoskeleton are effected that are essential to activate and regulate host defenses.…”

Section: Paxillin Phosphorylation a Tyrosine Phosphorylationmentioning

confidence: 99%

Paxillin: Adapting to Change

Brown¹,

Turner²

2004

Physiological Reviews

551

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Molecular scaffold or adaptor proteins facilitate precise spatiotemporal regulation and integration of multiple signaling pathways to effect the optimal cellular response to changes in the immediate environment. Paxillin is a multidomain adaptor that recruits both structural and signaling molecules to focal adhesions, sites of integrin engagement with the extracellular matrix, where it performs a critical role in transducing adhesion and growth factor signals to elicit changes in cell migration and gene expression.

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Section: Paxillin Phosphorylation a Tyrosine Phosphorylationmentioning

confidence: 99%

Paxillin: Adapting to Change

Brown¹,

Turner²

2004

Physiological Reviews

551

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“…PMT stimulates phospholipase C␤1 (PLC␤1) in a G q -dependent manner (16), resulting in calcium mobilization, accumulation of diacylglycerol, and activation of protein kinase C (11). In addition, PMT activates the small GTPase RhoA, thereby inducing formation of stress fibers, focal adhesions, and tyrosine phosphorylation of focal adhesion kinase and paxillin (12,17). The activation of Rho, extracellular signal-regulated kinase, and Jun kinase appears to be independent of G q , indicating that PMT activates signaling pathways in a G q -dependent and -independent manner (18).…”

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Action of Pasteurella multocida Toxin Depends on the Helical Domain of Gαq

Orth

Lang

Aktories

2004

Journal of Biological Chemistry

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Pasteurella multocida produces a 146-kDa protein toxin (PMT), which activates multiple cellular signal transduction pathways, resulting in the activation of phospholipase C␤, RhoA, Jun kinase, and extracellular signal-regulated kinase. Using G␣ q /G␣ 11 -deficient cells, it was shown that the PMT-induced pleiotropic effects are mediated by G␣ q but not by the highly related G␣ 11 protein (Zywietz, A., Gohla, A., Schmelz, M., Schultz, G., and Offermanns, S. (2001) J. Biol. Chem. 276, 3840 -3845). Here we studied the molecular basis of the unique specificity of PMT to distinguish between G␣ q and/or G␣ 11 . Infection of G␣ q/11 -deficient cells with retrovirus-encoding G␣ q caused reconstitution of PMT-induced activation of phospholipase C␤, whereas G␣ 11 -encoding virus did not reconstitute PMT activity. Chimeras between G␣ q and/or G␣ 11 revealed that a peptide region of G␣ q , covering amino acid residues 105-113, is essential for the action of PMT to activate phospholipase C␤. Exchange of glutamine 105 or asparagine 109 of G␣ 11 , which are located in the all-helical domain of the G␣ subunit, with the equally positioned histidines of G␣ q , renders G␣ 11 capable of transmission PMT-induced phospholipase C␤ activation. The data indicate that the all-helical domain of G␣ q is essential for the action of PMT and suggest an essential functional role of this domain in signal transduction via G q proteins.The Pasteurella multocida is a facultative pathogen, which cause bite wound infections, pneumonia, endocarditis, and septicemia in men. In pigs, the pathogen induces atrophic rhinitis, which is characterized by a loss of nasal turbinate bone (1, 2). The 146-kDa protein toxin P. multocida toxin (PMT) 1 is the major virulence factor of the pathogen, the causative agent of atrophic rhinitis, and is responsible for the osteolytic activity of bacteria (1,(3)(4)(5). PMT consists of 1285 amino acid residues. It is generally accepted that the toxin is structured according to a typical AB toxin. Initial studies revealed that the N terminus of PMT is involved in the binding and in translocation of the toxin into target cells (6), whereas the biologically active domain is located in the C-terminal part of the protein (6, 7). This concept is in line with a significant sequence similarity of PMT at its N terminus with the N-terminal part of the cytotoxic necrotizing factor of Escherichia coli that is also involved in binding and translocation. According to the hypothesis that the C terminus of PMT carries the biological activity, an essential cysteine residue (Cys 1165 ) was identified at the C terminus (8). The change of Cys 1165 to serine blocked toxin activity but not cell binding. In addition, histidine residues (His 1205 and His 1223 ) in this part of the toxin were recognized to be essential for the activity of PMT (9).PMT activates numerous cellular signal transduction pathways. It is a strong mitogen and stimulates DNA synthesis and proliferation in several cell lines (10 -14). The mitogenic actions of PMT appear to d...

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“…In particular, FAK is activated and tyrosine-phosphorylated in response to integrin clustering induced by cell adhesion or antibody cross-linking (1, 2, 6 -9). In addition, FAK is rapidly tyrosine-phosphorylated in cells stimulated by mitogenic neuropeptide agonists including bombesin (10 -16) and bioactive lipids including LPA (17-19) that act via heptahelical GPCRs, polypeptide growth factors (20 -24), bacterial toxins (25,26), and activated variants of pp60 Src (27,28). The importance of FAK-mediated signal transduction is underscored by experiments implicating this tyrosine kinase in embryonic development (29) and in the control of cell migration (30 -33), proliferation (30, 34), and apoptosis (35,36).…”

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confidence: 99%

mentioning

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Src Family Kinases Are Required for Integrin-mediated but Not for G Protein-coupled Receptor Stimulation of Focal Adhesion Kinase Autophosphorylation at Tyr-397

Salazar¹,

Rozengurt²

2001

Journal of Biological Chemistry

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117

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A rapid increase in the tyrosine phosphorylation of the nonreceptor tyrosine kinase FAK 1 (1, 2), which localizes to focal adhesion plaques, has been identified as a prominent early event in cells stimulated by diverse signaling molecules that regulate cell proliferation, migration, and apoptosis (3-5). In particular, FAK is activated and tyrosine-phosphorylated in response to integrin clustering induced by cell adhesion or antibody cross-linking (1, 2, 6 -9). In addition, FAK is rapidly tyrosine-phosphorylated in cells stimulated by mitogenic neuropeptide agonists including bombesin (10 -16) and bioactive lipids including LPA (17-19) that act via heptahelical GPCRs, polypeptide growth factors (20 -24), bacterial toxins (25,26), and activated variants of pp60 Src (27,28). The importance of FAK-mediated signal transduction is underscored by experiments implicating this tyrosine kinase in embryonic development (29) and in the control of cell migration (30 -33), proliferation (30, 34), and apoptosis (35,36). In addition, there is increasing evidence linking overexpression of FAK to the invasive properties of cancer cells (37,38). It is increasingly recognized that the tyrosine phosphorylation and activation of FAK is an important point of convergence in the action of integrins, GPCR agonists, growth factors, and oncogenes (5, 39, 40). However, the molecular pathways leading to FAK tyrosine phosphorylation in response to multiple extracellular factors remain incompletely understood.Plating suspended cells onto fibronectin-coated dishes, a paradigm of integrin receptor activation (41), induces adhesion-dependent phosphorylation of FAK at multiple sites including tyrosines 397, 576, 577, 861, and 925 (32, 42-45). Tyr-397, the only apparent autophosphorylation site (46 -51), has emerged as a critical residue in FAK-mediated signaling (5). The autophosphorylation of FAK at Tyr-397 creates a high affinity binding site for the SH2 domain of Src family kinases including Src, Yes, and Fyn and leads to the formation of a signaling complex between FAK and Src family kinases (46, 47, 49 -52). A model has recently been proposed that envisages reciprocal catalytic activation of FAK and Src family kinases in response to adhesiondependent signals. Src family kinases associated with FAK are thought to phosphorylate FAK at additional sites including Tyr-576 and Tyr-577 that are located in the activation loop of the kinase catalytic domain of FAK (32, 42, 53), thereby promoting maximal FAK catalytic activation. Because phenylalanine mutation of Tyr-576 and Tyr-577 reduced adhesion-mediated FAK autophosphorylation (at Tyr-397), it has been proposed that activation loop phosphorylation of FAK by Src stimulates intermolecular phosphorylation at Tyr-397, thereby leading to signal amplification at sites of integrin-mediated cell adhesion (32). Therefore, in this model Src family kinases are thought to play a major role leading to autophosphorylation of FAK at Tyr-397 as part of an adhesion-dependent signaling response. Recently, we demons...

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Pasteurella multocida Toxin, a Potent Intracellularly Acting Mitogen, Induces p125FAK@ and Paxillin Tyrosine Phosphorylation, Actin Stress Fiber Formation, and Focal Contact Assembly in Swiss 3T3 Cells

Cited by 81 publications

References 66 publications

Paxillin: Adapting to Change

Paxillin: Adapting to Change

Action of Pasteurella multocida Toxin Depends on the Helical Domain of Gαq

Src Family Kinases Are Required for Integrin-mediated but Not for G Protein-coupled Receptor Stimulation of Focal Adhesion Kinase Autophosphorylation at Tyr-397

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