Pertussis toxin directly activates endothelial cell p42/p44 MAP kinases via a novel signaling pathway

Joe G.N. Gaecia, Peiyi Wang, Feng Liu, Marc B. Hershenson, Talaibek Borbiev, Alexander D. Verin

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Bordetella pertussis generates a bacterial toxin utilized in signal transduction investigation because of its ability to ADP ribosylate specific G proteins. We previously noted that pertussis toxin (PTX) directly activates endothelial cells, resulting in disruption of monolayer integrity and intercellular gap formation via a signaling pathway that involves protein kinase C (PKC). We studied the effect of PTX on the activity of the 42and 44-kDa extracellular signal-regulated kinases (ERK), members of a kinase family known to be activated by PKC. PTX caused a rapid time-dependent increase in bovine pulmonary artery endothelial cell ERK activity that was significantly attenuated by 1) pharmacological inhibition of MEK, the upstream ERK activating kinase, 2) an MEK dominant-negative construct, and 3) PKC inhibition with bisindolylmaleimide. There was little evidence for the involvement of either Gβγ-subunits, Ras GTPases, Raf-1, p60src, or phosphatidylinositol 3′-kinases in PTX-mediated ERK activation. Both the purified β-oligomer binding subunit of the PTX holotoxin and a PTX holotoxin mutant genetically engineered to eliminate intrinsic ADP ribosyltransferase activity completely reproduced PTX effects on ERK activation, suggesting that PTX-indueed ERK activation involves a novel PKC-dependent signaling mechanism that is independent of either Ras or Raf-1 activities and does not require G protein ADP ribosylation.

Original languageEnglish (US)
Pages (from-to)C1233-C1241
JournalAmerican Journal of Physiology - Cell Physiology
Volume280
Issue number5 49-5
StatePublished - May 23 2001
Externally publishedYes

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Keywords

  • Adenosine 5′-diphosphate ribosylation
  • Bacterial toxin
  • Endothelium
  • Extracellular signal-regulated kinases
  • Raf-1 activation
  • Signal transduction
  • p21 Ras activity
  • β-Oligomer

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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