G(i) proteins use a novel βγ- and Ras-independent pathway to activate extracellular signal-regulated kinase and mobilize AP-1 transcription factors in jurkat T lymphocytes

Karen E. Hedin, Michael P. Bell, Catherine J. Huntoon, Larry M. Karnitz, David J. McKean

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Receptors coupled to pertussis toxin (PTX)-sensitive G(i) proteins regulate T lymphocyte cytokine secretion, proliferation, and chemotaxis, yet little is known about the molecular mechanisms of G(i) protein signaling in mammalian lymphocytes. Using the Jurkat T lymphocyte cell line, we found that a stably expressed G(i) protein-coupled receptor (the δ-opioid receptor (DOR1)) stimulates MEK-1 and extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) and transcriptional activity by an ERK target, Elk-1, via a mechanism requiring a PTX-sensitive G(i) protein. Levels of β-adrenergic receptor kinase-1 C-terminal fragment that inhibited signaling by G(i) protein βγ subunits in these cells had no effect on DOR1 stimulation of either MEK-1- or Elk-1-dependent transcription, indicating that this pathway is independent of βγ. Analysis of this βγ-independent pathway indicates a role for a herbimycin A-sensitive tyrosine kinase. Unlike βγ-mediated pathways, the βγ-independent pathway was insensitive to RasN17, inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase), and constitutive PI 3-kinase activity. The βγ-independent pathway regulates downstream events, since blocking it abrogated both Elk-1-dependent transcription and mobilization of the mitogenic transcription factor, AP-1, in response to DOR1 signaling. These results characterize a novel, Ras- and PI 3-kinase-independent pathway for ERK activation by G(i) protein signaling that is distinct from ERK activation by βγ and may therefore be mediated by the αi subunit.

Original languageEnglish (US)
Pages (from-to)19992-20001
Number of pages10
JournalJournal of Biological Chemistry
Volume274
Issue number28
DOIs
StatePublished - Jul 9 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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