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J Biol Chem, Vol. 274, Issue 28, 19992-20001, July 9, 1999

G_i Proteins Use a Novel - 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, and David J. McKean

From the ^§ Department of Surgery,  Department of Immunology, and  Division of Radiation Oncology, The Mayo Clinic and Foundation, Rochester, Minnesota 55905

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 -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 -adrenergic receptor kinase-1 C-terminal fragment that inhibited signaling by G_i protein 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 . Analysis of this -independent pathway indicates a role for a herbimycin A-sensitive tyrosine kinase. Unlike -mediated pathways, the -independent pathway was insensitive to RasN17, inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase), and constitutive PI 3-kinase activity. The -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 3kinase-independent pathway for ERK activation by G_i protein signaling that is distinct from ERK activation by and may therefore be mediated by the i subunit.

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