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Ligand-induced assembly and activation of the gamma interferon receptor in intact cells

E A Bach1, J W Tanner, S Marsters

  • 1Department of Pathology, Washington University School of Medicine St. Louis, Missouri 63110, USA.

Molecular and Cellular Biology
|June 1, 1996
PubMed

Insights

The interferon-gamma (IFN-gamma) receptor beta chain is crucial for signaling by recruiting the JAK-2 tyrosine kinase. Specific intracellular sequences in the beta chain mediate this essential interaction for IFN-gamma signal transduction.

Area of Science:

  • Immunology
  • Cellular Signaling
  • Molecular Biology

Background:

  • Interferon-gamma (IFN-gamma) receptors mediate cellular responses to IFN-gamma.
  • The receptor comprises alpha and beta subunits, with the alpha subunit binding ligand and the beta subunit primarily involved in signaling.
  • The precise function of the IFN-gamma receptor beta chain in signal transduction remains largely uncharacterized.

Purpose of the Study:

  • To elucidate the specific role of the IFN-gamma receptor beta chain in IFN-gamma signaling.
  • To identify the functional domains within the beta chain's intracellular region responsible for signal transduction.
  • To investigate the interaction between the IFN-gamma receptor beta chain and associated kinases.

Main Methods:

  • Expression of wild-type and mutated human IFN-gamma receptor beta chains in murine L cells.
  • Site-directed mutagenesis of the beta chain's intracellular domain.
  • Coprecipitation assays to study protein-protein interactions.
  • Construction of chimeric proteins to assess functional complementation.

Main Results:

  • Specific membrane-proximal sequences (P263PSIP267 and I270EEYL274) in the beta chain's intracellular domain are essential for function.
  • These sequences mediate the constitutive association of the beta chain with JAK-2 tyrosine kinase.
  • IFN-gamma receptor alpha and beta chains associate upon ligand binding, not preassociated.
  • A chimera replacing the beta chain's intracellular domain with JAK-2 rescued IFN-gamma signaling.

Conclusions:

  • The IFN-gamma receptor beta chain's primary role in signaling is to recruit JAK-2 into the ligand-assembled receptor complex.
  • The identified intracellular sequences are critical for JAK-2 recruitment and subsequent signal transduction.
  • This study clarifies the mechanism by which the IFN-gamma receptor beta chain contributes to IFN-gamma signal activation.

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