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Dual regulation of T cell receptor-mediated signaling by oncogenic Cbl mutant 70Z

Z Zhang1, C Elly, A Altman

  • 1Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.

The Journal of Biological Chemistry
|February 13, 1999
PubMed

Insights

An oncogenic Cbl mutant (70Z) activates nuclear factor at activated T cells (NFAT) transcription. Amino-terminal interactions with Zap-70 promote this activation, while carboxyl-terminal interactions inhibit it.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cell Signaling

Background:

  • Oncogenic Cbl mutants, like 70Z, exhibit constitutive activity in nuclear factor at activated T cells (NFAT) transcriptional activation.
  • The precise molecular mechanisms driving this Cbl-mediated NFAT activation remain incompletely understood.

Purpose of the Study:

  • To elucidate the mechanism by which the oncogenic Cbl mutant 70Z activates NFAT.
  • To investigate the roles of specific Cbl domains and phosphorylation sites in mediating interactions with signaling proteins and NFAT activation.

Main Methods:

  • Analysis of 70Z mutant constructs with specific amino-terminal (Gly-306) and carboxyl-terminal (tyrosine/serine phosphorylation sites) mutations.
  • Assessment of protein-protein interactions with signaling molecules.
  • Quantification of NFAT transcriptional activity under basal and stimulated conditions.

Main Results:

  • Mutation at Gly-306 disrupted 70Z association with Zap-70 and abolished NFAT activation.
  • Carboxyl-terminal mutations had minimal impact; specific tyrosine-to-phenylalanine mutations enhanced NFAT activity compared to wild-type 70Z.
  • 70Z reduced T cell receptor-induced NFAT activation, an effect amplified by wild-type Cbl.

Conclusions:

  • Amino-terminal interactions of 70Z with Zap-70 positively regulate NFAT activation.
  • Carboxyl-terminal, phosphotyrosine-dependent interactions negatively regulate 70Z-mediated NFAT activation.
  • Both wild-type Cbl and the 70Z mutant utilize similar dual regulatory mechanisms in T cell receptor signaling.

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