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Functional cooperation between c-Cbl and Src-like adaptor protein 2 in the negative regulation of T-cell receptor

Michael P Loreto1, Donna M Berry, C Jane McGlade

  • 1Department of Medical Biophysics, University of Toronto and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.

Molecular and Cellular Biology
|May 25, 2002
PubMed

Insights

A newly identified protein, Src-like adaptor protein 2 (SLAP-2), negatively regulates T-cell signaling by promoting the degradation of key tyrosine kinases and reducing CD3 surface expression.

Area of Science:

  • Immunology
  • Cell Signaling
  • Molecular Biology

Background:

  • Adaptor proteins are crucial for intracellular signal transduction.
  • Some adaptor proteins act as negative regulators of signaling pathways.

Purpose of the Study:

  • To identify and characterize a novel hematopoiesis-specific adaptor protein, SLAP-2.
  • To elucidate the mechanism by which SLAP-2 regulates T-cell receptor signaling.

Main Methods:

  • Co-immunoprecipitation assays to identify binding partners of SLAP-2.
  • Overexpression studies in T-cell lines (Jurkat) and COS cells.
  • Analysis of T-cell activation markers and kinase degradation.

Main Results:

  • SLAP-2 binds to c-Cbl and the tyrosine kinases ZAP-70 and an unknown 72 kDa protein.
  • SLAP-2 overexpression inhibits T-cell receptor-induced NFAT activation.
  • SLAP-2 promotes the degradation of SYK and ZAP-70 and reduces surface CD3 expression.

Conclusions:

  • SLAP-2 functions as a negative regulator of T-cell signaling.
  • SLAP-2 mediates c-Cbl-dependent degradation of SYK and ZAP-70.
  • SLAP-2 down-regulates T-cell activation by reducing surface CD3 expression.

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