Proteolysis-independent Regulation of PI3K by Cbl-b-mediated Ubiquitination in T Cells

Nat Immunol. 2001 Sep;2(9):870-5. doi: 10.1038/ni0901-870.

Abstract

Cbl-b, a ring-type E3 ubiquitin protein ligase, is implicated in setting the threshold of T lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (PI3K) was identified as a substrate for Cbl-b. We have shown that Cbl-b negatively regulated p85 in a proteolysis-independent manner. Cbl-b is involved in the recruitment of p85 to CD28 and T cell antigen receptor zeta through its E3 ubiquitin ligase activity. The enhanced activation of Cbl-b(-/-) T cells was suppressed by the inhibition of PI3K. The results suggest a proteolysis-independent function for Cbl-b in the modification of protein recruitment.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • CD28 Antigens / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cells, Cultured
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • Protein Transport
  • Proto-Oncogene Proteins c-cbl
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / immunology*
  • Ubiquitin-Protein Ligases*
  • Ubiquitins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • CD28 Antigens
  • Carrier Proteins
  • Cblb protein, mouse
  • Membrane Proteins
  • Phosphoproteins
  • Receptors, Antigen, T-Cell
  • Ubiquitins
  • antigen T cell receptor, zeta chain
  • CBLB protein, human
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • Phosphatidylinositol 3-Kinases