The carboxy-terminal region of CD5 is required for c-CBL mediated TCR signaling downmodulation in thymocytes

Biochem Biophys Res Commun. 2013 Mar 1;432(1):52-9. doi: 10.1016/j.bbrc.2013.01.086. Epub 2013 Jan 30.

Abstract

CD5 functions as a negative regulator of TCR signaling during thymocyte development, however, the molecular mechanisms involved in this process remain elusive. A key molecule involved in the down modulation of TCR signaling is c-Cbl, an ubiquitin ligase that physically associates with CD5. Crosslinking of TCR in thymocytes leads to ubiquitylation and lysosomal/proteasomal degradation of TCR downstream signaling effectors and CD5 itself. The present report shows that co-engagement of CD3 with CD5 enhanced c-Cbl phosphorylation, which was not affected by the deletion of the pseudo-ITAM domain of CD5, the putative binding site for c-Cbl. However, amino acids present in the carboxy-terminal region of CD5, were necessary for this effect, indicating that ITAM-independent sites were involved in the interaction of c-Cbl with CD5. The carboxy-terminal region of CD5 was also required for Vav degradation, a well-known target for c-Cbl-dependent ubiquitylation. These results support the notion that the distal cytoplasmic domain of CD5, including Y463, plays a relevant role in the downmodulation of TCR signals in thymocytes via c-Cbl.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CD5 Antigens / chemistry
  • CD5 Antigens / genetics
  • CD5 Antigens / metabolism*
  • Cells, Cultured
  • Down-Regulation
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-cbl / metabolism*
  • Receptors, Antigen, T-Cell / metabolism*
  • Sequence Deletion
  • Signal Transduction
  • Thymocytes / metabolism*

Substances

  • CD5 Antigens
  • Cd5 protein, mouse
  • Receptors, Antigen, T-Cell
  • Proto-Oncogene Proteins c-cbl
  • Cbl protein, mouse