A direct interaction between the adaptor protein Cbl-b and the kinase zap-70 induces a positive signal in T cells

Curr Biol. 1999 Feb 25;9(4):203-6. doi: 10.1016/s0960-9822(99)80090-6.


Engagement of the T-cell receptor (TCR)-CD3 complex induces a rapid increase in the activities of Src-family and Syk/Zap-70-family kinases [1] [2]. These activated kinases then induce the tyrosine phosphorylation of multiple intracellular proteins, eventually leading to T-cell activation. One of the prominent substrates for these kinases is the adaptor protein Cbl [3] and recent studies suggest that Cbl negatively regulates upstream kinases such as Syk and Zap-70 [4] [5]. Cbl-b, a homologue of Cbl, is widely expressed in many tissues and cells including hematopoietic cells [6] [7]. Cbl-b undergoes rapid tyrosine phosphorylation upon stimulation of the TCR and cytokine receptors [8] [9]. The role of Cbl-b is unclear, however. Here, we show that overexpression of Cbl-b in T cells induced the constitutive activation of the transcription factor nuclear factor of activated T cells (NFAT). A loss-of-function mutation in Cbl-b disrupted the interaction between Cbl-b and Zap-70 and nearly completely abrogated the Cbl-b-mediated activation of NFAT. Unlike the proposed role of Cbl as a negative regulator, our results suggest that the Cbl homologue Cbl-b has a positive role in T-cell signaling, most likely via a direct interaction with the upstream kinase Zap-70.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Carrier Proteins / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Jurkat Cells
  • Kinetics
  • Lymphocyte Activation
  • Muromonab-CD3 / pharmacology
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Oncogene Protein v-cbl
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins c-cbl
  • Receptor-CD3 Complex, Antigen, T-Cell / physiology*
  • Receptors, Antigen, T-Cell / physiology
  • Recombinant Proteins / metabolism
  • Retroviridae Proteins, Oncogenic / metabolism*
  • Signal Transduction*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / physiology*
  • Transcription Factors / metabolism*
  • Transfection
  • Ubiquitin-Protein Ligases*
  • ZAP-70 Protein-Tyrosine Kinase


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA-Binding Proteins
  • Muromonab-CD3
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Oncogene Protein v-cbl
  • Phosphoproteins
  • Receptor-CD3 Complex, Antigen, T-Cell
  • Receptors, Antigen, T-Cell
  • Recombinant Proteins
  • Retroviridae Proteins, Oncogenic
  • Transcription Factors
  • CBLB protein, human
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • Protein-Tyrosine Kinases
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human