TI  - Proto-oncoprotein  <prot>Vav</prot>  interacts with  <prot>c-Cbl</prot>  in activated thymocytes and
      peripheral T cells.
PG  - 70-6
AB  - The molecular adapter <prot>c-Cbl</prot> is rapidly tyrosine phosphorylated following
      stimulation through the  <prot>TCR</prot>  and associates with <prot>Src</prot> homology domain-2
      (SH2)/SH3 domain-containing adapters such as  <prot>Grb2</prot> ,  <prot>Crk</prot> , and  <prot>Crk-L</prot> , which
      interact with guanine nucleotide exchange factors specific for the Ras
      family. This suggests that <prot>c-Cbl</prot> may link <prot>TCR</prot> activation to molecules that
      regulate GTP binding proteins. The SH2/SH3-containing protein <prot>Vav</prot> also
      contains a guanine nucleotide exchange factor domain, and  <prot>Vav</prot>  has a
      crucial role in thymocyte development and activation of peripheral T cells
      following stimulation through the  <prot>TCR</prot> . Here we show that <prot>Vav</prot> and <prot>c-Cbl</prot>
      form inducible molecular complexes in <prot>TCR</prot>-activated murine thymocytes and
      peripheral T cells as well as pervanadate-treated T cells.  <prot>Vav</prot> / <prot>c-Cbl</prot> 
      interactions are also detectable in freshly isolated T cells from
      gene-targeted mice that lack the T cell-specific inhibitory receptor
      <prot>CTLA-4</prot>, in which <prot>c-Cbl</prot> is hyperphosphorylated on tyrosine residues. The
      interaction between  <prot>Vav</prot>  and  <prot>c-Cbl</prot>  is directly mediated via the SH2 domain
      of <prot>Vav</prot> and is dependent on tyrosine phosphorylation of <prot>c-Cbl</prot>. In addition,
      we show that the conserved motif Y699 MTP present in  <prot>c-Cbl</prot>  is the binding
      site for the  <prot>Vav</prot>  SH2 domain in vitro. These data imply that <prot>c-Cbl</prot> is a
      molecular adapter that regulates the function of <prot>Vav</prot> in thymocytes and
      peripheral T cells.
AD  - Amgen Institute, and Department of Medical Biophysics, University of
