A SPONTANEOUSLY ARISING MUTATION IN THE DLAARN MOTIF OF MURINE ZAP-7OABROGATES KINASE-ACTIVITY AND ARRESTS THYMOCYTE DEVELOPMENT

Development of immature CD4(+)CD8(+) thymocytes into functionally matu re CD4(+) and CD8(+) T cells is driven by selection events that requir e signals transduced through the T cell antigen receptor (TCR). Transd uction of TCR signals in the thymus involves tyrosine phosphorylation of the protein tyrosine kinase ZAP-70 by p56(lck) and results in induc tion of ZAP-70 enzymatic activity. We have identified a novel, spontan eously arising point mutation within a highly conserved motif (DLAARN) in the kinase domain of murine ZAP-70 that uncouples tyrosine phospho rylation of ZAP-70 from induction of ZAP-70 kinase activity. Mice homo zygous for this mutation are devoid of mature T cells because thymocyt e development is arrested at the CD4(+)CD8(+) stage of differentiation . The developmental arrest is due to the inability of CD4(+)CD8(+) thy mocytes to propagate TCR signals in the absence of ZAP-70 kinase activ ity despite tyrosine phosphorylation of TCR-associated ZAP-70 molecule s.