LYMPHOCYTE ANTIGEN RECEPTOR ACTIVATION OF A FOCAL ADHESION KINASE-RELATED TYROSINE KINASE SUBSTRATE

One of the earliest responses of T and B lymphocytes to stimulation th rough their antigen receptors is the activation of protein tyrosine ki nases and the tyrosine phosphorylation of multiple cellular substrates . Here we describe a tyrosine kinase substrate, fakB, a putative homol ogue of the focal adhesion kinase ppl25(FAK) Tyrosine phosphorylation of fakB was rapidly augmented in human T and B cells following antigen receptor cross-linking with antibody, while ppl25(FAK) was nonrespons ive. Costimulation of the T-cell antigen receptor (TCR/CD3) with eithe r the CD2 or CD4 costimulatory receptors induced synergistic fakB tyro sine phosphorylation in normal human T cells. Engagement of TCR/CD3 in duced the stable association of fakB with ZAP-70, the TCR/CD3 xi-chain -associated tyrosine kinase involved in antigen receptor-induced T-cel l activation. In addition, preformed complexes of fakB and ZAP-70 were observed in T-cell leukemia lines. Phosphorylation of fakB on serine, threonine, and tyrosine residues was observed both in vivo and in vit ro, where a functional increase of in vitro kinase activity was observ ed following TCR/CD3 stimulation. fakB is thus a focal adhesion kinase -related tyrosine kinase substrate that is differentially regulated fr om that of pp125(FAK) and likely plays a role in antigen-induced lymph ocyte signaling.