Phosphorylation of protein kinase C (PKC) substrates in T lymphocytes was analyzed after stimulation with specific pairs of anti‐CD2 monoclonal antibodies (mAb) or an anti‐CD3 mAb. The results show that the appropriate stimulation of both CD2 or CD3 antigens results in phosphorylation of a 80‐kDa putative PKC substrate and that this phosphorylation event is sensitive to a PKC inhibitor, sphinganine. CD2‐ and CD3‐dependent phosphorylation was found to be strongly dependent on an extensive cross‐linking of surface antigens. The biological importance of cross‐linking of CD2 and CD3 was also evident for other biological responses such as interleukin 2 production and induction of an autocrine growth response. Finally, we also present evidence for interaction between the CD2 and CD3 signal transducing pathways.