ACTIVATION OF P21-CDC42 RAC-ACTIVATED KINASES BY CD28 SIGNALING - P21-ACTIVATED-KINASE (PAK) AND MEK-KINASE-1 (MEKK1) MAY MEDIATE THE INTERPLAY BETWEEN CD3 AND CD28 SIGNALS/

CD28, a T cell costimulatory receptor, provides a signal that induces both optimal proliferation and the production of IL-2 by TCR-activated T cells. We show that the stimulation of CD28 leads to the activation of p21-activated kinase and MEK kinase 1, The same pathway was also s timulated in T cells treated,vith the cell-permeable ceramide analogue , C2-ceramide. The combined stimulation of either CD3 and CD28 or CD3 concurrently with C2-ceramide largely enhanced the activity of p21-act ivated kinase and MEK kinase 1. Therefore the Rac1/CDC42-coupled pathw ay(s) is a candidate that transduces and facilitates cross-talk betwee n the CD28 costimulatory signal and the TCR signal.