CD28 and the tyrosine kinase Lck stimulate mitogen-activated protein kinase activity in T cells via inhibition of the small G protein Rap1

Proliferation of T cells via activation of the T-cell receptor (TCR) requir es concurrent engagement of accessory costimulatory molecules to achieve fu ll activation. The best-studied costimulatory molecule, CD28, achieves thes e effects, in part, by augmenting signals from the TCR to the mitogen-activ ated protein (MAP) kinase cascade. We show here that TCR-mediated stimulati on of MAP kinase extracellular-signal-regulated kinases (ERKs) is limited b y activation of the Ras antagonist Rap1. CD28 increases ERK signaling by bl ocking Rap1 action. CD28 inhibits Rap1 activation because it selectively st imulates an extrinsic Rap1 GTPase activity. The ability of CD28 to stimulat e Rap1 GTPase activity was dependent on the tyrosine kinase Lck. Our result s suggest that CD28-mediated Rap1 GTPase-activating protein activation can help explain the augmentation of ERKs during CD28 costimulation.