Inhibition of T-cell antigen receptor signaling by overexpression of p120GAP.

T-cell antigen receptor triggering results in activation of protein kinase C and mobilization of calcium. These two signals are necessary and sufficient to activate the T-cell specific transcription factor NF-AT, which cooperates with other transcription factors activated by accessory signals to initiate expression of interleukin 2 and its receptor. The protein kinase C mediated pathway involves activation of ras proteins. In a Jurkat cell model of T-cell activation, treatment with antigen receptor agonists results in induction of expression of a reporter gene under the control of a NF-AT dependent promoter. Overexpression of the ras GTPase activating protein p120GAP in these cells caused a significant inhibition of T-cell antigen receptor mediated induction, suggesting a role for p120GAP in regulation of ras. The inhibition was overcome by expression of a valine-12 mutant ras which lacks GTPase activity.