Proposed model for signal transduction by PMA/CD28 stimulation.
PI3-K is activated on CD28 ligation. PI3-K then activates Akt by generating phosphatidylinositols. In association with PKC-theta, activated Akt then initiates IL-2 gene transcription. Activated Akt also modulates mTOR/FRAP, which in turn suppresses constitutively active PP2A. mTOR/FRAP is also involved in regulating the activity of p70S6K and 4EBP-1 and thus controlling IL-2 translation. In presence of rapamycin, inhibition of mTOR/FRAP activates PP2A. JNK-1 activated by PI3-K/vav/rac pathway acts to stabilize IL-2 message. Activated JNK-1 becomes the target of dephosphorylation and inactivation by activated PP2A; suppression of JNK-1 activity results in decreased IL-2 mRNA stability. Whether rapamycin-mediated dephosphorylation of 4EBP-1 is mediated by activated PP2A, as it has been shown during amino acid deprivation,51 needs to be determined.
