Figure 1

Positive and negative regulations in the Ras/cAMP/PKA pathway. The diagram shows the logical relationships among the principal components of the Ras/cAMP/PKA pathway. The switch cycle of Ras2 protein between its inactive state (Ras2-GDP) and active state (Ras2-GTP) is regulated by the activity of Cdc25 (a) and Ira2 (b). The intracellular ratio of GTP and GDP also contributes to the regulation of the activity of Ras proteins (a), since Cdc25 stimulates the exchange of these nucleotides on Ras according to their relative concentration. Ras2-GTP controls the activity of the adenylate cyclase Cyr1 (c), which mediates the synthesis of the second messenger cAMP (d). cAMP activates PKA (e) by binding to its regulatory subunits and releasing its catalytic subunits. The degradation of cAMP is governed by Pde1 (i) and Pde2 (j), which constitute a major negative feedback in this pathway, as they both contribute to decrease the intracellular level of the second messenger. The active form of PKA exerts three main regulations in this pathway through the phosphorylation of different components: a positive regulation of Pde1 (h) and of Ira2 (g), and a negative regulation of Cdc25 (f). Since the increased activity of the phosphorylated forms of both Pde1 and Ira2 result in switching off the signal—that is, they both contribute to reducing the intracellular level of cAMP—due either to a faster degradation of cAMP by Pde1 (i) or to a diminished fraction of active Ras2 by Ira2 proteins (b), these two positive regulations actually have the effect of a negative feedback control on the whole pathway. The negative regulation of Cdc25 by PKA results in a partial inactivation of the GEF activity (a), and thus a reduced activation of the Ras2 protein, which results in a decreased activity of the adenylate cyclase and therefore contributes to lowering the cAMP level.