Broad-Scale Phosphoprotein Profiling of Beta Adrenergic Receptor (β-AR) Signaling Reveals Novel Phosphorylation and Dephosphorylation Events
Figure 6
A model of phosphoprotein signaling mediated by β-AR agonists and forskolin.
Cyclic AMP (cAMP) is generated by activation of adenylyl cyclase (AC) through β-AR stimulation or by direct activation by forskolin. PKA is then activated by cAMP and phosphorylates a variety of targets either directly (single arrow) or through intermediates (sequential arrows). Independent of PKA kinase activity, cAMP can inhibit basal PI3K/AKT activity leading to the dephosphorylation of downstream targets for PI3K/AKT. PP1α is also dephosphorylated by agents that increase cAMP levels, but this dephosphorylation is not dependent on PI3K/AKT inhibition, as neither treatment with LY294002 (LY) nor wortmannin (Wort) led to dephosphorylation of PP1α. GSK3β can be phosphorylated by both PKA and AKT. When MEFs are stimulated by isoproterenol or forskolin in the presence of H89 (PKA inhibitor), enhanced dephosphorylation of GSK3β is observed because the rapid phosphorylation of GSK3β by PKA is blocked. Basal phosphorylation of GSK3β by AKT is inhibited by cAMP leading to the dephosphorylation of GSK3β. Solid arrows represent phosphorylation, double line arrows represent activation, and blocked lines represent inhibition.