"A-kinase" regulator runs amok to provide a paradigm shift in cAMP signaling

Abstract

The activity of the archetypal protein kinase A (PKA) is typically thought of in regards to the catalytic subunit, which is inhibited by the regulatory subunits in the absence of cAMP. However, it is now reported that one of the regulatory subunit isoforms (PKA-RIα) takes on a function of its own upon binding to cAMP, acting independently of this canonical cAMP signaling mechanism. PKA-RIα instead binds to and stimulates the catalytic activity of a guanine nucleotide exchange factor (P-REX1) that itself promotes Rac1 GTPase activation. This newly discovered function of PKA-RIα adds an additional layer of complexity to our understanding of cAMP signal transduction.

Figure 1.

Effects of PKA on P-REX1 activity. A, at low levels of cAMP, PKA exists mainly as a holoenzyme consisting of regulatory (RIα) and catalytic (Cα) subunits that do not bind to or phosphorylate P-REX1. B, when levels of cAMP rise, the A and B binding sites on RIα are occupied by cAMP, thereby stimulating PKA holoenzyme dissociation. RIα then binds to PDZ domains of P-REX1 to stimulate the GEF activity of the DH domain, thereby activating Rac1. C, activated PKA Cα subunits phosphorylate P-REX1 at Ser-436 of the DEP1 domain, so that P-REX1 GEF activity is inhibited. Phosphatases maintain P-REX1 in the unphosphorylated state so that it can be activated by RIα, whereas phosphorylated P-REX1 cannot be activated by RIα. These actions of cAMP are counteracted by cyclic nucleotide phosphodiesterases (PDEs) that hydrolyze cAMP. Thus, the balance of P-REX1 cycling between nonphospho and phospho states dictates up- or down-regulation of P-REX1 GEF activity in response to cAMP.