A-kinase anchoring proteins: from protein complexes to physiology and disease

Abstract

Protein scaffold complexes are a key mechanism by which a common signaling pathway can serve many different functions. Sequestering a signaling enzyme to a specific subcellular environment not only ensures that the enzyme is near its relevant targets, but also segregates this activity to prevent indiscriminate phosphorylation of other substrates. One family of diverse, well-studied scaffolding proteins are the A-kinase anchoring proteins (AKAPs). These anchoring proteins form multi-protein complexes that integrate cAMP signaling with other pathways and signaling events. In this review, we focus on recent advances in the elucidation of AKAP function.

Figure 1. Properties of AKAPs

AKAPs bind to the regulatory subunit of PKA. AKAPs also bind additional signaling proteins (for example other protein kinases, protein phosphatases, phopshodiesterases, adenylyl cyclases and small G proteins). AKAPs function to target signaling complexes to discreet locations inside a cell.

Figure 2. Study of AKAP function by peptide-mediated disruption of PKA anchoring

A) The AKAP-amphipathic helix-PKA-RII interaction can be disrupted in vivo by introduction of a competing peptide called Ht31. B) Ht31 will bind to PKA-RII, thereby displacing PKA from an AKAP inside a cell. C) Mislocalization of PKA by displacement from an AKAP may lead to uncoupling of site-specific PKA signaling. This has been demonstrated in the processes of channel regulation, insulin secretion, sperm motility and oocyte maturation.

Figure 3. Development – sperm function, oocyte maturation and embryogenesis

AKAPs are highly abundant in testes, where they play important roles in sperm function including regulation of motility, capacitation and the acrosome reaction. AKAPs also function in oogenesis where they function to regulate PKA localization maintaining initial meiotic arrest, followed by subsequent meiotic divisions to produce an egg ready for fertilization. Following fertilization, AKAPs play a role in embryogenesis. Specifically, gravin has been demonstrated to play a role in gastrulation regulating the movement of germ layer cells to form an embryonic body plan.

Figure 4. Cardiac AKAPs

AKAPs play a prominent role in the regulation of cardiac function. To date AKAP18, AKAP79 and yotiao fuction in channel regulation, while myospryn and synemin act to target PKA to intermediate filaments. mAKAP and AKAP-Lbc appear to play a role in the disease process of cardiac hypertrophy.