The many faces of compartmentalized PKA signalosomes

Abstract

Cellular signal transmission requires the dynamic formation of spatiotemporally controlled molecular interactions. At the cell surface information is received by receptor complexes and relayed through intracellular signaling platforms which organize the actions of functionally interacting signaling enzymes and substrates. The list of hormone or neurotransmitter pathways that utilize the ubiquitous cAMP-sensing protein kinase A (PKA) system is expansive. This requires that the specificity, duration, and intensity of PKA responses are spatially and temporally restricted. Hereby, scaffolding proteins take the center stage for ensuring proper signal transmission. They unite second messenger sensors, activators, effectors, and kinase substrates within cellular micro-domains to precisely control and route signal propagation. A-kinase anchoring proteins (AKAPs) organize such subcellular signalosomes by tethering the PKA holoenzyme to distinct cell compartments. AKAPs differ in their modular organization showing pathway specific arrangements of interaction motifs or domains. This enables the cell- and compartment- guided assembly of signalosomes with unique enzyme composition and function. The AKAP-mediated clustering of cAMP and other second messenger sensing and interacting signaling components along with functional successive enzymes facilitates the rapid and precise dissemination of incoming signals. This review article delineates examples for different means of PKA regulation and for snapshots of compartmentalized PKA signalosomes.

Integrin α9 depletion promotes β‐catenin degradation to suppress triple‐negative breast cancer tumor growth and metastasis

“…Increased PKA activity is observed in cancer and PKA has been proposed as an important target for cancer treatment . Previous studies showed that cellular compartmentalized regulation of PKA activity is mainly achieved by A‐kinase anchoring proteins, a group of proteins interacting with PKA regulatory subunits, recruiting PKA to cellular specific loci, and directing PKA kinase activity to specific substrates . Using Co‐IF staining and Co‐IP experiments, we demonstrated that ITGA9 KO significantly increases the interaction between ILK and PKA.…”

“…40 Previous studies showed that cellular compartmentalized regulation of PKA activity is mainly achieved by A-kinase anchoring proteins, a group of proteins interacting with PKA regulatory subunits, recruiting PKA to cellular specific loci, and directing PKA kinase activity to specific substrates. 39,46,47 Using Co-IF staining and Co-IP experiments, we demonstrated that ITGA9 KO significantly increases the interaction between ILK and PKA. Although it remains to be determined whether ILK directly interacts with PKA regulatory subunit or catalytic subunit, this interaction reduces PKA activity.…”

“…The binding of two cyclic adenosine monophosphates (cAMP) to each of the two regulatory subunits releases and activates the catalytic subunits, which phosphorylate serine and threonine residues on the substrate proteins. Proteins interacting with PKA regulatory or catalytic subunits may enhance or inhibit PKA activity . One of the important proteins that regulate integrin α9β1 signaling is the scaffold protein ILK, which was found to interact with ITGB1 cytoplasmic tail and other proteins at cellular membrane region .…”

“…Proteins interacting with PKA regulatory or catalytic subunits may enhance or inhibit PKA activity. [39][40][41][42] One of the important proteins that regulate integrin α9β1 signaling is the scaffold protein ILK, which was found to interact with ITGB1 cytoplasmic tail and other proteins at cellular membrane region. 43,44 We hypothesize that ITGA9 KO disrupts the interaction between ITGA9 and ITGB1, which leads to ILK translocation from cellular membrane region to cytoplasm and interacts with PKA regulatory subunits and reduces PKA activity.…”

A new sensitive and subunit‐selective molecular tool for investigating protein kinase A in the brain

“…Three PKA catalytic subunits (Cα, Cβ, and Cγ) and four regulatory subunits (RIα, RIβ, RIIα, and RIIβ) have been described in mammalian tissues, with different expression in the various tissues and developmental time course of appearance. Apparently, they are precisely docked at selected intracellular sites [ 1 ] and have different binding affinities for their ligands. [ 2 ] Each regulatory subunit binds two cAMP molecules, leading to the release of the catalytic subunit from the tetrameric complex, thus allowing phosphorylation of target proteins.…”