Mechanisms of Protein Kinase A Anchoring

Skroblin, Philipp; Großmann, Solveig; Schäfer, Gesa; Rosenthal, Walter; Klussmann, Enno

doi:10.1016/s1937-6448(10)83005-9

Cited by 156 publications

(207 citation statements)

References 537 publications

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“…Most AKAPs possess unique targeting domains, which direct the AKAP-PKA complex to defined cellular compartments including membranes, cytoskeletal components, or other structures (2,3,44,45). Some AKAPs, however, lack canonical targeting domains.…”

Section: Lihrleavqrtreamentioning

confidence: 99%

The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3β Interaction Protein (GSKIP) Regulates β-Catenin through Its Interactions with Both Protein Kinase A (PKA) and GSK3β

Dema

Schröter

Perets

et al. 2016

Journal of Biological Chemistry

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The A-kinase anchoring protein (AKAP) GSK3␤ interaction protein (GSKIP) is a cytosolic scaffolding protein binding protein kinase A (PKA) and glycogen synthase kinase 3␤ (GSK3␤). Here we show that both the AKAP function of GSKIP, i.e. its direct interaction with PKA, and its direct interaction with GSK3␤ are required for the regulation of ␤-catenin and thus Wnt signaling. A cytoplasmic destruction complex targets ␤-catenin for degradation and thus prevents Wnt signaling. Wnt signals cause ␤-catenin accumulation and translocation into the nucleus, where it induces Wnt target gene expression. GSKIP facilitates control of the ␤-catenin stabilizing phosphorylation at Ser-675 by PKA. Its interaction with GSK3␤ facilitates control of the destabilizing phosphorylation of ␤-catenin at Ser-33/Ser-37/Thr-41. The influence of GSKIP on ␤-catenin is explained by its scavenger function; it recruits the kinases away from the destruction complex without forming a complex with ␤-catenin. The regulation of ␤-catenin by GSKIP is specific for this AKAP as AKAP220, which also binds PKA and GSK3␤, did not affect Wnt signaling. We find that the binding domain of AKAP220 for GSK3␤ is a conserved GSK3␤ interaction domain (GID), which is also present in GSKIP. Our findings highlight an essential compartmentalization of both PKA and GSK3␤ by GSKIP, and ascribe a function to a cytosolic AKAP-PKA interaction as a regulatory factor in the control of canonical Wnt signaling. Wnt signaling controls different biological processes, including embryonic development, cell cycle progression, glycogen metabolism, and immune regulation; deregulation is associated with diseases such as cancer, type 2 diabetes, inflammatory, and Alzheimer's and Parkinson's diseases.A-kinase anchoring proteins (AKAPs) 3 are a family of about 50 scaffolding proteins. Their conserved function is the compartmentalization of protein kinase A (PKA). PKA holoenzyme consists of a dimer of regulatory (RI␣, RI␤, RII␣, or RII␤) and two catalytic subunits each bound to one R subunit. AKAPs directly interact with R subunits and tether the kinase to defined cellular compartments such as vesicles, the sarcoplasmic reticulum, or the cytoskeleton. This compartmentalization confers a tight spatiotemporal control to PKA signaling, and enables PKA to elicit a specific cellular response to each of the many stimuli that cause cAMP elevation and thereby lead to activation of this ubiquitous kinase. AKAPs directly interact with further signaling proteins, thus mediating crosstalk between signaling systems: phosphatases, dephosphorylating PKA-phosphorylated substrates, adenylyl cyclases, synthesizing cAMP, and phosphodiesterases (PDEs), hydrolyzing cAMP. Several AKAPs bind further kinases such as protein kinase C (PKC), which are activated by signals other than cAMP, e.g. Ca 2ϩ . AKAPs and their interactions play key roles in a variety of physiological processes such as vasopressin-mediated water reabsorption in renal principal cells and cardiac myocyte contractility (1-5, 7, 8).A new example...

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Section: Lihrleavqrtreamentioning

confidence: 99%

The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3β Interaction Protein (GSKIP) Regulates β-Catenin through Its Interactions with Both Protein Kinase A (PKA) and GSK3β

Dema

Schröter

Perets

et al. 2016

Journal of Biological Chemistry

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“…PDEs are tethered to subcellular compartments through direct association with membranes [5,6], or through interactions with proteins that direct them to defined compartments. Protein binding partners include scaffolding proteins such as the A-kinase anchoring proteins (AKAPs), a heterogeneous family of around 50 proteins characterised by their common ability to directly interact with PKA [7,8]. In addition to a conserved domain for the interaction with PKA, AKAPs posses docking domains for direct binding of additional proteins such as PDEs and they possess anchoring domains tethering the AKAP-based protein complex to defined cellular compartments [9,10].…”

Section: Introduction To Compartmentalized Camp Signallingmentioning

confidence: 99%

Protein–protein interactions of PDE4 family members — Functions, interactions and therapeutic value

Klussmann

2016

Cellular Signalling

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The second messenger cyclic adenosine monophosphate (cAMP) is ubiquitous and directs a plethora of functions in all cells. Although theoretically freely diffusible through the cell from the site of its synthesis it is not evenly distributed. It rather is shaped into gradients and these gradients are established by phospodiesterases (PDEs), the only enzymes that hydrolyse cAMP and thereby terminate cAMP signalling upstream of cAMP's effector systems. Miles D.Houslay has devoted most of his scientific life highly successfully to a particular family of PDEs, the PDE4 family. The family is encoded by four genes and gives rise to around 20 enzymes, all with different functions. M. Houslay has discovered many of these functions and realised early on that PDE4 family enzymes are attractive drug targets in a variety of human diseases, but not their catalytic activity as that is encoded in conserved domains in all family members. He postulated that targeting the intracellular location would provide the specificity that modern innovative drugs require to improve disease conditions with fewer side effects than conventional drugs.Due to the wealth of M. Houslay's work, this article can only summarize some of his discoveries and, therefore, focuses on protein-protein interactions of PDE4. The aim is to discuss functions of selected protein-protein interactions and peptide spot technology, which M.Houslay introduced into the PDE4 field for identifying interacting domains. The therapeutic potential of PDE4 interactions will also be discussed.

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“…to the cytoskeleton, plasma membrane, the Golgi, vesicles, nucleus or mitochondria), and thereby regulate PKA signaling spatially and temporally (Fig. 2) [7,9,10]. The interaction of AKAPs with PKA increases the specificity of PKA signaling and facilitates specific cellular responses to each of the extracellular cues.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease

Deák¹,

Klussmann

2016

CDT

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A--kinase anchoring proteins (AKAPs) control the localization of cAMP--dependent protein kinase A (PKA) by tethering PKA to distinct cellular compartments. Through additional direct protein--protein interactions with PKA substrates and other signaling molecules they form multi--protein complexes. Thereby, AKAPs regulate the access of PKA to its substrates in a temporal and spatial manner as well as the local crosstalk of cAMP/PKA with other signaling pathways.Due to the increasing information on their molecular functioning and three--dimensional structures, and their emerging roles in the development of diseases, AKAPs move into the focus as potential drug targets. In particular, targeting AKAP--dependent protein--protein interactions for interference with local signal processing inside cells potentially allows for the development of therapeutics with high selectivity and fewer side effects.4

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Mechanisms of Protein Kinase A Anchoring

Cited by 156 publications

References 537 publications

The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3β Interaction Protein (GSKIP) Regulates β-Catenin through Its Interactions with Both Protein Kinase A (PKA) and GSK3β

The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3β Interaction Protein (GSKIP) Regulates β-Catenin through Its Interactions with Both Protein Kinase A (PKA) and GSK3β

Protein–protein interactions of PDE4 family members — Functions, interactions and therapeutic value

Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease

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