AKAPs (A-kinase anchoring proteins) and molecules that compose their G-protein-coupled receptor signalling complexes

Malbon, Craig C.; Tao, Jiangchuan; Wang, Hsien‐yu

doi:10.1042/bj20031648

Cited by 100 publications

(94 citation statements)

References 72 publications

(127 reference statements)

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“…Ion channels, exchangers, and G protein-coupled receptors form a subset of proteins that are PKA-phosphorylated and for which a number of AKAPs have been reported to contribute to targeting of PKA phosphorylation (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). I Ks is a slow heart potassium current carried by the I Ks potassium channel, critically important in the regulation of the cardiac action potential, particularly in the face of sympathetic nervous system stimulation (16), which belongs to this subset of proteins.…”

mentioning

confidence: 99%

Regulatory actions of the A-kinase anchoring protein Yotiao on a heart potassium channel downstream of PKA phosphorylation

Kurokawa

Motoike

Rao

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

114

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A-kinase anchoring proteins (AKAPs) are thought to be passive members of protein complexes that coordinate the association of cAMP-dependent protein kinase A (PKA) with cellular substrates to facilitate targeted PKA protein phosphorylation. IKs, the slow heart postassium current, is carried by the IKs potassium channel, a substrate for PKA phosphorylation in response to sympathetic nerve stimulation, is a macromolecular complex that includes the KCNQ1 α subunit, the KCNE1 regulatory subunit, and the AKAP Yotiao. Disruption of this regulation by mutation in the long QT syndrome is associated with elevated risk of sudden death. Here, we have studied the effects of the AKAP Yotiao on the function of the IKs channel that had been mutated to simulate channel phosphorylation, and we report direct AKAP-mediated alteration of channel function distinct from its role in the coordination of channel phosphorylation by PKA. These data reveal previously undescribed actions of Yotiao that occur subsequent to channel phosphorylation and provide evidence that this adaptor protein also may serve as an effector in regulating this important ion channel

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mentioning

confidence: 99%

Regulatory actions of the A-kinase anchoring protein Yotiao on a heart potassium channel downstream of PKA phosphorylation

Kurokawa

Motoike

Rao

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

114

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“…Interestingly, another scaffolding protein with AKAP properties, WAVE-1, directs actin reorganization by relaying signals from the GTPase Rac to downstream effectors. Overall several AKAPs (like AKAPlbc or AKAP220) group PKA, other Rho GTPases, and their regulator molecules together, thereby regulating small GTPase activities affecting cytoskeleton reorganizations (9,10,48,51). Several means have been described how the second messenger cAMP alters signaling through the Ras-Raf-Erk cascade positively or negatively.…”

Section: Discussionmentioning

confidence: 99%

“…9 and 10). It has been long regarded that the GPCR-cAMP-PKA signaling axis participates, among others, in the regulation of cell growth, differentiation, and motility (9)(10)(11)(12)(13). Such fundamental cellular functions are controlled by mitogenic signals that are transmitted through cascades involving crucially regulated mitogen-activated protein kinases (MAPK) like Erk1/2 (14).…”

mentioning

confidence: 99%

Reciprocal regulation of PKA and Rac signaling

Bachmann

Riml

Huber

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Activated G protein-coupled receptors (GPCRs) and receptor tyrosine kinases relay extracellular signals through spatial and temporal controlled kinase and GTPase entities. These enzymes are coordinated by multifunctional scaffolding proteins for precise intracellular signal processing. The cAMP-dependent protein kinase A (PKA) is the prime example for compartmentalized signal transmission downstream of distinct GPCRs. A-kinase anchoring proteins tether PKA to specific intracellular sites to ensure precision and directionality of PKA phosphorylation events. Here, we show that the Rho-GTPase Rac contains A-kinase anchoring protein properties and forms a dynamic cellular protein complex with PKA. The formation of this transient core complex depends on binary interactions with PKA subunits, cAMP levels and cellular GTP-loading accounting for bidirectional consequences on PKA and Rac downstream signaling. We show that GTP-Rac stabilizes the inactive PKA holoenzyme. However, β-adrenergic receptor-mediated activation of GTP-Rac-bound PKA routes signals to the Raf-Mek-Erk cascade, which is critically implicated in cell proliferation. We describe a further mechanism of how cAMP enhances nuclear Erk1/2 signaling: It emanates from transphosphorylation of p21-activated kinases in their evolutionary conserved kinase-activation loop through GTPRac compartmentalized PKA activities. Sole transphosphorylation of p21-activated kinases is not sufficient to activate Erk1/2. It requires complex formation of both kinases with GTP-Rac1 to unleash cAMP-PKA-boosted activation of Raf-Mek-Erk. Consequently GTPRac functions as a dual kinase-tuning scaffold that favors the PKA holoenzyme and contributes to potentiate Erk1/2 signaling. Our findings offer additional mechanistic insights how β-adrenergic receptor-controlled PKA activities enhance GTP-Rac-mediated activation of nuclear Erk1/2 signaling. signal transduction | cross-talk S ignal transduction cascades coordinate the plethora of extracellular stimuli into biological responses within cells. The specificity of receptor-initiated signaling responses is encoded by spatial and temporal dynamics of downstream signaling networks (1). These networks, initiating from e.g., the G protein-coupled receptor (GPCR) superfamily and receptor tyrosine kinases (RTK), tightly regulate signaling pathways at several critical points via feedback loops and cross-talk among other pathways (2-5). A large number of GPCR signaling cascades uses cAMP as an intracellular second messenger (3, 6). In response to hormone binding to distinct GPCRs, cAMP is produced and binds to its canonical effector, the cAMP-dependent protein kinase A (PKA). cAMP binding to the PKA regulatory subunits (R) induces dissociation of the tetrameric PKA holoenzyme, resulting in active PKA catalytic subunits (PKAc; Fig. 1C) (7, 8). To ensure substrate specificity, PKA is tethered to distinct subcellular compartments through physical interaction with A-kinase anchoring proteins (AKAPs; refs. 9 and 10). It has been long regarded that the...

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“…For example, in neurons, calcineurin is associated with A-kinase anchoring protein (AKAP), which inhibits its phosphatase activity. Protein kinases A and C are also associated with AKAP in these complexes (50,51). Thus, complexes of AKAP, calcineurin, and protein kinases constitute a signal regulation complex that may reversibly modulate the phosphorylation status and activity of signaling molecules.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin Negatively Regulates TLR-Mediated Activation Pathways

Kang

Kusler

Otsuka

et al. 2007

The Journal of Immunology

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In innate immunity, microbial components stimulate macrophages to produce antimicrobial substances, cytokines, other proinflammatory mediators, and IFNs via TLRs, which trigger signaling pathways activating NF-κB, MAPKs, and IFN response factors. We show in this study that, in contrast to its activating role in T cells, in macrophages the protein phosphatase calcineurin negatively regulates NF-κB, MAPKs, and IFN response factor activation by inhibiting the TLR-mediated signaling pathways. Evidence for this novel role for calcineurin was provided by the findings that these signaling pathways are activated when calcineurin is inhibited either by the inhibitors cyclosporin A or FK506 or by small interfering RNA-targeting calcineurin, and that activation of these pathways by TLR ligands is inhibited by the overexpression of a constitutively active form of calcineurin. We further found that IκB-α degradation, MAPK activation, and TNF-α production by FK506 were reduced in macrophages from mice deficient in MyD88, Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF), TLR2, or TLR4, whereas macrophages from TLR3-deficient or TLR9 mutant mice showed the same responses to FK506 as those of wild-type cells. Biochemical studies indicate that calcineurin interacts with MyD88, TRIF, TLR2, and TLR4, but not with TLR3 or TLR9. Collectively, these results suggest that calcineurin negatively regulates TLR-mediated activation pathways in macrophages by inhibiting the adaptor proteins MyD88 and TRIF, and a subset of TLRs.

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AKAPs (A-kinase anchoring proteins) and molecules that compose their G-protein-coupled receptor signalling complexes

Cited by 100 publications

References 72 publications

Regulatory actions of the A-kinase anchoring protein Yotiao on a heart potassium channel downstream of PKA phosphorylation

Regulatory actions of the A-kinase anchoring protein Yotiao on a heart potassium channel downstream of PKA phosphorylation

Reciprocal regulation of PKA and Rac signaling

Calcineurin Negatively Regulates TLR-Mediated Activation Pathways

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