Pharmacological targeting of AKAP-directed compartmentalized cAMP signalling

Dema, Alessandro; Perets, Ekaterina; Schulz, Maike Svenja; Deák, Veronika; Klussmann, Enno

doi:10.1016/j.cellsig.2015.09.008

Cited by 67 publications

(67 citation statements)

References 261 publications

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“…Although all AKAPs are provided from a specific structural motif for binding the regulatory subunit of PKA, they have been implicated in a variety of cellular functions that do not necessarily depend on PKA. Whereas the elucidation of their mechanisms responsible for their pleiotropic functions will require further work, AKAPs are already targets of pharmacological intervention in immunodeficiency disorders, such as AIDS [163,164]. Hence, their functional characterization in T cells, which are major players in these diseases, has become a priority.…”

Section: Effector Pathways-pka and Epac1mentioning

confidence: 99%

cAMP: a multifaceted modulator of immune synapse assembly and T cell activation

Arumugham

Baldari

2017

Journal of Leukocyte Biology

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T Lymphocyte activation involves a substantial reorganization of the membranous and intracellular compartments. Signaling complexes assemble and dismantle in a highly ordered fashion in both compartments and orchestrate the activation of T cells with high sensitivity and specificity. TCR ligation leads to a short burst of cAMP production, which is centrally required for T cell activation; however, sustained elevations in intracellular cAMP concentrations are immunosuppressive. Emerging evidence of the existence of local cAMP pools gleaned from studies on other cell types suggests that cAMP compartmentalization may account, in part, for these opposing effects. Whereas cAMP compartmentalization has been identified as a central factor in the control of the cAMP-dependent processes in other cell types, this has, as yet, not been addressed in T lymphocytes. In this review, we discuss the role of cAMP in T cell activation and differentiation, with an emphasis on the effects mediated by the cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (EPAC)1, and on the regulatory proteins that may control the generation of local cAMP pools in T cells. We also present an overview of the available tools to image cAMP production at the subcellular level and discuss how bacterial adenylate cyclase (AC) toxins that are known to generate local cAMP pools can be exploited to address the role of cAMP compartmentalization in T cell activation.

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Section: Effector Pathways-pka and Epac1mentioning

confidence: 99%

cAMP: a multifaceted modulator of immune synapse assembly and T cell activation

Arumugham

Baldari

2017

Journal of Leukocyte Biology

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“…A-kinase anchoring proteins (AKAPs) 2 directly interact with the regulatory (R) subunits of PKA and facilitate PKA phosphorylation of its substrates at specific intracellular compartments (3)(4)(5). This coordinating function of AKAPs is not limited to PKA signaling; AKAPs directly bind further signaling proteins and thereby coordinate crosstalk between multiple signaling pathways.…”

mentioning

confidence: 99%

The A-kinase Anchoring Protein GSKIP Regulates GSK3β Activity and Controls Palatal Shelf Fusion in Mice

Deák

Dittmayer

Knobeloch

et al. 2016

Journal of Biological Chemistry

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A-kinase anchoring proteins (AKAPs) represent a family of structurally diverse proteins, all of which bind PKA. A member of this family is glycogen synthase kinase 3␤ (GSK3␤) interaction protein (GSKIP). GSKIP interacts with PKA and also directly interacts with GSK3␤. The physiological function of the GSKIP protein in vivo is unknown. We developed and characterized a conditional knock-out mouse model and found that GSKIP deficiency caused lethality at birth. Embryos obtained through Caesarean section at embryonic day 18.5 were cyanotic, suffered from respiratory distress, and failed to initiate breathing properly. Additionally, all GSKIP-deficient embryos showed an incomplete closure of the palatal shelves accompanied by a delay in ossification along the fusion area of secondary palatal bones. On the molecular level, GSKIP deficiency resulted in decreased phosphorylation of GSK3␤ at Ser-9 starting early in development (embryonic day 10.5), leading to enhanced GSK3␤ activity. At embryonic day 18.5, GSK3␤ activity decreased to levels close to that of wild type. Our findings reveal a novel, crucial role for GSKIP in the coordination of GSK3␤ signaling in palatal shelf fusion.PKA is a serine/threonine kinase that controls a wide variety of cellular processes (1, 2). A-kinase anchoring proteins (AKAPs) 2 directly interact with the regulatory (R) subunits of PKA and facilitate PKA phosphorylation of its substrates at specific intracellular compartments (3-5). This coordinating function of AKAPs is not limited to PKA signaling; AKAPs directly bind further signaling proteins and thereby coordinate crosstalk between multiple signaling pathways. An example is the AKAP glycogen synthase kinase 3␤ (GSK3␤) interaction protein (GSKIP). GSKIP directly interacts with PKA and GSK3␤ (6), but its functions have not been determined. Recently, an autosomal dominant 700-kb duplication encompassing the Gskip gene was identified in humans; this alteration causes a predisposition for myeloid malignancies, indicating a likely role in tumorigenesis (7).To date, functional analyses of the GSKIP protein have been limited to in vitro and overexpression studies. GSKIP contains a structurally conserved PKA-binding domain (amino acids 28 -52) that is characteristic for AKAPs and specifically binds regulatory RII subunits of PKA. GSK3␤ binds GSKIP at its C-terminal conserved GSK3␤-binding domain (GID; amino acids 115-139) (6,8). The interaction between GSKIP and GSK3␤ through the GID is conserved among vertebrates and invertebrates, whereas its interaction with PKA RII subunits is restricted to vertebrates. This indicates that it functions as an AKAP exclusively in vertebrates (6).GSK3 is a highly conserved serine-threonine kinase involved in a plethora of cellular processes including glycogen metabolism, proliferation, differentiation, and development. It is found in the cytosol, nucleus, and mitochondria of all eukaryotic cells (9). There are two homologous genes encoding two isoforms of GSK3, GSK3␣ (51 kDa) and GSK3␤ (47 kDa). Both isoforms o...

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“…These anchor points may generally influence the binding affinity between AKAPs and R subunits of PKA, and may thus also lead to new strategies for pharmacological targeting of other AKAP–PKA interactions. This is so far not possible because only global disruptors of AKAP–PKA interactions are available [4]. …”

Section: Discussionmentioning

confidence: 99%

“…Peptides derived from AKBs of AKAPs such as AKAP-Lbc (peptide Ht31) or AKAP18 δ (peptide AKAP18 δ L314E) bind regulatory subunits of PKA with nanomolar affinity, and thereby globally uncouple PKA from AKAPs [4,34,35]. More recent studies led to peptides that preferentially disrupt AKAP–RI or AKAP–RII interactions [36–41].…”

Section: Introductionmentioning

confidence: 99%

AKAP18:PKA-RIIα structure reveals crucial anchor points for recognition of regulatory subunits of PKA

Götz

Roske

Schulz

et al. 2016

Biochemical Journal

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A-kinase anchoring proteins (AKAPs) interact with the dimerization/docking (D/D) domains of regulatory subunits of the ubiquitous protein kinase A (PKA). AKAPs tether PKA to defined cellular compartments establishing distinct pools to increase the specificity of PKA signalling. Here, we elucidated the structure of an extended PKA-binding domain of AKAP18β bound to the D/D domain of the regulatory RIIα subunits of PKA. We identified three hydrophilic anchor points in AKAP18β outside the core PKA-binding domain, which mediate contacts with the D/D domain. Such anchor points are conserved within AKAPs that bind regulatory RII subunits of PKA. We derived a different set of anchor points in AKAPs binding regulatory RI subunits of PKA. In vitro and cell-based experiments confirm the relevance of these sites for the interaction of RII subunits with AKAP18 and of RI subunits with the RI-specific smAKAP. Thus we report a novel mechanism governing interactions of AKAPs with PKA. The sequence specificity of each AKAP around the anchor points and the requirement of these points for the tight binding of PKA allow the development of selective inhibitors to unequivocally ascribe cellular functions to the AKAP18-PKA and other AKAP-PKA interactions.

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Pharmacological targeting of AKAP-directed compartmentalized cAMP signalling

Cited by 67 publications

References 261 publications

cAMP: a multifaceted modulator of immune synapse assembly and T cell activation

cAMP: a multifaceted modulator of immune synapse assembly and T cell activation

The A-kinase Anchoring Protein GSKIP Regulates GSK3β Activity and Controls Palatal Shelf Fusion in Mice

AKAP18:PKA-RIIα structure reveals crucial anchor points for recognition of regulatory subunits of PKA

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