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Showing AKAP6 — MAKAP is a alias.

AKAP6

A-kinase anchor protein 6 · UniProt Q13023

Length
2319 aa
Mass
256.7 kDa
Annotated
2026-06-09
24 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AKAP6 (mAKAP) is a large scaffold protein that organizes a multi-protein signalosome at the nuclear envelope of striated myocytes to integrate cAMP, Ca2+, and MAP-kinase signals controlling cardiomyocyte hypertrophy and myocyte differentiation (PMID:11296225, PMID:16177794, PMID:16306226). It was first identified as a PKA type II regulatory subunit-binding protein targeting PKA to the sarcoplasmic reticulum of cardiac and skeletal muscle (PMID:7721854), and is anchored to the nuclear membrane through spectrin-repeat regions that bind the amino-terminal dimerization domain of nesprin-1alpha (PMID:10413680, PMID:15652351). At this site AKAP6 nucleates a cAMP module containing PKA and PDE4D3, where PKA stimulates PDE4D3 and PKA-phosphorylation of PDE4D3 (Ser-13) raises its affinity for the scaffold, establishing a negative feedback loop for cAMP termination (PMID:11296225, PMID:15182229); an associated PP2A/B56delta phosphatase reverses PDE4D3 activation as a counterbalancing positive-feedback arm (PMID:20106966), and an ERK5/Epac1 module couples this network to hypertrophic growth (PMID:16177794). The complex localizes ryanodine receptor and calcineurin to enable PKA-mediated RyR phosphorylation, Ca2+ release, and calcineurin-dependent activation of the pro-hypertrophic transcription factor NFATc (PMID:12709444, PMID:16306226). AKAP6 directly binds MEF2 and organizes calcineurin/MEF2 signaling to drive myoblast differentiation, with myogenin feeding back to upregulate AKAP6 transcription (PMID:23261540, PMID:22484155, PMID:26563778). It also organizes ubiquitin E3 ligases that govern HIF-1alpha stability and hypoxic gene responses (PMID:19109240). Independently of its kinase-anchoring role, AKAP6 is the central organizer of the nuclear-envelope microtubule-organizing center, bridging nesprin-1alpha to the centrosomal proteins pericentrin and AKAP9 and tethering the Golgi to the nucleus, a function induced downstream of myogenin (PMID:33295871, PMID:34605406). Beyond striated muscle, AKAP6 anchors calcineurin and NFATc4 in neurons to mediate BDNF-dependent transcription and neuroprotection (PMID:39578909).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1995 High

    Established AKAP6 as a PKA-anchoring protein, defining its founding molecular activity of targeting PKA type II to muscle sarcoplasmic reticulum.

    Evidence Interaction cloning with RII probe, overlay assay, and cAMP-agarose co-purification from muscle extracts

    PMID:7721854

    Open questions at the time
    • Did not define the nuclear-envelope targeting mechanism
    • No downstream substrates identified at this stage
  2. 1999 High

    Mapped the spectrin-repeat regions responsible for nuclear-membrane targeting, locating the scaffold to a defined subcellular compartment in differentiated myocytes.

    Evidence GFP fusion constructs and competitive displacement of endogenous mAKAP in myocytes

    PMID:10413680

    Open questions at the time
    • The nuclear-envelope receptor binding these repeats was not yet identified
  3. 2005 High

    Identified nesprin-1alpha as the nuclear-envelope receptor, explaining how AKAP6 is physically anchored to the perinuclear membrane.

    Evidence Direct binding assays and in-cell displacement mapping nesprin-1alpha N-terminus to the third spectrin repeat of mAKAP

    PMID:15652351

    Open questions at the time
    • Structural basis of the spectrin-repeat/nesprin interface not resolved
  4. 2006 High

    Defined the core cAMP-handling logic of the signalosome: a PKA/PDE4D3 module with reciprocal feedback regulating local cAMP.

    Evidence Co-IP from heart tissue, kinase/PDE activity assays, PKA-binding disruption, and PDE4D3 Ser-13 mutagenesis

    PMID:11296225 PMID:15182229

    Open questions at the time
    • How the cAMP module integrates with Ca2+ and MAPK arms not yet defined
  5. 2005 High

    Connected the scaffold to Ca2+ handling and hypertrophy, showing PKA anchoring enhances RyR phosphorylation and Ca2+ flux and that mAKAP is required for adrenergic hypertrophy via calcineurin/NFATc.

    Evidence PKA-binding-deficient mutant, Ca2+ transient and phosphorylation assays, RNAi, calcineurin co-IP, and NFATc reporters in cardiomyocytes

    PMID:11590243 PMID:12709444 PMID:16306226

    Open questions at the time
    • Stoichiometry of RyR recruitment to nuclear-envelope mAKAP unclear
    • RyR co-IP/fractionation results from a single lab
  6. 2005 High

    Revealed integration of MAPK signaling, with an ERK5 module and Epac1 coupling cAMP to hypertrophic growth control through the scaffold.

    Evidence Co-IP, RNAi, pharmacology, dominant-negatives, and cardiomyocyte hypertrophy assays

    PMID:16177794

    Open questions at the time
    • Quantitative contribution of ERK5 versus calcineurin arms to hypertrophy not separated
  7. 2010 Medium

    Added a PP2A/B56delta counter-regulatory arm and extended the scaffold to hypoxic signaling via HIF-1alpha-controlling E3 ligases.

    Evidence Domain mapping, phosphatase activity assays, B56delta mutagenesis, and HIF-1alpha stability/reporter assays with mAKAP depletion

    PMID:19109240 PMID:20106966

    Open questions at the time
    • Identity of the HIF-1alpha E3 ligases not fully defined
    • HIF-1alpha findings from a single lab
  8. 2015 High

    Defined AKAP6's role in myocyte differentiation through direct MEF2/calcineurin binding and a myogenin feedback loop driving its own expression.

    Evidence MEF2 binding-domain mapping, dominant-interference peptides, ChIP of myogenin at the AKAP6 promoter, reporter and myotube assays, in vivo shRNA

    PMID:22484155 PMID:23261540 PMID:26563778

    Open questions at the time
    • Discrete MEF2-binding domain structure not resolved
  9. 2021 High

    Established a kinase-anchoring-independent function: AKAP6 as the central organizer of the nuclear-envelope MTOC, bridging nesprin-1alpha to centrosomal proteins and Golgi, downstream of myogenin.

    Evidence Loss/gain-of-function, co-IP, microtubule nucleation, and myogenin KO/rescue in cardiomyocytes, osteoclasts, and myoblasts

    PMID:33295871 PMID:34605406

    Open questions at the time
    • How NE-MTOC scaffolding and the signalosome roles are partitioned on the same protein is unresolved
  10. 2024 Medium

    Extended AKAP6 scaffolding beyond muscle, showing it anchors calcineurin/NFATc4 in neurons for BDNF-dependent transcription and neuroprotection.

    Evidence Calcineurin-anchoring disruption peptide, NFAT reporters, NFATc4 KO mice, and neuronal survival assays

    PMID:39578909

    Open questions at the time
    • Neuronal localization of AKAP6 not mapped
    • Findings from a single lab
  11. 2025 Medium

    Placed AKAP6 downstream of Wnt/beta-catenin, linking its transcriptional upregulation to pathological RyR2 hyperphosphorylation and Ca2+ leak.

    Evidence Wnt activation, transcriptomics, AKAP6 over/knockdown, and RyR2 phosphorylation/Ca2+ assays in cardiomyocytes

    PMID:40097291

    Open questions at the time
    • Direct Wnt-responsive element on AKAP6 promoter not confirmed
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the same scaffold molecule simultaneously coordinates the cAMP/Ca2+ signalosome and the NE-MTOC, and whether disease-associated coding variants alter these functions in vivo, remains unresolved.
  • No structural model of the assembled signalosome
  • In vivo phenotype of AKAP6 polymorphisms not established
  • Mechanism dividing scaffold pools between functions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0008092 cytoskeletal protein binding 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005635 nuclear envelope 3 GO:0005783 endoplasmic reticulum 3 GO:0005634 nucleus 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
AKAP9PCNTPDE4D3PPP2 (PP2A B56DELTA)PPP3CB (CALCINEURIN)PRKAR2/PKARYR2SYNE1 (NESPRIN-1ALPHA)
Complex memberships
mAKAP signalosome (nuclear envelope)nuclear-envelope MTOC (NE-MTOC)

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 AKAP100 (AKAP6) was identified as a PKA type II regulatory subunit (RII)-binding protein that targets PKA type II to the sarcoplasmic reticulum in cardiac and skeletal muscle cells, demonstrated by RII overlay assay and co-purification with RII from cell extracts. Interaction cloning with RII probe, solid-phase overlay assay, immunohistochemistry, cAMP-agarose affinity co-purification The Journal of biological chemistry High 7721854
1998 AKAP100 (AKAP6) localizes to multiple subcellular compartments in adult rat cardiomyocytes including the nucleus, sarcolemma, intercalated disc, Z-line, and transverse tubule/junctional SR; RII (but not RI) co-localizes with AKAP100 at these sites. Immunofluorescence, confocal microscopy, double immunostaining with alpha-actinin and ryanodine receptor antibodies The Journal of cell biology Medium 9679148
1999 mAKAP (AKAP6) is targeted to the nuclear membrane of differentiated myocytes; nuclear membrane targeting is conferred by two regions (residues 772–915 and 915–1065) containing spectrin-like repeat sequences, as shown by GFP fusion constructs and displacement experiments. GFP fusion construct expression in myocytes, heterologous overexpression of targeting domains to displace endogenous mAKAP, immunolocalization Journal of cell science High 10413680
2001 mAKAP (AKAP6) assembles a cAMP signaling module containing PKA and PDE4D3 at the nuclear envelope of cardiac myocytes; tonic PDE4D3 activity reduces anchored PKA activity, while PKA activation stimulates mAKAP-associated PDE4D3, forming a negative feedback loop; disruption of PKA–mAKAP interaction prevents PKA-mediated enhancement of PDE4D3 activity. Co-immunoprecipitation from heart tissue, functional kinase and phosphodiesterase assays, PKA-mAKAP interaction disruption experiments The EMBO journal High 11296225
2001 The mAKAP (AKAP6) complex at the cardiac nuclear envelope also includes ryanodine receptors and protein phosphatase 2A; a subset of cardiac ryanodine receptor binds to mAKAP at the nuclear envelope, potentially enabling PKA-mediated phosphorylation of ryanodine receptor. Co-immunoprecipitation, immunohistochemistry, tissue fractionation Journal of cell science Medium 11590243
2003 Anchoring of PKA by mAKAP (AKAP6) at the sarcoplasmic reticulum co-localizes with RyR1 and increases PKA-dependent phosphorylation of RyR1 and Ca2+ efflux through RyR1; a PKA-binding-deficient mAKAP mutant (mAKAP-P) fails to enhance RyR1 phosphorylation or Ca2+ transient amplitude. Immunoelectron microscopy, Ca2+ transient measurements, phosphorylation assays in CHO cells stably expressing RyR1, expression of wild-type vs. PKA-binding-deficient mAKAP mutant The Journal of biological chemistry High 12709444
2004 PKA phosphorylation of PDE4D3 on Ser-13 increases the affinity of PDE4D3 for mAKAP (AKAP6), facilitating recruitment of PDE4D3 to the mAKAP signaling complex for faster cAMP signal termination. In vitro phosphorylation assays, co-immunoprecipitation, site-directed mutagenesis of PDE4D3 Ser-13, cellular experiments The Biochemical journal High 15182229
2005 mAKAP (AKAP6) coordinates two integrated cAMP effector pathways: anchored PKA stimulates PDE4D3 to reduce local cAMP, while an mAKAP-associated ERK5 module suppresses PDE4D3; PDE4D3 also recruits Epac1 to enable cAMP-dependent attenuation of ERK5; anchored ERK5 can induce cardiomyocyte hypertrophy. Co-immunoprecipitation, pharmacological inhibitors, RNA interference, dominant-negative constructs, cardiomyocyte hypertrophy assays Nature High 16177794
2005 Nesprin-1alpha serves as a receptor for mAKAP (AKAP6) on the nuclear envelope; the amino-terminal dimerization domain of nesprin-1alpha directly binds the third spectrin repeat of mAKAP to target it to the nuclear envelope; overexpression of these spectrin repeat domains displaces mAKAP from nesprin-1alpha. Co-immunoprecipitation, direct binding assays, overexpression of spectrin repeat domains, displacement experiments in myocytes Experimental cell research High 15652351
2005 The mAKAP (AKAP6) complex facilitates PKA-catalyzed phosphorylation of the ryanodine receptor Ca2+-release channel and is required for adrenergic-mediated cardiomyocyte hypertrophy; calcineurin Abeta associates with mAKAP and formation of the mAKAP complex is required for full activation of the pro-hypertrophic transcription factor NFATc. RNA interference of mAKAP, expression of PKA-binding-deficient mAKAP mutant, ryanodine receptor inhibition, co-immunoprecipitation of calcineurin, NFATc reporter assays Journal of cell science High 16306226
2008 mAKAP (AKAP6) organizes ubiquitin E3 ligases that control the stability of HIF-1alpha near the nuclear envelope; depletion of mAKAP or disruption of its perinuclear targeting alters HIF-1alpha stability and transcriptional activation of hypoxia-responsive genes in cardiomyocytes. mAKAP depletion (RNAi), disruption of perinuclear targeting, HIF-1alpha stability assays, transcriptional reporter assays, co-immunoprecipitation of E3 ligases Science signaling Medium 19109240
2010 PP2A associated with mAKAP (AKAP6) complexes (containing B56delta subunit) dephosphorylates PDE4D3 at Ser-54, reversing PKA-mediated activation of PDE4D3; a C-terminal mAKAP domain (residues 2085–2319) binds PP2A; PKA phosphorylation of B56delta enhances PP2A activity 2-fold in the complex, creating a cAMP-induced positive feedback loop. Domain mapping, co-immunoprecipitation, phosphatase activity assays, site-directed mutagenesis of B56delta PKA phosphorylation site, deletion of mAKAP C-terminal domain The Journal of biological chemistry High 20106966
2012 mAKAP (AKAP6) organizes a calcineurin/MEF2 signaling complex in myocytes; a calcineurin/mAKAP/MEF2 complex can be isolated from C2C12 cells and cardiac myocytes; calcineurin–MEF2 association is dependent on mAKAP expression; disruption of calcineurin–mAKAP binding blunts MEF2 transcriptional activity during myoblast differentiation and inhibits adrenergic-induced cardiac hypertrophy. Co-immunoprecipitation from C2C12 cells and cardiac myocytes, dominant-interference peptide disrupting calcineurin–mAKAP binding, MEF2 transcriptional reporter assays, siRNA knockdown Experimental cell research High 23261540
2012 mAKAP (AKAP6) directly binds MEF2 through discrete interaction domains; disruption of MEF2–mAKAP binding blocks MEF2 activation during early myoblast differentiation and inhibits myotube formation and expression of differentiation markers. Direct binding assays identifying discrete binding domains, dominant-interference expression, MEF2 transcriptional reporter assays, myotube formation assays Cellular signalling Medium 22484155
2013 Human mAKAP coding polymorphism P1400S (in the PDE4D3 binding site) reduces mAKAP–PDE4D3 binding without affecting PKA binding or activity; S2195F (near the PP2A binding site) increases PKA binding and PKA activity; L717V (flanking the spectrin repeat domain) increases PKA binding without changing PKA activity. Site-directed mutagenesis of mAKAP, co-immunoprecipitation, surface plasmon resonance (Biacore), PKA activity assays, Ca2+ measurements Journal of molecular biology High 23806656
2015 AKAP6 knockdown in skeletal myoblasts halts myotube formation and decreases myogenin and myosin heavy chain expression; AKAP6 promotes myogenin expression through MEF2A; myogenin in turn binds an E-box site on the AKAP6 promoter to increase AKAP6 expression, forming a positive feedback loop. siRNA knockdown, shRNA lentiviral delivery in vivo (cardiotoxin muscle injury model), chromatin immunoprecipitation, luciferase reporter assays, motor function assessment Scientific reports High 26563778
2019 AKAP6 physically interacts with phospholamban (PLN) at the perinuclear SR region in HEK-293T cells and cardiomyocytes; AKAP6 promotes Ca2+ uptake activity of SERCA1 in cotransfected cells even in the presence of PLN. Immunofluorescence colocalization, co-immunoprecipitation from HEK-293T cells and adult rat cardiomyocytes, Ca2+ uptake assay Physiological reports Medium 31325238
2020 AKAP6 is a key organizer of the nuclear envelope MTOC (NE-MTOC) in cardiomyocytes and osteoclasts; AKAP6 anchors centrosomal proteins (Pcnt, AKAP9) to the nuclear envelope via its spectrin repeats, acting as an adaptor between nesprin-1alpha and Pcnt/AKAP9; AKAP6 and AKAP9 form a protein platform tethering the Golgi to the nucleus; ectopic AKAP6 expression in epithelial cells is sufficient to recruit endogenous centrosomal proteins; AKAP6 is required for cardiomyocyte hypertrophy and osteoclast bone resorption. Loss-of-function (siRNA/shRNA), gain-of-function (ectopic expression), co-immunoprecipitation, immunofluorescence in cardiomyocytes and osteoclasts, microtubule nucleation assays eLife High 33295871
2021 Myogenin transcription factor is required and sufficient for NE-MTOC formation and induces AKAP6 expression; overexpression of AKAP6beta and nesprin-1alpha together is sufficient to recruit endogenous MTOC proteins to the nuclear envelope of myoblasts in the absence of myogenin, identifying AKAP6 as a central effector of myogenin-controlled NE-MTOC assembly. Loss-of-function (myogenin KO), gain-of-function (overexpression in fibroblasts and myoblasts), promoter reporter assays, bioinformatics, immunofluorescence eLife High 34605406
2024 AKAP6 anchors calcineurin (CaN) and NFATc4 in neurons, and this scaffolding is required for BDNF-mediated NFATc4 transcriptional activity and neuroprotection; disruption of calcineurin anchoring to AKAP6 diminishes BDNF's pro-survival effect; NFATc4 knockout mice show reduced BDNF neuroprotection in vivo. AKAP6 disruption experiments (calcineurin anchoring domain peptide), NFAT transcriptional reporter assays, NFATc4 knockout mice, neuronal survival assays Molecular brain Medium 39578909
2025 Wnt/β-catenin pathway transcriptionally upregulates AKAP6 expression in cardiomyocytes; increased AKAP6 enhances PKA-mediated RyR2 phosphorylation, causing sarcoplasmic reticulum Ca2+ leakage and cardiomyocyte dysfunction. Wnt pathway activation, transcriptome analysis, AKAP6 overexpression/knockdown, RyR2 phosphorylation assays, Ca2+ measurements Journal of molecular cell biology Medium 40097291

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways. Nature 450 16177794
2001 mAKAP assembles a protein kinase A/PDE4 phosphodiesterase cAMP signaling module. The EMBO journal 389 11296225
1999 mAKAP: an A-kinase anchoring protein targeted to the nuclear membrane of differentiated myocytes. Journal of cell science 154 10413680
2001 mAKAP and the ryanodine receptor are part of a multi-component signaling complex on the cardiomyocyte nuclear envelope. Journal of cell science 128 11590243
2005 The mAKAP complex participates in the induction of cardiac myocyte hypertrophy by adrenergic receptor signaling. Journal of cell science 109 16306226
2005 Nesprin-1alpha contributes to the targeting of mAKAP to the cardiac myocyte nuclear envelope. Experimental cell research 100 15652351
1995 Cloning and characterization of A-kinase anchor protein 100 (AKAP100). A protein that targets A-kinase to the sarcoplasmic reticulum. The Journal of biological chemistry 94 7721854
2004 PKA-phosphorylation of PDE4D3 facilitates recruitment of the mAKAP signalling complex. The Biochemical journal 90 15182229
1998 A-kinase anchoring protein 100 (AKAP100) is localized in multiple subcellular compartments in the adult rat heart. The Journal of cell biology 90 9679148
2010 cAMP-stimulated protein phosphatase 2A activity associated with muscle A kinase-anchoring protein (mAKAP) signaling complexes inhibits the phosphorylation and activity of the cAMP-specific phosphodiesterase PDE4D3. The Journal of biological chemistry 81 20106966
2003 Targeting of protein kinase A by muscle A kinase-anchoring protein (mAKAP) regulates phosphorylation and function of the skeletal muscle ryanodine receptor. The Journal of biological chemistry 57 12709444
2006 The mAKAP signaling complex: integration of cAMP, calcium, and MAP kinase signaling pathways. European journal of cell biology 56 16460834
2008 mAKAP compartmentalizes oxygen-dependent control of HIF-1alpha. Science signaling 54 19109240
2015 mAKAP-a master scaffold for cardiac remodeling. Journal of cardiovascular pharmacology 44 25551320
2020 AKAP6 orchestrates the nuclear envelope microtubule-organizing center by linking golgi and nucleus via AKAP9. eLife 43 33295871
2012 Regulation of MEF2 transcriptional activity by calcineurin/mAKAP complexes. Experimental cell research 35 23261540
2007 The mAKAP signalosome and cardiac myocyte hypertrophy. IUBMB life 30 17487687
2012 Myocyte enhancer factor 2 (MEF2) tethering to muscle selective A-kinase anchoring protein (mAKAP) is necessary for myogenic differentiation. Cellular signalling 23 22484155
2015 AKAP6 inhibition impairs myoblast differentiation and muscle regeneration: Positive loop between AKAP6 and myogenin. Scientific reports 20 26563778
2021 Myogenin controls via AKAP6 non-centrosomal microtubule-organizing center formation at the nuclear envelope. eLife 17 34605406
2013 Protein kinase A and phosphodiesterase-4D3 binding to coding polymorphisms of cardiac muscle anchoring protein (mAKAP). Journal of molecular biology 15 23806656
2019 AKAP6 and phospholamban colocalize and interact in HEK-293T cells and primary murine cardiomyocytes. Physiological reports 8 31325238
2025 Wnt/β-catenin pathway induces cardiac dysfunction via AKAP6-mediated RyR2 phosphorylation and sarcoplasmic reticulum calcium leakage. Journal of molecular cell biology 3 40097291
2024 AKAP6 controls NFATc4 activity for BDNF-mediated neuroprotection. Molecular brain 1 39578909

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