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AKAP11

A-kinase anchor protein 11 · UniProt Q9UKA4

Length
1901 aa
Mass
210.5 kDa
Annotated
2026-06-09
24 papers in source corpus 15 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AKAP11 (AKAP220) is a multivalent A-kinase anchoring protein that assembles a signaling complex containing PKA, the type 1 protein phosphatase catalytic subunit (PP1c), and GSK-3β, coordinating kinase and phosphatase activities on a single scaffold (PMID:10209101, PMID:12147701). It binds PP1c with high affinity through a consensus KVQF targeting motif while a distinct C-terminal region competitively inhibits PP1 catalytic activity, and assembly with the PKA RII subunit synergistically enhances this inhibition (PMID:11152471). Within this quaternary complex, PKA activation selectively suppresses the AKAP11-bound pool of GSK-3β, allowing the scaffold to exert compartmentalized control over substrate phosphorylation (PMID:12147701). Beyond scaffolding, AKAP11 functions as a selective autophagy receptor: through an LC3-interacting (LIR) region it recruits the PKA regulatory subunit RIα to autophagosomes for degradation, releasing active PKA catalytic subunit to drive CREB signaling, mitochondrial respiration, and cell survival under glucose starvation (PMID:33785595). The Cα–RIα–AKAP11 holocomplex is delivered to lysosomes via the LIR motif, with an AKAP11-dependent phosphorylation site (RIα Ser83) tuning RIα–Cα binding and cAMP-induced PKA output, and AKAP11 engages SPHKAP and ER-resident VAPA/B to couple this degradative route to PKA-RI proteostasis (PMID:40263600, PMID:39211170, PMID:41315293, PMID:39803523, PMID:40162211). Loss of AKAP11 elevates PKA subunit levels and substrate phosphorylation, raises basal PKA activity in brain, and disrupts compartment-specific PKA and GSK3α/β activities, impairing synaptic transmission and reducing dendritic spine and synapse density (PMID:41315293, PMID:39803523, PMID:40162211, PMID:41315276, PMID:40408419). In the kidney, AKAP11 controls RhoA-dependent apical actin networks and AQP2 trafficking to maintain water homeostasis, with its knockout reducing active RhoA, causing apical AQP2 accumulation, and preventing appropriate urine dilution (PMID:19008911, PMID:27402760).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1999 High

    Established that AKAP11 is not merely a PKA anchor but a multivalent scaffold capable of simultaneously binding a phosphatase, raising the question of how it integrates opposing enzymatic activities.

    Evidence In vitro KD measurement, microcystin-Sepharose affinity chromatography, and reciprocal co-IP with immunocytochemistry in rat hippocampal neurons

    PMID:10209101

    Open questions at the time
    • Did not define how PP1 binding affects phosphatase activity
    • Physiological substrates of the scaffolded enzymes not identified
  2. 2001 High

    Resolved how AKAP11 engages PP1 by separating binding from inhibition, showing it both targets and competitively inhibits PP1 with synergistic enhancement upon PKA subunit recruitment.

    Evidence In vitro PP1 phosphatase assays with truncation/deletion mapping and chimeric PP1/PP2A catalytic subunit analysis

    PMID:11152471

    Open questions at the time
    • Structural basis of the inhibitory region undefined
    • Cellular consequences of PP1 inhibition not tested
  3. 2002 High

    Extended the scaffold to a quaternary PKA–PP1–GSK-3β complex and showed that anchoring enables preferential, compartmentalized PKA-dependent inhibition of GSK-3β.

    Evidence Yeast two-hybrid, endogenous co-IP from COS cells, and GSK-3β kinase activity assays after PKA activation

    PMID:12147701

    Open questions at the time
    • GSK-3β substrates regulated within the complex not identified
    • Spatial organization in intact cells not resolved
  4. 2011 Medium

    Connected AKAP11 scaffolding to cytoskeletal dynamics, showing localized GSK-3β suppression at cell leading edges controls microtubule behavior and migration.

    Evidence Co-IP with IQGAP1, siRNA silencing, live-cell microtubule imaging, and migration assays in metastatic cancer cells

    PMID:21890631

    Open questions at the time
    • Single-lab functional data
    • Direct vs indirect AKAP11–CLASP2 link not established
  5. 2014 Medium

    Placed AKAP11 at endothelial adherens junctions, where PKA anchoring maintains barrier integrity and Rac1 activity.

    Evidence Co-IP with VE-cadherin/β-catenin, siRNA depletion, transendothelial resistance, and in vivo microvessel conductivity with AKAP-disrupting peptide

    PMID:25188285

    Open questions at the time
    • Peptide disruption affects all AKAPs, not AKAP11 selectively
    • Direct VE-cadherin binding interface undefined
  6. 2008 Medium

    Identified AKAP11 as an AQP2-binding scaffold that promotes PKA phosphorylation of AQP2, linking it to collecting duct water handling.

    Evidence Yeast two-hybrid, immunofluorescence and immunoelectron microscopy in inner medullary collecting ducts, and co-expression phosphorylation assay

    PMID:19008911

    Open questions at the time
    • In vivo physiological role not yet tested
    • Single lab, heterologous phosphorylation readout
  7. 2016 High

    Established the in vivo renal function of AKAP11, showing it controls RhoA-dependent apical actin and AQP2 trafficking required for urine dilution.

    Evidence CRISPR/Cas9 knockout mice and organoids, RhoA GTPase pull-downs, fluorescence imaging, and in vivo urine concentration assays

    PMID:27402760

    Open questions at the time
    • Mechanism linking PKA/PP1 scaffolding to RhoA regulation not detailed
    • Connection to earlier AQP2-binding data not directly bridged
  8. 2021 High

    Reframed AKAP11 as a selective autophagy receptor, showing its LIR motif targets PKA-RIα for autophagic degradation to activate PKA and support metabolism under starvation.

    Evidence Co-IP of AKAP11–LC3, autophagy flux and PKA activity assays, KO under glucose deprivation, and Seahorse respirometry

    PMID:33785595

    Open questions at the time
    • Signal triggering AKAP11-mediated RIα capture not defined
    • Tissue-specific relevance beyond cultured cells not addressed here
  9. 2024 High

    Defined the autophagy-associated Cα–RIα–AKAP11 holocomplex on lysosomes and identified RIα Ser83 as an AKAP11-dependent regulatory phosphosite tuning PKA activation.

    Evidence LysoIP proteomics, LIR motif mutagenesis, phosphoproteomic mapping of Ser83, and AKAP11 ablation in iPSC-derived neurons

    PMID:39211170 PMID:40263600

    Open questions at the time
    • Kinase responsible for Ser83 phosphorylation not identified
    • Quantitative contribution of Ser83 to overall PKA output unresolved
  10. 2025 High

    Mapped AKAP11 partners (SPHKAP, VAPA/B) and demonstrated that AKAP11 loss disrupts compartment-specific PKA and GSK3α/β activity, elevates PKA proteostasis, and impairs neurotransmission, linking the autophagy-PKA axis to synaptic and astrocytic dysfunction.

    Evidence Multi-omics, reciprocal co-IP (SPHKAP, VAPA/B), real-time PKA activity measurements, electrophysiology, electron microscopy, and behavioral assays across mouse and human induced-neuron models

    PMID:39803523 PMID:40162211 PMID:40408419 PMID:41315276 PMID:41315293

    Open questions at the time
    • Causal chain from PKA dysregulation to specific behavioral phenotypes incomplete
    • Astrocytic lipid-metabolism arm rests on preprint evidence

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct AKAP11 functions — PP1 inhibition, GSK-3β suppression, autophagy-receptor RIα degradation, and RhoA/actin control — are coordinated within a single protein across cell types remains unresolved.
  • No structural model integrating the multiple binding/inhibitory domains
  • Mechanism coupling scaffolding to RhoA regulation in kidney undefined
  • Whether autophagy-receptor and scaffold functions operate simultaneously or context-dependently is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0008092 cytoskeletal protein binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 2 GO:0005764 lysosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-9612973 Autophagy 2 R-HSA-382551 Transport of small molecules 1
Partners
AQP2GSK-3ΒIQGAP1MAP1LC3PP1CSPHKAPVAPBVE-CADHERIN
Complex memberships
Cα–RIα–AKAP11 autophagy-associated PKA holocomplexPKA–PP1–GSK-3β quaternary scaffold complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 AKAP220 (AKAP11) binds the type 1 protein phosphatase catalytic subunit (PP1c) with a KD of ~12 nM in vitro, and immunoprecipitation of PP1 from cell extracts co-enriches PKA activity, establishing AKAP220 as a multivalent anchoring protein that simultaneously scaffolds both PKA and PP1 in a signaling complex. In vitro binding assay (KD measurement), affinity chromatography on microcystin-Sepharose, co-immunoprecipitation from cell extracts, immunocytochemistry in rat hippocampal neurons Current Biology High 10209101
2001 AKAP220 (AKAP11) acts as a competitive inhibitor of PP1c activity (Ki = 2.9 µM); a consensus targeting motif (residues 1195–1198, KVQF) mediates PP1 binding without inhibiting it, while a distinct region (residues 1711–1901) is required for inhibition. Addition of PKA regulatory subunit (RII) to the complex further enhances PP1 inhibition, indicating synergistic intra- and inter-molecular regulation. In vitro PP1 phosphatase activity assay with AKAP220 fragments, deletion/truncation mapping, chimeric PP1/PP2A catalytic subunit analysis Journal of Biological Chemistry High 11152471
2002 AKAP220 (AKAP11) binds GSK-3β via yeast two-hybrid and forms a quaternary complex with GSK-3β, PKA, and PP1 in intact cells. PKA activation (via dibutyryl-cAMP) reduces GSK-3β activity within the AKAP220-bound pool more markedly than total cellular GSK-3β activity, demonstrating that the scaffold enables efficient PKA-dependent inhibition of GSK-3β. Yeast two-hybrid screen, co-immunoprecipitation from COS cells at endogenous level, GSK-3β kinase activity assay after PKA activation, calyculin A (phosphatase inhibitor) treatment Journal of Biological Chemistry High 12147701
2008 AKAP220 (AKAP11) binds AQP2 (aquaporin-2) identified by yeast two-hybrid, co-localizes with AQP2 in the cytosol of inner medullary collecting ducts by immunofluorescence and immunoelectron microscopy, and its co-expression in COS cells increases forskolin-stimulated PKA phosphorylation of AQP2 at Ser256. Yeast two-hybrid, double immunofluorescence, immunoelectron microscopy, co-expression phosphorylation assay in COS cells Kidney International Medium 19008911
2011 AKAP220 (AKAP11) interacts with the cytoskeletal scaffolding protein IQGAP1, and this complex positions signaling enzymes (including GSK-3β suppression) at leading edges of migrating cells. AKAP220 suppresses GSK-3β activity locally to allow CLASP2 (a plus-end microtubule tracking protein) recruitment. Gene silencing of AKAP220 alters microtubule polymerization rate, lateral microtubule tracking, and retards cell migration in metastatic human cancer cells. Co-immunoprecipitation (AKAP220–IQGAP1 interaction), gene silencing (siRNA), live-cell imaging of microtubule dynamics, cell migration assays Journal of Biological Chemistry Medium 21890631
2014 AKAP220 (AKAP11) localizes to endothelial junctions and immunoprecipitation shows it interacts not only with PKA but also with VE-cadherin and β-catenin. Depletion of AKAP220 impairs endothelial barrier function, and displacement of PKA from AKAPs with a competing peptide (TAT-Ahx-AKAPis) disrupts adherens junctions, actin cytoskeleton, and causes Rac1 inactivation. Co-immunoprecipitation (AKAP220 with VE-cadherin/β-catenin), siRNA depletion, transendothelial electrical resistance measurement, immunofluorescence, in vivo microvessel hydraulic conductivity PLOS ONE Medium 25188285
2016 AKAP220 (AKAP11, product of the Akap11 gene) controls apical actin networks in kidney collecting duct principal cells. CRISPR/Cas9 knockout of AKAP220 disrupts apical actin networks in organoid cultures and in vivo, reduces active RhoA GTPase levels, causes AQP2 and RhoA accumulation at the apical surface, and prevents appropriate urine dilution in response to overhydration. CRISPR/Cas9 gene editing (knockout mice and organoids), fluorescence imaging of kidney sections, biochemical measurement of active RhoA (GTPase pull-down), urine concentration assays in vivo PNAS High 27402760
2021 AKAP11 acts as an autophagy receptor that recruits the PKA regulatory subunit RI to autophagosomes via a LC3-interacting region (LIR motif). Glucose starvation induces AKAP11-dependent selective autophagic degradation of RI, leading to PKA catalytic subunit activation, enhanced CREB signaling, mitochondrial respiration, ATP production, and mitochondrial elongation. AKAP11 deficiency blocks PKA activation and impairs cell survival under glucose deprivation. Co-immunoprecipitation (AKAP11–LC3 interaction), autophagy flux assays, PKA activity measurements, AKAP11 knockdown/knockout, mitochondrial respiration (Seahorse), cell viability assays under glucose starvation PNAS High 33785595
2024 The Cα-RIα-AKAP11 holocomplex is identified as a prominent autophagy-associated protein kinase complex by proteomic analysis of immunopurified lysosomes. AKAP11 scaffolds Cα-RIα to the autophagic machinery via its LIR motif. Ser83 on the RIα linker-hinge region is an AKAP11-dependent phosphorylation site that modulates RIα-Cα binding to the autophagosome and cAMP-induced PKA activation. Decoupling AKAP11-PKA from autophagy alters Ser83 phosphorylation and downstream PKA signaling in iPSC-derived neurons. Lysosome immunopurification with proteomics (LysoIP-MS), LIR motif mutagenesis, phosphoproteomics (Ser83 identification), AKAP11 ablation in iPSC-derived neurons The EMBO Journal (published 2025) / bioRxiv preprint 2024 High 39211170 40263600
2025 AKAP11 interacts with the PKA-RI adaptor SPHKAP and the ER-resident autophagy-related proteins VAPA/B through interactions identified by multi-omics; these proteins co-adapt to mediate PKA-RI complex degradation in neurons. Loss of AKAP11 distorts compartment-specific PKA and GSK3α/β activities and impairs neurotransmission in mouse models and human induced neurons. Multi-omics (proteomics, phosphoproteomics), co-immunoprecipitation (AKAP11–SPHKAP, AKAP11–VAPA/B), electrophysiology in mouse models and human induced neurons, AKAP11 knockout Nature Communications High 39803523 40162211 41315293
2025 Loss of AKAP11 in mouse brain leads to dramatically increased levels of PKA subunits (RI and catalytic) and phosphorylated PKA substrates, especially in synapses, establishing AKAP11 as a key regulator of PKA proteostasis. Real-time PKA activity measurements reveal elevated basal PKA activity in the striatum of Akap11−/− mice with exaggerated responses to dopamine receptor antagonists. Multi-omic analysis of Akap11 mutant mouse brains, real-time PKA activity measurements (FRET biosensors or equivalent), quantitative proteomics/phosphoproteomics of synaptic fractions, behavioral assays Nature Communications High 41315276
2025 Immunoprecipitation mass spectrometry in Akap11-deficient mice identified 222 high-confidence AKAP11 interaction proteins, including synaptic proteins (Exoc4, Ncam1, Picalm, Vapb) and actin-related proteins (Actb, Diaph1). Akap11 deficiency reduces dendritic spine density (particularly thin spines), decreases synapse density and synaptic vesicle density, and reduces PSD length as assessed by electron microscopy. Immunoprecipitation mass spectrometry (IP-MS), neuronal sparse labeling assays, electron microscopy, behavioral evaluation (prepulse inhibition) Schizophrenia Bulletin Medium 40408419
2025 In Akap11 mutant astrocytes, loss of AKAP11 leads to upregulation of cholesterol and fatty acid metabolic pathways, accumulation of lipid droplets, and elevated cAMP/PKA signaling. AKAP11 interacts with ER-resident VAPA and VAPB via an FFAT motif, linking its autophagy receptor function to lipid metabolism regulation. Co-culture experiments show that Akap11-deficient astrocytes increase excitatory neurotransmission and neuronal activity. Multi-omic analysis (transcriptomics, proteomics, metabolomics) of Akap11 mutant mouse astrocytes, lipid droplet staining, FFAT motif identification, co-culture electrophysiology with iPSC-derived neurons bioRxiv (preprint)preprint Medium

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia. Nature genetics 149 35410376
2002 A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3beta (GSK-3beta ) and mediates protein kinase A-dependent inhibition of GSK-3beta. The Journal of biological chemistry 111 12147701
1999 Association of the type 1 protein phosphatase PP1 with the A-kinase anchoring protein AKAP220. Current biology : CB 102 10209101
2023 Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients. Translational psychiatry 50 36914641
2001 Multiple interactions within the AKAP220 signaling complex contribute to protein phosphatase 1 regulation. The Journal of biological chemistry 50 11152471
2016 AKAP220 manages apical actin networks that coordinate aquaporin-2 location and renal water reabsorption. Proceedings of the National Academy of Sciences of the United States of America 48 27402760
2021 Selective autophagy of AKAP11 activates cAMP/PKA to fuel mitochondrial metabolism and tumor cell growth. Proceedings of the National Academy of Sciences of the United States of America 44 33785595
2008 AKAP220 colocalizes with AQP2 in the inner medullary collecting ducts. Kidney international 43 19008911
2014 PKA compartmentalization via AKAP220 and AKAP12 contributes to endothelial barrier regulation. PloS one 42 25188285
2011 AKAP220 protein organizes signaling elements that impact cell migration. The Journal of biological chemistry 39 21890631
2020 Gene-gene and gene-lifestyle interactions of AKAP11, KCNMA1, PUM1, SPTBN1, and EPDR1 on osteoporosis risk in middle-aged adults. Nutrition (Burbank, Los Angeles County, Calif.) 19 32619791
2005 Alteration of AKAP220, an upstream component of the Rb pathway, in oral carcinogenesis. International journal of cancer 14 15849745
2025 Autophagosomes anchor an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling. The EMBO journal 8 40263600
2025 Rare loss-of-function variants in HECTD2 and AKAP11 confer risk of bipolar disorder. Nature genetics 7 40133559
2025 Bipolar and schizophrenia risk gene AKAP11 encodes an autophagy receptor coupling the regulation of PKA kinase network homeostasis to synaptic transmission. Nature communications 5 41315293
2018 AKAP11 gene polymorphism is associated with bone mass measured by quantitative ultrasound in young adults. International journal of medical sciences 5 30013441
2025 Bipolar and schizophrenia risk gene AKAP11 encodes an autophagy receptor coupling the regulation of PKA kinase network homeostasis to synaptic transmission. bioRxiv : the preprint server for biology 4 39803523
2025 Transcriptomic and epigenomic consequences of heterozygous loss-of-function mutations in AKAP11, a shared risk gene for bipolar disorder and schizophrenia. Molecular psychiatry 3 40316678
2025 Elevated synaptic PKA activity and abnormal striatal dopamine signaling in Akap11 mutant mice, a genetic model of schizophrenia and bipolar disorder. bioRxiv : the preprint server for biology 3 41332738
2026 Schizophrenia-Related Synaptic Dysfunction and Abnormal Sensorimotor Gating in Akap11-Deficient Mice. Schizophrenia bulletin 2 40408419
2025 Elevated synaptic PKA activity and abnormal striatal dopamine signaling in Akap11 mutant mice, a genetic model of schizophrenia and bipolar disorder. Nature communications 2 41315276
2024 Autophagosomes coordinate an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling. bioRxiv : the preprint server for biology 1 39211170
2025 Bipolar and schizophrenia risk gene AKAP11 encodes an autophagy receptor coupling the regulation of PKA kinase network homeostasis to synaptic transmission. Research square 0 40162211
2025 Associations of Rare Variants in the AKAP11 Gene with Bipolar Disorder in Chinese Population. Neuropsychiatric disease and treatment 0 40904767

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