Affinage

AKAP1

A-kinase anchor protein 1, mitochondrial · UniProt Q92667

Length
903 aa
Mass
97.3 kDa
Annotated
2026-06-09
62 papers in source corpus 42 papers cited in narrative 42 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

AKAP1 is an A-kinase anchoring protein that organizes a PKA-centered signaling complex on the outer mitochondrial membrane (and, in an alternatively spliced N1 variant, the endoplasmic reticulum) to govern mitochondrial dynamics, bioenergetics, and metabolism (PMID:7499250, PMID:10352013, PMID:11994283). Its N-terminal targeting helix is necessary and sufficient for mitochondrial anchoring through a hydrophobic membrane-interacting surface, while an additional N1 segment redirects the protein to the ER (PMID:10352013, PMID:11994283, PMID:15499565). AKAP1 anchors type II PKA regulatory subunits and assembles a multivalent platform that additionally recruits the tyrosine phosphatase PTPD1 with associated Src, supporting mitochondrial cytochrome c oxidase activity, membrane potential, and ATP synthesis (PMID:7499250, PMID:15143158, PMID:16251349). Its principal mechanistic output is to sustain PKA-mediated inhibitory phosphorylation of the fission GTPase Drp1 (Ser637/Ser656), which blocks GTP hydrolysis-driven Drp1 disassembly and thereby suppresses mitochondrial fission and promotes elongation, with PP2A and calcineurin acting as the opposing dephosphorylating activities (PMID:21526220, PMID:22049414, PMID:32312949). Through this axis AKAP1 is broadly protective: genetic deletion in mice increases injury in cardiac infarction, pressure overload, cerebral ischemia, and glaucoma, with reduced Drp1 phosphorylation, ETC/complex dysfunction, elevated ROS, and increased mitophagy and apoptosis (PMID:27136357, PMID:30093535, PMID:29892230, PMID:32312949). Oxygen and redox status regulate the complex by controlling AKAP1 abundance: the E3 ligase Siah2 ubiquitinates and degrades AKAP1 under hypoxia, relieving both PKA-dependent and PKA-independent (Drp1–Fis1) inhibition of fission (PMID:18323779, PMID:22099302). Beyond fission control, AKAP1-anchored PKA directly phosphorylates and inactivates metabolic enzymes ACSL1 and GPAT1 to restrain fatty acid oxidation/thermogenesis and hepatic lipid synthesis (PMID:33747723, PMID:40341440), and phosphorylates GRP75 to stabilize Nrf2 and confer antiferroptotic protection (PMID:39537840). An N-terminal KH domain confers RNA binding that tethers nuclear-encoded mRNAs such as MnSOD and StAR to mitochondria for local translation; this site overlaps a PP1-binding RVXF motif, and in a distinct nuclear-envelope role AKAP1 recruits PP1 to direct B-type lamin assembly during post-mitotic nuclear reformation (PMID:10995432, PMID:12654270, PMID:12697839, PMID:19074462).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1995 High

    Established AKAP1 as a bona fide A-kinase anchoring protein that tethers type II PKA regulatory subunits to mitochondria, defining its founding molecular identity.

    Evidence cDNA cloning, RII-binding assay, and immunofluorescence in male germ cells

    PMID:7499250

    Open questions at the time
    • Did not identify downstream substrates of the anchored PKA
    • Functional consequence of mitochondrial PKA anchoring not addressed
  2. 1999 High

    Resolved how a single gene targets two organelles, showing splice-variant N-terminal motifs route AKAP1 to mitochondria (N0) versus ER (N1).

    Evidence Microinjected epitope-tagged constructs, GFP truncation/deletion analysis, immunocytochemistry

    PMID:10352013

    Open questions at the time
    • Physiological role of the ER-targeted variant not defined
    • Structural basis of membrane interaction not yet resolved
  3. 2002 High

    Defined the membrane-targeting determinant at residue resolution, identifying a bifunctional helical element required for both mitochondrial and ER targeting.

    Evidence Site-directed mutagenesis, GFP-fusion localization, subcellular fractionation in adipocytes; later NMR confirmed an α-helical conformation

    PMID:11994283 PMID:15499565

    Open questions at the time
    • Membrane receptor/insertion machinery not identified
    • No functional mutagenesis tied to NMR structure
  4. 2003 High

    Demonstrated AKAP1 is an RNA-binding scaffold, showing its KH domain binds specific 3′ UTRs and relocalizes MnSOD mRNA to mitochondria in a cAMP/PKA-stimulated manner.

    Evidence Purified KH-domain EMSA, phosphomimetic mutation, subcellular mRNA fractionation in HeLa cells

    PMID:12654270

    Open questions at the time
    • Did not establish local translation output quantitatively
    • Generality across the mitochondrial mRNA repertoire unresolved
  5. 2003 High

    Revealed a nuclear-envelope function distinct from mitochondria, where AKAP1 acts as a PP1-specifying subunit that maintains lamin dephosphorylation and is regulated by PKC phosphorylation at the G1/S transition.

    Evidence In vitro nuclear reassembly, immunodepletion/rescue, PP1 substrate-specificity activity assays, kinase assays on immunoprecipitated AKAP149

    PMID:10995432 PMID:12697839 PMID:16669629

    Open questions at the time
    • Relationship between nuclear and mitochondrial pools not reconciled
    • Whether the same splice variant performs both roles unclear
  6. 2005 High

    Linked the AKAP1 scaffold to bioenergetic output, showing it recruits PTPD1/Src and PKA to enhance respiratory chain activity and ATP synthesis.

    Evidence siRNA silencing, Src and cytochrome c oxidase activity assays, membrane potential and ATP measurements; PTPD1 complex defined by reciprocal co-IP

    PMID:15143158 PMID:16251349

    Open questions at the time
    • Direct Src substrates on mitochondria not enumerated
    • Quantitative contribution of each kinase to ATP output unresolved
  7. 2008 High

    Identified the regulatory input controlling AKAP1 abundance, establishing Siah2-mediated ubiquitination and degradation as the hypoxia/ischemia switch that lowers mitochondrial capacity.

    Evidence Co-IP, ubiquitination assay, OGD and in vivo cerebral ischemia, membrane potential measurements

    PMID:18323779

    Open questions at the time
    • Ubiquitin acceptor sites on AKAP1 not mapped
    • Did not yet connect degradation to fission machinery
  8. 2009 Medium

    Showed AKAP1 integrates a calcineurin–NFAT node, restraining the cardiac hypertrophic transcriptional program.

    Evidence Co-IP with calcineurin, siRNA knockdown, NFATc3 translocation and hypertrophy assays

    PMID:19358331

    Open questions at the time
    • Single co-IP for the calcineurin interaction without reciprocal validation
    • Direct versus indirect regulation of calcineurin not distinguished
  9. 2011 High

    Defined the central mechanism of AKAP1 function: anchored PKA phosphorylates Drp1 at a conserved serine to inhibit fission, with PP2A providing the opposing activity and the balance tuning neuronal mitochondrial morphology and survival.

    Evidence RNAi, OMM-targeted PKA, Drp1 phospho-site mutant epistasis, GTPase assays, neuronal survival and synapse/dendrite quantification

    PMID:21526220 PMID:22049414

    Open questions at the time
    • In vivo stoichiometry of Drp1 phosphorylation not quantified
    • How PKA versus PP2A access is spatially partitioned unclear
  10. 2011 High

    Unified the Siah2 input with fission control, showing AKAP1 inhibits Drp1 by both PKA-dependent phosphorylation and PKA-independent blockade of Drp1–Fis1, both relieved by hypoxic Siah2 degradation.

    Evidence Siah2 knockout mice, simulated ischemia/infarction, Drp1–Fis1 co-IP, phosphorylation assays

    PMID:22099302

    Open questions at the time
    • Molecular basis of the PKA-independent Drp1–Fis1 inhibition not defined
    • Relative contribution of the two mechanisms in vivo unresolved
  11. 2008 High

    Connected the KH RNA-binding site to phosphatase regulation and organelle integrity, showing PP1 and RNA bind the same RVXF motif competitively and that RNA-binding loss collapses the mitochondrial network.

    Evidence RVXF motif mutation, PP1/RNA competition binding assays, mitochondrial network imaging

    PMID:19074462

    Open questions at the time
    • Endogenous RNAs governing network integrity not identified
    • Switch logic between PP1 and RNA occupancy in cells not directly observed
  12. 2013 Medium

    Extended AKAP1's mitochondrial signaling roles, placing it as an anchor for the StAR mRNA, the NCX3 calcium exchanger, and PKA-dependent control of oocyte meiotic resumption.

    Evidence EMSA and RNA-IP for StAR; co-IP and Ca²⁺ efflux assays for NCX3; overexpression/knockdown in oocytes

    PMID:23077346 PMID:23426434 PMID:24101730

    Open questions at the time
    • PKA-stimulated StAR mRNA binding gave a negative result
    • Single-lab interactions without reciprocal/structural confirmation
  13. 2017 High

    Broadened AKAP1 from a fission regulator to a metabolic/growth signaling hub, linking it to Myc transcription, Sestrin2 recruitment and mTOR control, and ROS-driven degradation upstream of fission.

    Evidence ChIP, Sestrin2 co-IP and double-knockdown epistasis, mTOR assays; lipotoxic transgenic mouse with ubiquitination and phospho-Drp1 readouts

    PMID:28569781 PMID:29092894

    Open questions at the time
    • How Sestrin2 anchoring couples mechanistically to mTORC1 at mitochondria unclear
    • Sestrin2 finding is Medium-confidence single lab
  14. 2018 High

    Established AKAP1 as protective in vivo across ischemic and hypertrophic disease, with loss reducing Drp1 phosphorylation and Akt signaling and worsening ETC dysfunction, ROS, and apoptosis.

    Evidence Akap1 (and Siah2 double) knockout mice in stroke, infarction, pressure-overload, and neovascularization models; ETC assays, Ca²⁺ imaging, Akt rescue

    PMID:27136357 PMID:29335250 PMID:29892230 PMID:30093535

    Open questions at the time
    • Whether Akt sits directly downstream of the AKAP1 complex or in parallel not resolved
    • Tissue-specific versus systemic contributions of AKAP1 loss not separated
  15. 2020 High

    Identified AKAP1 as required for import of a respiratory complex I subunit, showing a direct NDUFS1 interaction that drives its mitochondrial translocation and complex I activity.

    Evidence Co-IP plus mass spectrometry, Akap1 KO and STZ-diabetic model, complex I assay, NDUFS1 fractionation, AAV9 rescue

    PMID:32072193

    Open questions at the time
    • Mechanism by which AKAP1 promotes NDUFS1 import not defined
    • Whether import depends on PKA activity unclear
  16. 2021 High

    Defined AKAP1-anchored PKA as a direct kinase on lipid-metabolic enzymes, phosphorylating and inactivating ACSL1 (and later GPAT1) to restrain fatty acid oxidation, thermogenesis, and hepatic triglyceride synthesis.

    Evidence Akap1 KO mice, PKA-dependent substrate phosphorylation and enzymatic activity assays, FAO/thermogenesis measurement, tissue-specific rescue; GPAT1 KD epistasis in MASLD models

    PMID:33747723 PMID:40341440

    Open questions at the time
    • Phosphosites on ACSL1/GPAT1 not fully mapped in all reports
    • Coordination between fission control and direct enzyme phosphorylation unclear
  17. 2024 High

    Revealed a redox-protective output via direct GRP75 phosphorylation that stabilizes Nrf2 by competing for Keap1, coupling the AKAP1/PKA axis to ferroptosis resistance.

    Evidence Subcellular fractionation, AKAP1–PKA co-IP, GRP75-S148 mutagenesis, Nrf2–Keap1 competition co-IP, antiferroptotic reporters, xenograft

    PMID:39537840

    Open questions at the time
    • How phospho-GRP75 exits mitochondria/MAMs to the cytosol not detailed
    • Generality across cancer types not established
  18. 2025 Medium

    Refined regulation of the anchoring step itself, showing TRIB3 disrupts the AKAP1–PKARIIα interaction to relieve Drp1 inhibition and drive pathological fission.

    Evidence Co-IP of complex disruption with/without TRIB3, Drp1 phosphorylation assay, in vivo intervertebral disc degeneration model

    PMID:40848982

    Open questions at the time
    • Single-lab co-IP for the disruption mechanism
    • Whether TRIB3 acts on AKAP1 or PKARIIα directly not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AKAP1 spatially and temporally coordinates its many outputs—Drp1 fission control, direct metabolic-enzyme phosphorylation, RNA tethering, NDUFS1 import, and MAM-localized signaling—within a single scaffold remains unresolved.
  • No integrated structural model of the assembled complex
  • Substrate selection rules for the anchored kinases not defined
  • Stoichiometry and dynamics of RNA versus PP1 versus partner occupancy in cells unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0003723 RNA binding 3 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005739 mitochondrion 3 GO:0005635 nuclear envelope 2 GO:0005783 endoplasmic reticulum 2 GO:0005811 lipid droplet 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1430728 Metabolism 2 R-HSA-1640170 Cell Cycle 2
Partners
DNM1LNDUFS1PPP1CAPRKAR2APRKAR2BPTPD1SESN2SIAH2
Complex memberships
AKAP1–PKA(RII) anchoring complexAKAP1–PTPD1–Src–PKA mitochondrial complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 S-AKAP84 (AKAP1) is expressed in male germ cells and contains a central RII-binding domain that anchors type II PKA regulatory subunits (RIIα and RIIβ) to the outer mitochondrial membrane; immunofluorescence showed co-localization with mitochondria in the flagellar midpiece of spermatids. cDNA cloning, RII-binding assay, immunofluorescence co-localization with mitochondria The Journal of biological chemistry High 7499250
1996 AKAP149 (AKAP1 splice variant) is a membrane-anchored protein containing a K homology (KH) RNA-binding domain in addition to the PKA-anchoring domain, suggesting involvement in phosphorylation-dependent RNA processing. cDNA characterization, sequence analysis identifying KH domain Biochemical and biophysical research communications Low 8769136
1999 D-AKAP1 (AKAP1) contains two N-terminal splice variants that differentially target the protein to distinct organelles: the N0 motif (residues 1–30) is necessary and sufficient for mitochondrial targeting, while the N1 variant (with an additional 33 residues) redirects D-AKAP1 to the endoplasmic reticulum. Microinjection of epitope-tagged expression constructs, immunocytochemistry, GFP fusion truncation/deletion analysis The Journal of cell biology High 10352013
2000 AKAP149 (AKAP1) recruits protein phosphatase 1 (PP1) to the nuclear envelope via its PP1-binding domain (KGVLF motif), and this recruitment is a prerequisite for B-type lamin assembly during nuclear reformation after mitosis. In vitro nuclear reassembly assay, immunodepletion of AKAP149 from nuclear membranes, peptide competition, co-immunoprecipitation from nuclear envelope extracts, affinity isolation The Journal of cell biology High 10995432
2001 AMY-1 (associate of Myc-1) binds to S-AKAP84 (AKAP1) and forms a ternary complex with the RII regulatory subunit of PKA in mitochondria of sperm; S-AKAP84 localizes AMY-1 to mitochondria. Yeast two-hybrid screening, in vitro and in vivo binding assays, immunofluorescence co-localization The Journal of biological chemistry Medium 11483602
2002 D-AKAP1 is enriched in the mitochondrial fraction of adipocytes and is upregulated upon differentiation; a 15-residue bifunctional helical segment (homologous to hexokinase I N-terminal motif) within the N0 splice variant is required for mitochondrial targeting, and this same element (with additional hydrophobic residues) also mediates ER targeting in the N1 variant. Extensive site-directed mutagenesis of targeting motif, GFP-fusion localization assays, subcellular fractionation The Journal of biological chemistry High 11994283
2002 AMY-1 binds competitively to the RII-binding region of AKAP84/AKAP95, forming a ternary complex with RII that prevents the catalytic subunit of PKA from associating with the AKAP complex, thereby suppressing PKA activity. Co-immunoprecipitation, in vitro binding assays, PKA activity assays The Journal of biological chemistry Medium 12414807
2003 The KH domain of AKAP121 (AKAP1) directly binds the 3′ UTRs of transcripts encoding the Fo-f subunit of mitochondrial ATP synthase and MnSOD; binding requires a structural motif in the 3′ UTR and is stimulated by PKA phosphorylation of the KH domain. AKAP121 expression promotes translocation of MnSOD mRNA from cytosol to mitochondria and increases mitochondrial MnSOD protein, both effects stimulated by cAMP. Purified KH domain RNA-binding assay (EMSAs), phosphomimetic mutation, subcellular mRNA fractionation in HeLa cells, immunoblotting Journal of molecular biology High 12654270
2003 AKAP149/AKAP1 acts as a PP1-specifying subunit during G1: it keeps PP1 associated and active toward B-type lamins (while inhibiting PP1 activity toward glycogen phosphorylase), thereby maintaining nuclear architecture; PKC-mediated phosphorylation of AKAP149 at the G1/S transition releases PP1, leading to lamin phosphorylation and depolymerization. Cell-cycle synchronization, PP1 activity assays with substrate specificity, in vivo PP1 dissociation assay, PKA/PKC overlay binding and kinase activity assays on immunoprecipitated AKAP149 Journal of cell science High 12697839
2004 AKAP121/AKAP84 (AKAP1) directly binds PTPD1, a src-associated protein tyrosine phosphatase, assembling an in vivo signaling complex containing AKAP121, PKA, PTPD1, and src on mitochondria; AKAP121 binding redistributes PTPD1 from cytoplasm to mitochondria and attenuates PTPD1-enhanced EGF/ERK signaling. Co-immunoprecipitation (in vivo complex), domain mapping, immunofluorescence co-localization, functional EGF signaling assays (ERK1/2, Elk1) Molecular and cellular biology High 15143158
2004 The mitochondrial targeting peptide of AKAP121 (residues 10–30) adopts an α-helical conformation in solution; a hydrophobic surface on this helix (Trp16–Phe20 region) mediates mitochondrial membrane interaction. NMR spectroscopy and CD spectroscopy of synthetic peptide in water/TFE Biopolymers Medium 15499565
2005 AKAP121 (AKAP1) targets src tyrosine kinase to mitochondria via PTPD1 and enhances src-dependent phosphorylation of mitochondrial substrates; AKAP121 increases cytochrome c oxidase activity, mitochondrial membrane potential, and ATP synthesis in a src- and PKA-dependent manner; siRNA silencing of AKAP121 drastically impairs mitochondrial ATP synthesis. siRNA silencing, src kinase activity assays, cytochrome c oxidase activity assay, mitochondrial membrane potential measurement, ATP synthesis measurement Molecular biology of the cell High 16251349
2006 Phosphorylation of serines flanking the RVXF PP1-binding motif of AKAP149 (specifically S151 or S159) abolishes PP1 binding; PKC (not PKA) associated with AKAP149 phosphorylates these residues, promoting PP1 release from AKAP149 at the G1/S transition. Peptide binding assays with S→A and S→D mutants, in vitro kinase assays using immunoprecipitated AKAP149-associated PKA and PKC, PP1 co-immunoprecipitation Biochemistry High 16669629
2006 D-AKAP1 (AKAP1) is enriched in the lipid droplet fraction of primary adipocytes and was identified as the major PKA regulatory subunit (RII) and PP1 catalytic subunit binding protein in adipocytes. RII overlay assay, subcellular fractionation including lipid droplet fraction, immunoblotting, PP1 binding assay Biochemical and biophysical research communications Medium 16756943
2008 AKAP121 (AKAP1) is ubiquitinated and degraded by the E3 ubiquitin ligase Siah2 under hypoxic conditions; Siah2 forms a complex with AKAP121, and Siah2-mediated proteolysis of AKAP121 reduces mitochondrial membrane potential and oxidative capacity; during cerebral ischemia, AKAP121 is degraded in a Siah2-dependent manner. Co-immunoprecipitation, ubiquitination assay, overexpression of Siah2 or OGD treatment, mitochondrial membrane potential measurement, in vivo ischemia model with AKAP121 level assessment The EMBO journal High 18323779
2008 PP1 binding to AKAP149 (AKAP1) occurs through a conserved RVXF motif located within the KH domain; PP1 and RNA binding to this same site is mutually exclusive and controlled by a phosphorylation-dependent mechanism; RNA-binding-deficient mutants of AKAP149 cause collapse of the mitochondrial network. RVXF motif mutation, PP1 binding assay, RNA competition assay, mitochondrial network imaging with mutant constructs Human molecular genetics High 19074462
2009 AKAP121 (AKAP1) co-immunoprecipitates with calcineurin; knockdown of AKAP121 leads to dephosphorylation and nuclear translocation of NFATc3, activating the hypertrophic gene program, while AKAP121 overexpression blocks isoproterenol-induced hypertrophy. Co-immunoprecipitation (AKAP121–calcineurin interaction), siRNA knockdown, NFATc3 nuclear translocation assay, cell size measurement, overexpression hypertrophy assay Journal of molecular and cellular cardiology Medium 19358331
2010 Displacement of AKAP121 (AKAP1) from mitochondria by competitive synthetic peptides causes mitochondrial dysfunction, increased mitochondrial ROS, and cardiomyocyte apoptosis; in a rat cardiac hypertrophy model, AKAP121 is significantly downregulated and this correlates with mitochondrial dysfunction. Competitive peptide displacement, mitochondrial membrane potential assay, ROS measurement, apoptosis assay, in vivo pressure-overload model with immunoblotting Cardiovascular research Medium 20511238
2011 PKA anchored by AKAP1 at the outer mitochondrial membrane phosphorylates Drp1 at a conserved serine (Ser656 in rat), inhibiting mitochondrial fission; AKAP1 RNAi promotes fission and neuronal death, while AKAP1 overexpression promotes mitochondrial elongation and neuroprotection. Epistasis experiments with phosphorylation-site Drp1 mutants confirm that Drp1 phosphorylation at this PKA site is the principal mechanism. Drp1 phosphorylation inhibits GTP hydrolysis-driven disassembly, accumulating large Drp1 oligomers at the OMM. RNAi, overexpression, PKA catalytic subunit OMM-targeting, phosphorylation-site Drp1 mutant epistasis, GTPase assay, in vivo neuronal survival assay (axotomy model) PLoS biology High 21526220
2011 PKA/AKAP1 and PP2A/Bβ2 oppositely regulate Drp1 phosphorylation at Ser656 at the outer mitochondrial membrane in hippocampal neurons; PKA/AKAP1-mediated phosphorylation increases mitochondrial length and dendrite occupancy, enhancing dendritic outgrowth but decreasing synapse density, whereas PP2A/Bβ2-mediated dephosphorylation fragments mitochondria and augments synapse formation. Overexpression and RNAi in cultured rat hippocampal neurons, mitochondrial morphology and dendrite/synapse quantification, calcium manipulation The Journal of neuroscience High 22049414
2011 AKAP121 controls mitochondrial dynamics through two distinct mechanisms: (1) PKA-dependent inhibitory phosphorylation of Drp1 and (2) PKA-independent inhibition of the Drp1–Fis1 interaction. Siah2 ubiquitin ligase degrades AKAP121 under hypoxia, relieving both mechanisms of Drp1 inhibition and promoting mitochondrial fission. High AKAP121 in Siah2-null cells attenuates fission and reduces cardiomyocyte apoptosis under simulated ischemia. Siah2 knockout mice, simulated ischemia, myocardial infarction model, co-immunoprecipitation of Drp1–Fis1, PKA phosphorylation assays, AKAP121 overexpression/siRNA Molecular cell High 22099302
2012 The KH domain of AKAP1 binds the 3′ UTR of StAR mRNA in vitro; a phosphomimetic mutation of the KH domain did not enhance (or negatively affected) StAR mRNA binding under in vitro EMSA conditions. AKAP1 interacts with StAR mRNA in dibutyryl-cAMP-stimulated steroidogenic cells in vivo, and the C-terminal region of AKAP1 may interact with Argonaute 2 to mediate mRNA degradation. EMSA (electrophoretic mobility shift assay), in vitro selection of RNA aptamers, RNA immunoprecipitation from cell extracts Molecular endocrinology Medium 23077346
2013 NCX3 (sodium/calcium exchanger isoform 3) localizes to the outer mitochondrial membrane of neurons, co-localizes and co-immunoprecipitates with AKAP121 (AKAP1), and extrudes Ca²⁺ from mitochondria in a PKA-mediated manner through an AKAP121-anchored signaling complex under normoxia and hypoxia. Immunofluorescence co-localization, co-immunoprecipitation, Ca²⁺ efflux assay, PKA inhibitor treatment, cell survival assay Journal of cell science Medium 24101730
2013 AKAP1 regulates PKA subcellular localization in porcine oocytes; overexpression of AKAP1 alters PKA distribution and promotes meiotic resumption even in the presence of high cAMP concentrations that normally maintain meiotic arrest, while AKAP1 knockdown inhibits meiotic resumption and oocyte maturation. Far-Western blot (AKAP detection with RII subunit), AKAP1 overexpression, siRNA knockdown, meiotic maturation assay, PKA localization by immunofluorescence Biology of reproduction Medium 23426434
2016 Akap1 knockout mice subjected to myocardial infarction display larger infarct size, increased mitochondrial structural abnormalities, increased ROS, reduced mitochondrial function, and enhanced mitophagy and apoptosis compared to wild-type mice; autophagy inhibition by 3-methyladenine reduces apoptosis and improves cardiac function in Akap1-KO infarcted mice. Akap1 knockout mice, permanent coronary ligation, electron microscopy, ROS measurement, mitochondrial function assay, autophagy inhibition experiment, cardiac function echocardiography PloS one High 27136357
2017 In lipotoxic hearts, mitochondrial ROS increases ubiquitination of AKAP121 (AKAP1), leading to its degradation, which reduces PKA-mediated inhibitory phosphorylation of Drp1 at Ser637 and alters OPA1 proteolytic processing, collectively promoting mitochondrial fission; scavenging mitochondrial ROS restores mitochondrial morphology. Transgenic mouse model (ACSL1 overexpression), palmitate-treated neonatal cardiomyocytes, ubiquitination assay, phospho-Drp1 immunoblotting, OPA1 processing assay, mitochondrial ROS scavenger treatment, mitochondrial morphology quantification Circulation research High 29092894
2017 AKAP1 is a transcriptional target of Myc and assembles Sestrin2 (a leucine sensor and mTOR inhibitor) into its mitochondrial complex; AKAP1 knockdown impairs mTOR pathway activity and inhibits glioblastoma cell growth; simultaneous depletion of AKAP1 and Sestrin2 reverses these effects, establishing Sestrin2 as the downstream effector. Co-immunoprecipitation (AKAP1–Sestrin2 complex), siRNA double knockdown epistasis, mTOR phosphorylation assays, cell growth assays, ChIP for Myc binding Cell death & disease Medium 28569781
2018 Genetic deletion of AKAP1 in mice increases sensitivity to focal cerebral ischemia; mechanistically, AKAP1 loss reduces inhibitory phosphorylation of Drp1 at Ser637, dysregulates complex II of the electron transport chain, increases superoxide production, and impairs neuronal Ca²⁺ homeostasis under excitotoxic glutamate. AKAP1 knockout mice, middle cerebral artery occlusion model, ultrastructural electron microscopy, Drp1 phosphorylation immunoblotting, electron transport chain activity assays, superoxide measurement, Ca²⁺ imaging in neurons The Journal of neuroscience High 30093535
2018 Akap1 knockout in mice impairs postischemic neovascularization, reduces Akt phosphorylation in endothelial cells, enhances hypoxia-induced mitophagy, mitochondrial dysfunction, ROS, and apoptosis in endothelial cells; a constitutively active Akt mutant restores vascular reactivity and endothelial function in Akap1-null conditions, placing Akt downstream of AKAP1. Akap1 knockout mice, femoral artery ligation model, primary aortic endothelial cell culture, Akt phosphorylation assay, mitophagy markers, ROS measurement, constitutively active Akt rescue experiment Hypertension Medium 29335250
2018 Akap1 deletion exacerbates pressure overload-induced left ventricular hypertrophy and accelerates progression to heart failure; these changes are not observed when Siah2 is co-deleted (preventing AKAP121 degradation), genetically placing AKAP1 downstream of Siah2 in the hypertrophic response; Akap1 loss is associated with absence of Akt signaling activation. Akap1 and Siah2 knockout mice, transverse aortic constriction, echocardiography, cardiomyocyte size measurement, apoptosis assay, Akt phosphorylation Frontiers in physiology Medium 29892230
2019 AKAP121/PKA confers neuroprotection against glutamate toxicity by phosphorylating Drp1 to promote mitochondrial fusion; this increases ATP levels and elevates antioxidants (GSH, SOD2) while reducing mitochondrial superoxide. A PKA-binding-deficient AKAP121 mutant fails to protect neurons, confirming that PKA catalytic activity is required for AKAP121's protective effect. Transfection of AKAP121 wild-type, PKA-binding-deficient mutant, constitutively active OMM-PKA, and S-AKAP84 isoform; cell death assay, Drp1 phosphorylation immunoblotting, ATP measurement, GSH and SOD2 assays, mitochondrial superoxide measurement Molecular neurobiology Medium 30652267
2020 Akap1 deficiency in diabetic (STZ-induced) mice impairs mitochondrial respiratory function and increases ROS-mediated apoptosis; AKAP1 interacts with NDUFS1 (NADH-ubiquinone oxidoreductase 75 kDa subunit) and is required for translocation of NDUFS1 from cytosol to mitochondria; Akap1 deficiency inhibits complex I activity; AAV9-mediated AKAP1 restoration promotes NDUFS1 mitochondrial import and alleviates diabetic cardiomyopathy. Co-immunoprecipitation (AKAP1–NDUFS1), mass spectrometry, Akap1 knockout mice, STZ diabetes model, complex I activity assay, subcellular fractionation of NDUFS1, AAV9 overexpression rescue, echocardiography Diabetologia High 32072193
2020 AKAP1 interacts with Drp1 (shown by co-immunoprecipitation) and promotes PKA-mediated Drp1 phosphorylation at Ser637 in podocytes under high glucose; this phosphorylation drives Drp1 translocation to mitochondria and promotes mitochondrial fission and podocyte apoptosis; AKAP1 knockdown reduces these effects while overexpression worsens them; Drp1 phosphomutant transfer confirmed the pathway. Co-immunoprecipitation (AKAP1–Drp1), Drp1 phosphomutant transfection, AKAP1 knockdown/overexpression, mitochondrial membrane potential and ROS assays, apoptosis assay Journal of cellular physiology Medium 32108342
2020 Loss of AKAP1 in glaucomatous retinal ganglion cells activates calcineurin (CaN) and reduces Drp1 phosphorylation at Ser637, triggering mitochondrial fragmentation, loss, and mitophagosome formation; AKAP1 loss also decreases Akt phosphorylation and activates Bim/Bax apoptotic pathway; OXPHOS complex composition is deregulated with loss of AKAP1. AKAP1 knockout mice, glaucoma model, electron microscopy, Drp1 phosphorylation, CaN level assay, Akt phosphorylation, Bim/Bax immunoblotting, OXPHOS complex quantification Cell death & disease Medium 32312949
2021 AKAP1 directly phosphorylates ACSL1 (acyl-CoA synthetase long chain family member 1) in a PKA-dependent manner to inhibit its enzymatic activity, thereby reducing fatty acid β-oxidation and thermogenesis in brown adipocytes; AKAP1 knockout enhances FAO and thermogenesis, rendering mice resistant to diet-induced obesity. AKAP1 knockout mice, high-fat diet model, PKA-dependent phosphorylation assay of ACSL1, ACSL1 enzymatic activity assay, fatty acid oxidation measurement, thermogenesis assay, BAT-specific AKAP1 re-expression Advanced science High 33747723
2022 AKAP1 recruits PKC and mediates phosphorylation of Larp1 (La-related protein 1), which reduces expression of TFAM (mitochondrial transcription factor A), a key factor in mtDNA replication; this pathway is activated under hyperglycemic conditions and is responsible for impaired mtDNA replication and mitochondrial dysfunction in podocytes. AKAP1 overexpression/knockdown, PKC inhibitor (enzastaurin), Larp1 phosphorylation assay, TFAM expression measurement, mtDNA copy number assay, mtDNA replication assay, podocyte injury readouts International journal of biological sciences Medium 35844803
2023 MAMs (mitochondria-associated ER membranes) are increased in diabetic podocytes and AKAP1 localizes to MAMs; AKAP1 translocation to MAMs is increased under high glucose, promoting Drp1 phosphorylation at Ser637, Drp1 mitochondrial translocation, excessive mitochondrial fission, and podocyte injury. MAM isolation/fractionation, AKAP1 subcellular localization by immunofluorescence and fractionation, Drp1 phosphorylation assay, AKAP1 knockdown/overexpression, Drp1 inhibitor pharmacological assay, electron microscopy Experimental cell research Medium 36775185
2024 Under ferroptotic conditions, AKAP1-anchored PKA at the outer mitochondrial membrane phosphorylates GRP75 at Ser148 in MAMs; phosphorylated GRP75 translocates to the cytosol where it competes with Nrf2 for Keap1 binding (via an ETGE motif), stabilizing Nrf2 and activating antiferroptotic gene transcription; blockade of the AKAP1/PKA/GRP75 axis increases cancer cell sensitivity to ferroptosis. Subcellular fractionation, AKAP1–PKA complex co-IP, site-directed mutagenesis (GRP75-S148), Nrf2-Keap1 co-IP competition assay, antiferroptotic gene reporter assays, in vivo xenograft with PKA/GRP75 blockade Cell death and differentiation High 39537840
2024 AKAP1 overexpression in vascular smooth muscle cells (VSMCs) inhibits PDGF-BB-induced Drp1 activation and mitochondrial fission by maintaining PKA-mediated Drp1 phosphorylation at Ser637, suppressing VSMC proliferation/migration and neointima formation; PKA antagonist reverses this protection. AKAP1 overexpression/knockdown in VSMCs, balloon injury rat model, Drp1 phosphorylation assay, mitochondrial morphology analysis, PKA agonist/antagonist pharmacology, PKARIIβ localization Biomedicine & pharmacotherapy Medium 38850669
2025 Hepatocyte-specific AKAP1 directly phosphorylates and inactivates GPAT1 (glycerol-3-phosphate acyltransferase 1) in a PKA-dependent manner, suppressing lysophosphatidic acid (LPA) production; AKAP1 deficiency increases LPA, promoting hepatic triglyceride synthesis and inflammatory activation; GPAT1 knockdown rescues the MASLD phenotype caused by hepatic AKAP1 deletion. Hepatocyte-specific Akap1 knockout mice, GPAT1 phosphorylation and activity assay (PKA-dependent), LPA measurement, GPAT1 knockdown rescue epistasis, high-fat and fast-food diet MASLD models, AAV-mediated AKAP1 restoration Nature communications High 40341440
2025 TRIB3 (Tribbles homolog 3) disrupts the interaction between AKAP1 and PKA regulatory subunit RIIα, impairing PKA-mediated inhibitory phosphorylation of Drp1 at Ser656 and promoting mitochondrial fission in nucleus pulposus cells; L-arginine suppresses TRIB3 and preserves the AKAP1–PKARIIα interaction, blocking pathological fission. Co-immunoprecipitation (AKAP1–PKARIIα interaction with/without TRIB3), Drp1 phosphorylation assay, TRIB3 knockdown/overexpression, immunofluorescence colocalization, in vivo rat IDD model Osteoarthritis and cartilage Medium 40848982
2008 AKAP149 (AKAP1) interacts with HIV-1 reverse transcriptase via the RNase H domain of RT; AKAP149 silencing by RNAi inhibits HIV-1 replication at the reverse transcription step; a single RT point mutant (G462R) that loses AKAP149 binding retains intrinsic RT activity in vitro but fails to complete reverse transcription in infected cells. Yeast two-hybrid, co-immunoprecipitation in human cells, domain mapping, siRNA knockdown, RT point mutant (G462R) functional assay in infected cells Journal of molecular biology Medium 18786546

Source papers

Stage 0 corpus · 62 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission. Circulation research 285 29092894
2011 Fine-tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia. Molecular cell 212 22099302
2011 PKA/AKAP1 and PP2A/Bβ2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics. The Journal of neuroscience : the official journal of the Society for Neuroscience 178 22049414
2011 Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1. PLoS biology 176 21526220
1995 Characterization of S-AKAP84, a novel developmentally regulated A kinase anchor protein of male germ cells. The Journal of biological chemistry 166 7499250
1999 NH2-Terminal targeting motifs direct dual specificity A-kinase-anchoring protein 1 (D-AKAP1) to either mitochondria or endoplasmic reticulum. The Journal of cell biology 137 10352013
2005 Mitochondrial AKAP121 links cAMP and src signaling to oxidative metabolism. Molecular biology of the cell 133 16251349
2000 Recruitment of protein phosphatase 1 to the nuclear envelope by A-kinase anchoring protein AKAP149 is a prerequisite for nuclear lamina assembly. The Journal of cell biology 128 10995432
2018 AKAP1 Protects from Cerebral Ischemic Stroke by Inhibiting Drp1-Dependent Mitochondrial Fission. The Journal of neuroscience : the official journal of the Society for Neuroscience 110 30093535
2004 Mitochondrial AKAP121 binds and targets protein tyrosine phosphatase D1, a novel positive regulator of src signaling. Molecular and cellular biology 101 15143158
2020 Akap1 deficiency exacerbates diabetic cardiomyopathy in mice by NDUFS1-mediated mitochondrial dysfunction and apoptosis. Diabetologia 95 32072193
2008 Proteolysis of AKAP121 regulates mitochondrial activity during cellular hypoxia and brain ischaemia. The EMBO journal 89 18323779
2003 PKA-dependent binding of mRNA to the mitochondrial AKAP121 protein. Journal of molecular biology 86 12654270
2013 NCX3 regulates mitochondrial Ca(2+) handling through the AKAP121-anchored signaling complex and prevents hypoxia-induced neuronal death. Journal of cell science 72 24101730
1996 Molecular characterization of AKAP149, a novel A kinase anchor protein with a KH domain. Biochemical and biophysical research communications 71 8769136
2010 AKAP121 downregulation impairs protective cAMP signals, promotes mitochondrial dysfunction, and increases oxidative stress. Cardiovascular research 60 20511238
2020 AKAP1 mediates high glucose-induced mitochondrial fission through the phosphorylation of Drp1 in podocytes. Journal of cellular physiology 56 32108342
2003 AKAP149 is a novel PP1 specifier required to maintain nuclear envelope integrity in G1 phase. Journal of cell science 51 12697839
2017 Mitochondrial AKAP1 supports mTOR pathway and tumor growth. Cell death & disease 50 28569781
2022 AKAP1 contributes to impaired mtDNA replication and mitochondrial dysfunction in podocytes of diabetic kidney disease. International journal of biological sciences 47 35844803
2016 Akap1 Deficiency Promotes Mitochondrial Aberrations and Exacerbates Cardiac Injury Following Permanent Coronary Ligation via Enhanced Mitophagy and Apoptosis. PloS one 47 27136357
2009 The A-kinase anchor protein AKAP121 is a negative regulator of cardiomyocyte hypertrophy. Journal of molecular and cellular cardiology 47 19358331
2020 Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells. Cell death & disease 46 32312949
2018 Akap1 genetic deletion increases the severity of hyperoxia-induced acute lung injury in mice. American journal of physiology. Lung cellular and molecular physiology 45 29388469
2002 A 15-residue bifunctional element in D-AKAP1 is required for both endoplasmic reticulum and mitochondrial targeting. The Journal of biological chemistry 39 11994283
2018 Akap1 Regulates Vascular Function and Endothelial Cells Behavior. Hypertension (Dallas, Tex. : 1979) 37 29335250
2002 AMY-1 interacts with S-AKAP84 and AKAP95 in the cytoplasm and the nucleus, respectively, and inhibits cAMP-dependent protein kinase activity by preventing binding of its catalytic subunit to A-kinase-anchoring protein (AKAP) complex. The Journal of biological chemistry 35 12414807
2001 AMY-1, a c-Myc-binding protein, is localized in the mitochondria of sperm by association with S-AKAP84, an anchor protein of cAMP-dependent protein kinase. The Journal of biological chemistry 35 11483602
2021 AKAP1 Deficiency Attenuates Diet-Induced Obesity and Insulin Resistance by Promoting Fatty Acid Oxidation and Thermogenesis in Brown Adipocytes. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 31 33747723
2018 Loss of Akap1 Exacerbates Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure. Frontiers in physiology 31 29892230
2019 Neuroprotective Mitochondrial Remodeling by AKAP121/PKA Protects HT22 Cell from Glutamate-Induced Oxidative Stress. Molecular neurobiology 30 30652267
2012 Short RNA molecules with high binding affinity to the KH motif of A-kinase anchoring protein 1 (AKAP1): implications for the regulation of steroidogenesis. Molecular endocrinology (Baltimore, Md.) 29 23077346
2008 Mutually exclusive binding of PP1 and RNA to AKAP149 affects the mitochondrial network. Human molecular genetics 24 19074462
2006 Association of PP1 with its regulatory subunit AKAP149 is regulated by serine phosphorylation flanking the RVXF motif of AKAP149. Biochemistry 24 16669629
2020 Hypoxia-induced circular RNA hsa_circ_0008450 accelerates hepatocellular cancer progression via the miR-431/AKAP1 axis. Oncology letters 23 33193848
2016 Pivotal role of AKAP121 in mitochondrial physiology. American journal of physiology. Cell physiology 23 26825124
2023 Mitochondria-associated endoplasmic reticulum membranes promote mitochondrial fission through AKAP1-Drp1 pathway in podocytes under high glucose conditions. Experimental cell research 21 36775185
2019 A-kinase anchoring protein 1 (AKAP1) and its role in some cardiovascular diseases. Journal of molecular and cellular cardiology 20 31783032
2008 AKAP149 binds to HIV-1 reverse transcriptase and is involved in the reverse transcription. Journal of molecular biology 20 18786546
2024 AKAP1/PKA-mediated GRP75 phosphorylation at mitochondria-associated endoplasmic reticulum membranes protects cancer cells against ferroptosis. Cell death and differentiation 19 39537840
2006 Identification and characterization of D-AKAP1 as a major adipocyte PKA and PP1 binding protein. Biochemical and biophysical research communications 19 16756943
2024 AKAP1 alleviates VSMC phenotypic modulation and neointima formation by inhibiting Drp1-dependent mitochondrial fission. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 16 38850669
2022 1-Nitropyrene disrupts testosterone biogenesis via AKAP1 degradation promoted mitochondrial fission in mouse Leydig cell. Environmental pollution (Barking, Essex : 1987) 16 35613681
2020 Induction of UCP1 and thermogenesis by a small molecule via AKAP1/PKA modulation. The Journal of biological chemistry 16 32855239
2002 Characterization of RII(beta) and D-AKAP1 in differentiated adipocytes. American journal of physiology. Cell physiology 14 11742813
2023 Ligustilide-loaded liposome ameliorates mitochondrial impairments and improves cognitive function via the PKA/AKAP1 signaling pathway in a mouse model of Alzheimer's disease. CNS neuroscience & therapeutics 13 37718506
2020 Nuclear-encoded NCX3 and AKAP121: Two novel modulators of mitochondrial calcium efflux in normoxic and hypoxic neurons. Cell calcium 12 32193001
2013 A-kinase anchor protein 1 (AKAP1) regulates cAMP-dependent protein kinase (PKA) localization and is involved in meiotic maturation of porcine oocytes. Biology of reproduction 12 23426434
2022 miR-199b-5p-AKAP1-DRP1 Pathway Plays a Key Role in ox-LDL-induced Mitochondrial Fission and Endothelial Apoptosis. Current pharmaceutical biotechnology 9 35331106
2021 Epigenetic silencing of microRNA-199a-5p promotes the proliferation of non-small cell lung cancer cells by increasing AKAP1 expression. Oncology letters 8 33868472
2022 Mitochondrial Protein Akap1 Deletion Exacerbates Endoplasmic Reticulum Stress in Mice Exposed to Hyperoxia. Frontiers in pharmacology 7 35370705
2025 Hepatic AKAP1 deficiency exacerbates diet-induced MASLD by enhancing GPAT1-mediated lysophosphatidic acid synthesis. Nature communications 6 40341440
1999 Characterization of three genes, AKAP84, BAW and WSB1, located 3' to the neurofibromatosis type 1 locus in Fugu rubripes. Gene 6 10415327
2024 LINC00323 knockdown suppresses the proliferation, migration, and vascular mimicry of non-small cell lung cancer cells by promoting ubiquitinated degradation of AKAP1. Non-coding RNA research 4 39802612
2024 AKAP1 in Renal Patients with AHF to Reduce Ferroptosis of Cardiomyocyte. The heart surgery forum 3 38286648
2024 miR-199a-5p aggravates renal ischemia-reperfusion and transplant injury by targeting AKAP1 to disrupt mitochondrial dynamics. American journal of physiology. Renal physiology 3 39265082
2023 AKAP1 Regulates Mitochondrial Dynamics during the Fatty-Acid-Promoted Maturation of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes as Indicated by Proteomics Sequencing. International journal of molecular sciences 3 37175819
2004 A synthetic peptide reproducing the mitochondrial targeting motif of AKAP121: a conformational study. Biopolymers 3 15499565
2025 L-arginine alleviates intervertebral disc degeneration by suppressing TRIB3/AKAP1-mediated Drp1 phosphorylation dysregulation and mitochondrial fragmentation. Osteoarthritis and cartilage 2 40848982
2025 AKAP1-STABILIZED TIMP-4 ATTENUATES ANG-II-INDUCED OXIDATIVE STRESS AND INFLAMMATION IN VASCULAR SMOOTH MUSCLE CELLS BY INACTIVATING THE NF-ΚB SIGNALING. Shock (Augusta, Ga.) 1 39965635
2025 AKAP1 regulates mitochondrial and synaptic homeostasis to enable neuroprotection and repair in retinal ganglion cell degeneration. bioRxiv : the preprint server for biology 1 41357987
2023 [Protective effect and mechanism of AKAP1 on myocardial injury induced by highland hypobaric hypoxia]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 0 37524671

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