Affinage

AKAP12

A-kinase anchor protein 12 · UniProt Q02952

Length
1782 aa
Mass
191.5 kDa
Annotated
2026-06-09
100 papers in source corpus 44 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AKAP12 (SSeCKS/Gravin) is a large multivalent scaffold protein that spatiotemporally compartmentalizes kinases, cytoskeletal regulators, and signaling lipids to govern cytoskeletal architecture, cell-cycle progression, receptor recycling, and barriergenesis (PMID:9744295, PMID:10982843, PMID:14657015, PMID:12808449). Its scaffolding logic is built from defined, phosphorylation-gated binding modules: it carries a PKA RII-binding domain establishing it as a bona fide AKAP (PMID:9885289, PMID:10469144), cyclin-binding (CY) motifs that overlap PKC phosphorylation sites (Ser507/515) so that PKC phosphorylation releases cytoplasmically sequestered cyclin D1 for nuclear translocation (PMID:10982843, PMID:22249313), calmodulin-binding sites antagonized by PKC phosphorylation (PMID:11820772), and direct PKCα-binding motifs through which AKAP12 binds and dampens PKC activity to restrain Rb-mediated senescence and cytoskeletal remodeling (PMID:21099353, PMID:21903576). Through this architecture AKAP12 organizes actin-based cytoskeleton and adhesion, sequestering Src to caveolin-rich lipid rafts to disengage FAK and suppressing RhoA/Cdc42 to block podosome formation, and scaffolding phosphoinositides via MARCKS-like polybasic domains to direct lamellipodial chemotaxis (PMID:9744295, PMID:16547152, PMID:22710722, PMID:25356636). It functions as a tumor and metastasis suppressor by attenuating Raf/MEK/ERK signaling away from a sequestered PKC pool, reducing MMP-2, VEGF, and invasion (PMID:9187136, PMID:16740695, PMID:20018890). In endothelial and astrocytic compartments AKAP12 drives blood-brain/blood-retinal barrier formation by suppressing HIF-1α/VEGF and inducing angiopoietin-1, and by compartmentalizing PKA-VASP/Rac1 signaling at endothelial junctions and leading edges while restraining the Rho kinase pathway (PMID:12808449, PMID:17442832, PMID:31162891, PMID:33260683). As an AKAP it phosphorylation-dependently re-associates with the β2-adrenergic receptor to enable resensitization and recycling (PMID:14657015, PMID:19055733), and in cardiomyocytes couples to PDE8 to limit intracellular cAMP and contractility (PMID:38506047); it also scaffolds PKA-mediated phosphorylation of ATR-S435 to recruit XPA during nucleotide excision repair (PMID:27683220). AKAP12 expression and stability are tightly controlled, undergoing epigenetic silencing by HDAC3/HDAC7 and Src-driven HDAC1 recruitment, and HDAC6-mediated deacetylation that triggers ubiquitin-proteasomal degradation (PMID:17626016, PMID:20568114, PMID:22584896, PMID:36122629, PMID:29484387).

Mechanistic history

Synthesis pass · year-by-year structured walk · 38 steps
  1. 1997 High

    Establishing that re-expression of SSeCKS reverses oncogenic transformation answered whether this protein is a functional tumor suppressor and whether it acts on Src directly.

    Evidence Tetracycline-regulated SSeCKS re-expression in v-Src-transformed NIH3T3 with soft agar, invasion, and kinase assays

    PMID:9187136

    Open questions at the time
    • Did not identify the molecular target through which SSeCKS suppresses transformation downstream of intact Src activity
    • Did not define direct binding partners
  2. 1998 High

    Demonstrating that ectopic SSeCKS reorganizes the cortical cytoskeleton established its primary role as a controller of actin-based architecture and adhesion.

    Evidence Inducible expression in NIH3T3 with immunofluorescence, fractionation, and cytoskeletal inhibitor studies

    PMID:9744295

    Open questions at the time
    • Did not identify the signaling molecules scaffolded to drive cytoskeletal changes
    • Mechanism linking FAK phosphorylation to morphology unresolved
  3. 1999 High

    Identification of the PKA RII-binding domain and PKC-triggered translocation defined SSeCKS as an AKAP whose localization is phosphorylation-regulated.

    Evidence Deletion mutagenesis for RII binding and antisense knockdown with phorbol ester in mesangial cells

    PMID:10469144 PMID:9885289

    Open questions at the time
    • Did not link RII anchoring to a specific downstream PKA substrate
    • Functional consequence of perinuclear translocation undefined
  4. 2000 High

    Mapping cyclin-binding motifs overlapping PKC phosphorylation sites answered how SSeCKS couples kinase signaling to cell-cycle control via cyclin D1 sequestration.

    Evidence In vitro CY-domain binding, site-directed mutagenesis, confocal imaging, and pRb assays in NIH3T3

    PMID:10982843

    Open questions at the time
    • Forced cyclin D1 re-expression did not rescue G1 arrest, indicating uncharacterized additional mechanisms
    • ERK2-dependent cyclin D1 downregulation mechanism not fully resolved
  5. 2002 High

    Demonstrating calmodulin binding and phosphorylation-attenuated cyclin binding established that PKC phosphorylation is a master switch modulating multiple SSeCKS scaffolding outputs.

    Evidence In vitro binding of bacterial SSeCKS fragments with PKC pre-phosphorylation and deletion mapping

    PMID:11820772

    Open questions at the time
    • Cellular consequence of CaM binding not directly demonstrated
    • Single-lab in vitro reconstitution
  6. 2002 High

    Showing FAK-dependent, indirect tyrosine phosphorylation of SSeCKS clarified how mitogenic signaling modulates its actin association.

    Evidence FAK-/- MEF complementation, in vitro kinase assays, and F-actin co-sedimentation

    PMID:12083796

    Open questions at the time
    • The actual kinase phosphorylating SSeCKS downstream of FAK was not identified
    • Tyrosine sites on SSeCKS not mapped
  7. 2003 High

    Defining gravin-β2AR association through its AKAP domain and PKA phosphorylation answered how an AKAP scaffold enables receptor resensitization.

    Evidence Mutagenesis, metabolic labeling, Co-IP, and resensitization assays

    PMID:14657015

    Open questions at the time
    • Did not establish whether other receptors use the same docking mechanism
    • Dynamics of association/dissociation in cells incompletely resolved
  8. 2003 High

    Demonstrating SSeCKS-driven VEGF suppression and angiopoietin-1 induction in astrocytes established its role in blood-brain barrier differentiation.

    Evidence Astrocyte overexpression, conditioned media transfer, angiogenesis and sucrose permeability assays in vivo and in vitro

    PMID:12808449

    Open questions at the time
    • Molecular mechanism of VEGF suppression not yet defined
    • Endothelial signaling target of secreted factors unresolved
  9. 2004 High

    Characterization of three promoter-driven isoforms with distinct targeting (including myristoylation-driven ER localization) revealed isoform-specific subcellular compartmentalization.

    Evidence Comparative genomics, reporter assays, GFP chimeras, and myristoylation mutagenesis

    PMID:15496411

    Open questions at the time
    • Functional distinction between isoforms not established
    • ER-localized AKAP12α role undefined
  10. 2005 Medium

    Mapping NLS, nuclear-exclusion, and peripheral targeting domains established a hierarchy of localization signals governing AKAP12 distribution.

    Evidence Cross-species sequence analysis, deletion mapping, GFP chimera imaging, and fractionation

    PMID:15923193

    Open questions at the time
    • No functional consequence of differential localization directly demonstrated
    • Conditions triggering nuclear import not identified
  11. 2006 High

    Placing SSeCKS downstream of Src but upstream of RhoA/Cdc42 in podosome suppression connected its tumor-suppressor activity to GTPase-mediated cytoskeletal remodeling.

    Evidence Inducible expression, GTPase activity assays, constitutively active GTPase rescue, and invasion assays

    PMID:16547152

    Open questions at the time
    • Mechanism by which SSeCKS lowers RhoA/Cdc42 activity not defined
    • Direct GTPase regulators involved unidentified
  12. 2006 High

    Showing VEGF re-expression partially reverses metastasis suppression established VEGF/angiogenic gene control as a key effector of SSeCKS metastasis suppression in vivo.

    Evidence Inducible expression, spontaneous/experimental metastasis models, and VEGF isoform rescue

    PMID:16740695

    Open questions at the time
    • Partial reversal indicates VEGF-independent mechanisms remain
    • Transcriptional mechanism of VEGF/HIF-1α regulation not resolved here
  13. 2007 High

    Demonstrating AKAP12 enhances pVHL/PHD2-dependent HIF-1α degradation answered how it suppresses VEGF and promotes blood-retinal barrier formation.

    Evidence Astrocyte overexpression, Co-IP of HIF-1α with pVHL/PHD2, and conditioned media tight-junction assays

    PMID:17442832

    Open questions at the time
    • Whether AKAP12 directly contacts the HIF degradation machinery is not established
    • Mechanism enhancing the pVHL/PHD2 interaction unresolved
  14. 2007 High

    Defining v-Src-driven HDAC1/USF1/Sp1-Sp3/TFII-I promoter repression revealed the transcriptional mechanism by which oncogenic signaling silences SSeCKS.

    Evidence Promoter deletion, ChIP, HDAC1 siRNA, EMSA, and TFII-I phosphorylation mutants

    PMID:17626016 PMID:20568114

    Open questions at the time
    • Did not establish how Src activates this promoter complex mechanistically
    • Generality across cell types untested
  15. 2008 Medium

    Tracing an AKAP12→PKCζ→Rho kinase→VEGF/TSP-1 axis and the prostatic AKT phenotype connected AKAP12 loss to elevated angiogenic and PI3K/AKT signaling in tissue.

    Evidence Conditioned media with PKCζ siRNA and Rho kinase inhibitor; SSeCKS-null prostate histology with pAKT blots

    PMID:18397319 PMID:18593908

    Open questions at the time
    • Indirect conditioned-media readout for the PKCζ pathway
    • Mechanism linking AKAP12 to AKT attenuation in prostate not defined
  16. 2008 High

    Reciprocal siRNA dissection of AKAP12 versus AKAP5 established non-redundant segregation of β2AR resensitization (AKAP12) from ERK activation (AKAP5).

    Evidence Reciprocal siRNA knockdown in A431 and HEK293 with resensitization, recycling, and ERK assays

    PMID:19055733

    Open questions at the time
    • Structural basis for pathway segregation not determined
    • Whether the two AKAPs physically interact addressed only later
  17. 2009 High

    Showing SSeCKS attenuates Raf/MEK/ERK via its PKC-binding domain to reduce MMP-2 and invasion established the kinase-scaffolding basis of its anti-invasive activity.

    Evidence Inducible expression, constitutively active kinase rescue, domain deletion, and actin perturbation

    PMID:20018890

    Open questions at the time
    • Direct demonstration of PKC-Raf disengagement on the scaffold not shown
    • Link between actin and MEK/ERK attenuation mechanistically incomplete
  18. 2010 High

    Defining premature senescence in AKAP12-null MEF through PKCα/δ scaffolding revealed AKAP12 control over Rb-mediated aging and cytokinesis.

    Evidence KO MEF with PKC activity assays, MEK inhibitor epistasis, and senescence/polyploidy quantification

    PMID:21099353

    Open questions at the time
    • Direct PKCα/δ binding shown definitively in a later study
    • Connection between Lats1 downregulation and PKCδ not fully mapped
  19. 2011 High

    Mapping two PKCα-binding motifs and showing binding inhibits PKC activity provided the biochemical basis for AKAP12 as a PKC-sequestering scaffold.

    Evidence In vitro motif-defined binding and kinase assays plus KO MEF rescue with deletion constructs

    PMID:21903576

    Open questions at the time
    • Whether all PKC isoforms share the same binding mode unresolved
    • Single-lab in vitro reconstitution
  20. 2011 Medium

    Demonstrating AKAP12 homo-oligomerization and hetero-oligomerization with AKAP5 indicated higher-order scaffold assembly that potentiates ERK signaling.

    Evidence Steric-exclusion and affinity chromatography, Co-IP, and ERK assays with agonist

    PMID:21554706 PMID:21831305

    Open questions at the time
    • Physiological role of oligomerization not established in vivo
    • Stoichiometry and structural basis undefined
  21. 2012 High

    Identifying the caveolin-1-like Src-binding domain that sequesters Src to lipid rafts explained how SSeCKS disengages Src from FAK adhesion complexes.

    Evidence Domain identification, Co-IP, lipid raft fractionation, deletion mutants, and FAK/Src phosphorylation assays

    PMID:22710722

    Open questions at the time
    • Direct structural verification of raft targeting absent
    • How Src sequestration alters adhesion dynamics over time unresolved
  22. 2012 High

    Confirming cytoplasmic cyclin D1 sequestration in quiescent epithelial cells with a KO disease phenotype validated the cyclin-control model in vivo.

    Evidence Co-IP from primary glomeruli, confocal imaging, and SSeCKS-null nephritis model

    PMID:22249313

    Open questions at the time
    • PKC kinase identity driving release in vivo not specified
    • Generalizability beyond glomerular epithelium untested
  23. 2012 High

    Linking AKAP12 to PAK2/AF6-dependent endothelial junction integrity in zebrafish established its requirement for vascular barrier maintenance in vivo.

    Evidence Morpholino knockdown with in vivo imaging, cell culture siRNA, and PAK2+AF6 rescue

    PMID:22192928

    Open questions at the time
    • Mechanism by which AKAP12 controls PAK2/AF6 expression not defined
    • Direct binding to junctional components untested
  24. 2012 High

    Demonstrating HDAC7-mediated silencing and a PKC-STAT3 positive feedback loop revealed epigenetic control of AKAP12 in endothelial cells.

    Evidence HDAC7 siRNA, H3 acetylation ChIP, STAT3 ChIP at the promoter, and migration/tube assays

    PMID:22584896

    Open questions at the time
    • Direct STAT3-AKAP12 promoter regulatory architecture incompletely mapped
    • Whether feedback operates in other cell types untested
  25. 2013 High

    Identifying functional HIF-binding sites in the gravin promoter and a barrier-stabilizing role connected hypoxia sensing to AKAP12-mediated angiogenic braking.

    Evidence Promoter reporter assays, HIF-site mutagenesis, gain/loss-of-function, and transendothelial resistance

    PMID:24029533

    Open questions at the time
    • Interplay between HIF-driven induction and AKAP12-driven HIF-1α suppression unresolved
    • Single-lab promoter dissection
  26. 2014 High

    Showing AKAP12-anchored PKA and Rac1 are required for cAMP-mediated endothelial barrier stabilization defined a junctional compartmentalization mechanism.

    Evidence siRNA knockdown, transendothelial resistance, in vivo hydraulic conductivity, Rac1 assays, and AKAP-disruptor peptide

    PMID:25188285

    Open questions at the time
    • Direct PKA substrate at junctions not identified here
    • Link between PKA anchoring and Rac1 activation mechanistically incomplete
  27. 2014 High

    Establishing phosphoinositide scaffolding via MARCKS polybasic domains, ranked above Src binding, defined how SSeCKS directs lamellipodial chemotaxis.

    Evidence KO MEF, ΔPBD/ΔSrc deletion epistasis, Frabin knockdown, and leading-edge PIP3/GTPase imaging

    PMID:25356636

    Open questions at the time
    • Direct lipid-binding affinities not quantified
    • How PBD scaffolding spatially restricts Cdc42-GEF activity unresolved
  28. 2014 Medium

    Linking AKAP12 to TGF-β1-non-Smad-SNAI1 signaling in meningeal EMT established a role in CNS injury reconstruction.

    Evidence AKAP12-KO mice with CNS injury model and gain/loss-of-function under TGF-β1/RA/oxygen manipulation

    PMID:25229625

    Open questions at the time
    • Non-Smad SNAI1 mechanistic detail not fully characterized
    • Direct AKAP12 scaffolding role in the pathway undefined
  29. 2015 High

    Showing hypoxia induces AKAP12 variant 2 to shift PKA-mediated phosphorylation events connected localization-driven scaffold variation to metastatic behavior.

    Evidence Kinome-wide phosphoproteomics/MS, siRNA, variant gain-of-function, and orthotopic melanoma model

    PMID:25792458

    Open questions at the time
    • Specific PKA substrates driving the invasive shift not all defined
    • Mechanism of variant-specific localization unresolved
  30. 2016 High

    Defining the AKAP12-PKA-ATR-S435 complex that recruits XPA established a direct role for AKAP12 scaffolding in nucleotide excision repair.

    Evidence siRNA, interaction-blocking mutants, NER incision assay, XPA recruitment, and UV mutagenesis assay

    PMID:27683220

    Open questions at the time
    • Structural organization of the nuclear complex undefined
    • How UV signals to ATR-directed AKAP12 phosphorylation incompletely mapped
  31. 2017 High

    Demonstrating stromal SSeCKS suppresses peritoneal colonization via Cxcl9/10 control implicated scaffold-regulated stromal secretion in metastasis suppression.

    Evidence SSeCKS-null mice, peritoneal fluid adoptive transfer, Cxcr3 knockdown, scaffolding-site mutants, and kinase inhibitors

    PMID:29050279

    Open questions at the time
    • Relative contribution of PKC/PKA/PI3K pathways to chemokine control not separated
    • Link between fibroblast senescence and chemokine output mechanistically incomplete
  32. 2018 Medium

    Showing fibroblast SSeCKS attenuates Src/STAT3-dependent SASP extended its stromal metastasis-suppressor role to lung colonization.

    Evidence SSeCKS-null syngeneic hosts, co-injection assays, STAT3 activation, Src-scaffolding domain mutants, and E-Selectin blots

    PMID:30323895

    Open questions at the time
    • Direct Src-STAT3 scaffolding on AKAP12 not biochemically resolved
    • Endothelial E-Selectin regulation mechanism undefined
  33. 2018 Medium

    Identifying HDAC3 binding at AKAP12 intron-1 as repressive, with PI3K/AKT as a downstream effector, added a second epigenetic silencing mechanism in colorectal cancer.

    Evidence HDAC3 ChIP, inhibitor treatment, AKAP12 siRNA, and PI3K/AKT blots

    PMID:29484387

    Open questions at the time
    • How HDAC3 represses from an intronic site mechanistically unresolved
    • Direct vs indirect AKAP12 control of PI3K/AKT undefined
  34. 2019 High

    Localizing AKAP12 with PKA-RIIα, Arp2/3, and VASP at endothelial tip-cell leading edges defined a PKA-VASP compartment driving angiogenic sprouting.

    Evidence siRNA, AKAP12-/- mice, IP-MS, postnatal retinal imaging, and VASP-Ser157 phosphorylation assays

    PMID:31162891

    Open questions at the time
    • Direct AKAP12-VASP contact not established
    • Spatial coupling of Arp2/3 to the scaffold mechanistically incomplete
  35. 2020 High

    Placing AKAP12 upstream of Rho kinase in BBB maintenance, with pharmacological rescue after stroke, connected AKAP12 loss to junctional permeability through ROCK activation.

    Evidence siRNA in cerebral endothelial cells, Akap12 KO stroke model, Rho kinase assays, and Y-27632 rescue

    PMID:33260683

    Open questions at the time
    • Mechanism by which AKAP12 restrains Rho kinase not defined
    • Link to ZO-1/Claudin-5 regulation mechanistically incomplete
  36. 2020 Medium

    Showing Notch suppresses Akap12 and that ectopic Akap12 causes ciliary/lumen defects revealed a Notch-AKAP12 negative feedback loop in renal morphogenesis.

    Evidence dnMaml expression, Akap12 ectopic expression, cilia length and lumen assays, and Notch reporter

    PMID:32474964

    Open questions at the time
    • Mechanism by which Akap12 inhibits Notch transcription undefined
    • Direct molecular link to ciliary length control unresolved
  37. 2022 High

    Identifying HDAC6 deacetylation of AKAP12 at K531 as a trigger for ubiquitin-proteasomal degradation revealed post-translational control coupling AKAP12 stability to PKC reactivation in metastasis.

    Evidence Proteomics, HDAC6-AKAP12 Co-IP, acetylation site mapping, ubiquitination assay, and AKAP12 deletion rescue

    PMID:36122629

    Open questions at the time
    • E3 ligase mediating AKAP12 ubiquitination not identified
    • How acetylation status shifts under physiological cues unresolved
  38. 2024 High

    Demonstrating AKAP12 couples to PDE8 to limit cardiac cAMP, with a heart-failure phenotype and human validation, defined a cardiac cAMP-homeostasis role.

    Evidence GloSensor cAMP biosensor, primary cardiomyocyte contractility/calcium imaging, cardiac-specific overexpression mice, PDE8 inhibitor rescue, and human failing-heart samples

    PMID:38506047

    Open questions at the time
    • Direct AKAP12-PDE8 binding architecture not detailed
    • Whether endogenous AKAP12 loss has reciprocal cardiac effects untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many AKAP12 scaffolding modules are integrated structurally into a single multivalent platform, and how isoform/localization choice selects among its competing signaling outputs, remains unresolved.
  • No structural model of full-length AKAP12 or its assembled complexes
  • Rules selecting between PKA, PKC, cyclin, Src, and PIP scaffolding outputs in a given context unknown
  • In vivo stoichiometry of competing partner binding undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 4 GO:0008092 cytoskeletal protein binding 3 GO:0140313 molecular sequestering activity 3 GO:0008289 lipid binding 1
Localization
GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 3 GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-1640170 Cell Cycle 3 R-HSA-73894 DNA Repair 1
Partners
ADRB2AKAP5ATRB4GALT1CCND1PRKACAPRKCASRC

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SSeCKS/AKAP12 associates with and controls elaboration of a cortical cytoskeletal matrix resistant to Triton X-100 extraction; ectopic SSeCKS expression in NIH3T3 cells caused cell flattening, loss of actin stress fibers and vinculin-associated adhesion plaques, and increased integrin-independent FAK tyrosine phosphorylation, establishing a direct role for SSeCKS in controlling actin-based cytoskeletal architecture. Tetracycline-regulated ectopic expression in NIH3T3 fibroblasts; immunofluorescence; cytochalasin/nocodazole inhibitor studies; biochemical fractionation Cell motility and the cytoskeleton High 9744295
1997 SSeCKS re-expression in v-Src-transformed NIH3T3 cells suppressed oncogenic transformation parameters (soft agar growth, invasiveness, focus formation, low-serum growth) without inhibiting Src kinase activity or JNK activity, but induced ERK2 activity; SSeCKS restored vinculin-associated adhesion plaques, actin stress fibers, and filopodia, indicating tumor suppression via cytoskeletal and signaling control rather than direct Src kinase inhibition. Tetracycline-regulated SSeCKS expression in ts72v-src cell lines; soft agar assay; Matrigel invasion; in vivo/in vitro kinase assays; immunofluorescence Cancer research High 9187136
2000 SSeCKS induces G1 arrest by ERK2-dependent decrease in cyclin D1 expression and pRb phosphorylation; SSeCKS encodes two cyclin-binding (CY) motifs flanking PKC phosphorylation sites (Ser507/515) that bind cyclins D1 and E; K→S mutations in either CY motif ablate cyclin binding; PKC phosphorylation of SSeCKS at Ser507/515 releases cyclin D1 from cytoplasmic sequestration, allowing nuclear translocation; forced cyclin D1 re-expression fails to rescue SSeCKS-induced G1 arrest, demonstrating additional mechanisms. Tetracycline-regulated expression in NIH3T3; bacterially expressed SSeCKS-CY domain binding assays; site-directed mutagenesis; confocal microscopy; cell-permeable penetratin-linked peptides; pRb phosphorylation assays Molecular and cellular biology High 10982843
2002 SSeCKS encodes four calmodulin (CaM) binding sites conforming to the 1-5-10 motif; CaM binding is antagonized by PKC pre-phosphorylation of SSeCKS; two major cyclin-binding (CY) sites overlap the major PKC phosphorylation site (Ser507/515), and cyclin D binding is attenuated by PKC pre-phosphorylation, demonstrating phosphorylation-dependent modulation of SSeCKS scaffolding activity. In vitro binding assays with bacterially expressed SSeCKS fragments; PKC phosphorylation prior to binding; mapping by deletion analysis Biochemical and biophysical research communications High 11820772
2001 SSeCKS/AKAP12 directly binds the cytoplasmic domain of beta1,4-galactosyltransferase I (GalT); identified by yeast two-hybrid screen and confirmed by reciprocal co-immunoprecipitation of both endogenous and transfected proteins; SSeCKS domains localized to Golgi (2.52) and filopodia (1.12) recapitulate GalT distribution; SSeCKS-GalT interaction restores normal adhesive phenotype disrupted by a dominant-negative GalT construct. Yeast two-hybrid screen; reciprocal co-immunoprecipitation; GFP-fusion localization; functional adhesion rescue assay Journal of cell science High 11493668
2003 Gravin/AKAP12 (AKAP250) dynamically associates with the beta2-adrenergic receptor (β2AR); the AKAP domain of gravin is essential for receptor binding (deletion abolishes binding); agonist stimulation induces gravin phosphorylation at two canonical PKA sites within its AKAP domain; PKA phosphorylation of these sites is required for scaffold-receptor association and for receptor resensitization; the AKAP-anchored PKA provides the catalytic activity responsible for phosphorylating the scaffold. Mutagenesis; metabolic labeling; biochemical co-immunoprecipitation; PKA inhibitor studies; receptor resensitization assays The EMBO journal High 14657015
2003 SSeCKS in astrocytes decreases VEGF expression through AP-1 reduction and stimulates angiopoietin-1 expression; conditioned media from SSeCKS-overexpressing astrocytes blocks angiogenesis in vivo and in vitro, increases tight junction proteins in endothelial cells, and decreases sucrose permeability, establishing SSeCKS as a regulator of BBB differentiation. SSeCKS overexpression in astrocytes; conditioned media transfer to endothelial cells; in vivo and in vitro angiogenesis assays; [3H]sucrose permeability assay; immunofluorescence; in vivo BBB maturation immunostaining Nature medicine High 12808449
2004 AKAP12 encodes three isoforms (alpha, beta, gamma) from three independent promoters with distinct tissue expression profiles; the alpha isoform contains an N-terminal myristoylation motif shown by deletion mapping and GFP chimeras to be necessary and sufficient for targeting AKAP12alpha to the endoplasmic reticulum, a novel AKAP12 subcellular compartment. Comparative genomics; reporter assays; GFP chimera subcellular localization; myristoylation site mutagenesis The Journal of biological chemistry High 15496411
2005 AKAP12 contains five nuclear localization signals (NLS) in its central region (including a novel X2-NLS class) that confer nuclear targeting potential; this is suppressed by a negatively charged C-terminus mediating nuclear exclusion; three basic residue-rich regions in the N-terminal domain (similar to MARCKS) control AKAP12 localization to ganglioside-rich regions at the cell periphery, establishing a hierarchy of targeting domains. Cross-species sequence analysis; deletion mapping; GFP chimera live-cell imaging; subcellular fractionation The Journal of biological chemistry Medium 15923193
2006 SSeCKS re-expression suppresses podosome formation via inhibition of RhoA and Cdc42 activity (>5-fold reduction); activated RhoA and Cdc42 rescue podosome formation in SSeCKS-expressing v-Src cells; SSeCKS does not affect Tks5/Fish tyrosine phosphorylation or total cellular tyrosine phosphorylation, placing SSeCKS downstream of Src kinase activity but upstream of RhoA/Cdc42-mediated cytoskeletal remodeling. Tetracycline-regulated SSeCKS expression; RhoA/Cdc42 activity assays; constitutively active GTPase rescue; Matrigel invasion; immunofluorescence Molecular cancer research High 16547152
2006 SSeCKS metastasis-suppressor activity correlates with suppression of VEGF expression in prostate cancer cells and tumor stroma; forced re-expression of VEGF165 or VEGF121 is sufficient to partially reverse SSeCKS metastasis suppression in both experimental and spontaneous lung metastasis models; SSeCKS also upregulates antiangiogenic genes (vasostatin, collagen 18a1) and downregulates proangiogenic genes (osteopontin, HIF-1alpha, angiopoietin). Tetracycline-regulated SSeCKS expression; spontaneous and experimental in vivo metastasis models; VEGF isoform forced re-expression rescue; gene expression analysis Cancer research High 16740695
2007 AKAP12 downregulates HIF-1alpha protein by enhancing its interaction with pVHL (von Hippel-Lindau protein) and PHD2 (prolyl hydroxylase 2), leading to decreased VEGF and increased angiopoietin-1 in astrocytes; conditioned media from AKAP12-overexpressing astrocytes induces tight junction protein expression in human retinal microvascular endothelial cells, promoting blood-retinal barrier formation. AKAP12 overexpression in astrocytes; co-immunoprecipitation of HIF-1alpha with pVHL and PHD2; conditioned media transfer; tight junction protein western blot; in vivo immunostaining of human retinoblastoma samples The Journal of neuroscience High 17442832
2007 v-Src downregulates SSeCKS alpha promoter via recruitment of HDAC1 to a USF1-Sp1/Sp3 complex at E- and GC-box elements (-106 to -49); v-Src increases Sp1/Sp3 binding to the GC-box without altering protein abundance; Src-induced tyrosine phosphorylation of TFII-I increases its binding to the SSeCKS proximal promoter and is required for full transcriptional repression; trichostatin A (HDAC inhibitor) but not 5-azacytidine restores SSeCKS transcript levels. Promoter deletion analysis; chromatin immunoprecipitation; HDAC1 siRNA knockdown; electrophoretic mobility shift assay; TFII-I mass spectrometry identification; TFII-I tyrosine phosphorylation mutant The Journal of biological chemistry High 17626016 20568114
2008 AKAP12 in astrocytes reduces phosphorylation of PKCzeta in retinal endothelial cells; PKCzeta knockdown decreases VEGF and increases thrombospondin-1 (TSP-1); inhibition of Rho kinase (Y27632) downstream of PKCzeta also decreases VEGF and increases TSP-1, establishing an AKAP12→PKCzeta→Rho kinase→VEGF/TSP-1 pathway mediating barriergenesis. Conditioned media from AKAP12-overexpressing astrocytes; siRNA-mediated PKCzeta knockdown; Rho kinase inhibitor Y27632; western blot for VEGF and TSP-1 The FEBS journal Medium 18397319
2008 Loss of SSeCKS/AKAP12 in knockout mice results in prostatic hyperplasia with focal dysplasia; SSeCKS-null prostate tissues exhibit significantly higher AKT(pS473) levels relative to wild-type, suggesting SSeCKS attenuates PI3K/AKT signaling in vivo. SSeCKS-null (knockout) mouse histology; western blot for pAKT(S473); E-cadherin and cytokeratin immunostaining Cancer research Medium 18593908
2009 SSeCKS suppresses serum-induced Raf/MEK/ERK pathway activation, leading to decreased MMP-2 expression and inhibition of chemotaxis and Matrigel invasion; constitutively active MEK1, MEK2, ERK1, or PKCalpha restores invasiveness and chemotaxis; SSeCKS attenuation of ERK activation requires its PKC-binding domain (aa 553-900), suggesting direct PKC scaffolding; jasplakinolide (actin stabilizer) nullifies SSeCKS inhibition of MEK/ERK activation but not podosome inhibition. Tetracycline-regulated SSeCKS expression; constitutively active kinase rescue; SSeCKS domain deletion analysis; chemotaxis assay; Matrigel invasion; MEK/ERK phosphorylation western blot; actin cytoskeleton perturbation The Journal of biological chemistry High 20018890
2010 AKAP12-null MEF exhibit premature senescence marked by polyploidy and multinucleation; senescence is Rb-dependent; PKCα activation induces p16(Ink4a)/Rb through MEK-dependent downregulation of Id1; PKCδ downregulates Lats1/Warts kinase required for cytokinesis; Akap12 directly scaffolds and attenuates PKCα/δ, controlling Rb-mediated cell aging and cytokinesis. AKAP12-null (KO) mouse embryonic fibroblasts; PKC activity assays; p53/Rb pathway analysis; MEK inhibitor epistasis; senescence markers (SA-β-gal, p16, p21); polyploidy/multinucleation quantification Cell cycle High 21099353
2011 SSeCKS directly binds PKCα through two homologous motifs (EG(I/V)(T/S)XWXSFK(K/R)(M/L)VTP(K/R)K(K/R)X(K/R)XXXEXXXE(E/D); aa 592-620 and 741-769); SSeCKS binding to PKCα decreases kinase activity; SSeCKS scaffolding of PKC increases at confluence correlating with decreased PKCα activity; SSeCKS-null MEF show increased PKC activity and defective phorbol ester-induced actin cytoskeletal reorganization, rescued by full-length SSeCKS but not by PKC-binding domain-deleted SSeCKS. In vitro PKC binding assays with defined SSeCKS motifs; PKC kinase activity assays; SSeCKS-null MEF; domain deletion rescue; phorbol ester-induced cytoskeletal morphology The Journal of biological chemistry High 21903576
2012 SSeCKS sequesters cyclin D1 in the cytoplasm of quiescent glomerular parietal epithelial cells (PECs); PKC phosphorylation of SSeCKS disrupts binding, resulting in nuclear translocation of cyclin D1; co-immunoprecipitation demonstrates cyclin D1-SSeCKS complex in PECs; SSeCKS-null mice show PEC hyperplasia with increased nuclear cyclin D1 and worse glomerular disease. Co-immunoprecipitation from capsulated glomeruli; confocal microscopy; SSeCKS-null mouse model; nephrotoxic nephritis model; cell culture contact inhibition experiments Laboratory investigation High 22249313
2012 SSeCKS contains a Src-binding domain (aa 153-166) homologous to the caveolin-1 Src-binding domain; this domain mediates SSeCKS-Src interaction, SSeCKS-enhanced Src activity, and sequestration of Src to caveolin-rich lipid rafts; SSeCKS suppresses adhesion-induced Src activation (SrcpoY416) and FAK-Y925 phosphorylation while increasing FAK(pY397) and cell adhesion to fibronectin; lipid raft sequestration of Src disengages Src from FAK-associated adhesion complexes. In silico domain identification; co-immunoprecipitation; lipid raft fractionation; SSeCKS domain deletion mutants; FAK and Src phosphorylation western blots; cell adhesion assays Oncogene High 22710722
2012 AKAP12 depletion in zebrafish (akap12 morphants) causes severe hemorrhage due to disorganized interendothelial cell-cell adhesions; AKAP12 knockdown in endothelial cells reduces expression of PAK2 (actin cytoskeletal regulator) and AF6 (connector of intercellular adhesion molecules to actin); PAK2 or AF6 knockdown phenocopies AKAP12 depletion; overexpression of PAK2 and AF6 rescues hemorrhage in akap12 morphants. Zebrafish morpholino knockdown; in vivo time-lapse imaging; siRNA knockdown in cultured endothelial cells; PAK2/AF6 western blot; morphant rescue by PAK2+AF6 overexpression Experimental & molecular medicine High 22192928
2012 HDAC7 epigenetically silences AKAP12 in endothelial cells; siRNA depletion of HDAC7 causes H3 histone acetylation at the AKAP12 promoter, increasing AKAP12 mRNA and protein; elevated AKAP12 after HDAC7 depletion is responsible for inhibited migration and tube formation; AKAP12 mediates PKC-dependent phosphorylation of STAT3, which binds to the AKAP12 promoter and maintains elevated AKAP12 levels in a positive feedback loop. siRNA-mediated HDAC7 knockdown in HUVECs; proteomic analysis; ChIP for H3 acetylation; AKAP12 knockdown rescue; STAT3 ChIP at AKAP12 promoter; migration and tube formation assays Angiogenesis High 22584896
2013 AKAP12/gravin promoter contains two functional HIF-binding sites; site-directed mutagenesis identified the distal HIF-binding site as essential for hypoxia-induced gravin expression; gravin gain-of-function inhibits microvascular endothelial tube formation ('braking' system for angiogenesis); gravin functionally couples to control endothelial barrier function in response to PKA agonists. Cloned gravin promoter reporter assays; site-directed mutagenesis of HIF-binding sites; gravin gain/loss-of-function in endothelial cells; tube formation assays; transendothelial resistance measurements FASEB journal High 24029533
2014 PKA compartmentalization by AKAP12 is required for cAMP-mediated endothelial barrier stabilization; siRNA depletion of AKAP12 significantly impairs endothelial barrier function; AKAP12 depletion redistributes PKA and Rac1 away from endothelial junctions and inactivates Rac1; TAT-Ahx-AKAPis peptide (competitive PKA-AKAP disruptor) destabilizes barrier and dampens forskolin/rolipram-mediated barrier enhancement. siRNA knockdown in microvascular endothelial cells; transendothelial electrical resistance; in vivo microvessel hydraulic conductivity; immunofluorescence for PKA/Rac1 localization; Rac1 activity assay; co-immunoprecipitation PloS one High 25188285
2014 SSeCKS controls chemotaxis and lamellipodia formation by scaffolding phosphoinositides through its three MARCKS polybasic domains (PBD); loss of SSeCKS shifts leading edge from lamellipodia to filopodia-like extensions, enriches PIP3, Akt, PKC-ζ, Cdc42-GTP, and active Src at the leading edge, and recruits Frabin (Cdc42-GEF) via PIP2/3 binding; full-length SSeCKS or ΔPBD-deleted SSeCKS fails to rescue, whereas ΔSrc variant rescues, placing PIP scaffolding above Src-binding in chemotaxis control. SSeCKS-null MEF; domain deletion mutants (ΔPBD, ΔSrc); Frabin knockdown; leading-edge PIP3/Rac1/Cdc42 imaging; co-immunoprecipitation (negative for SSeCKS-Frabin/Cdc42/Rac1 interaction); PI3K constitutively-active epistasis PloS one High 25356636
2014 AKAP12 modulates meningeal EMT by regulating the TGF-β1-non-Smad-SNAI1 signaling pathway; AKAP12 expression in meningeal cells is regulated by integrated signals of TGF-β1, retinoic acid (RA), and oxygen tension; AKAP12-KO mice show impaired meningeal reconstruction after CNS injury. AKAP12-KO mice; CNS injury model; AKAP12 gain/loss-of-function in meningeal cells; TGF-β1/RA/oxygen tension manipulation; SNAI1 signaling analysis Nature communications Medium 25229625
2015 Hypoxia selectively induces AKAP12 variant 2 (AKAP12v2) in metastatic melanoma; AKAP12v2 causes a shift in PKA-mediated phosphorylation events (identified by kinome-wide phosphoproteomics and MS) under hypoxia; this shift is due to changes in AKAP12 localization rather than structural differences between variants; the AKAP12-dependent phosphorylation shift alters tumor cell invasion and migration in vitro and metastasis in vivo. Kinome-wide phosphoproteomic and MS analysis; siRNA knockdown; gain-of-function expression of specific variant; in vitro invasion/migration assays; in vivo orthotopic melanoma model; immunofluorescence for localization Proceedings of the National Academy of Sciences of the United States of America High 25792458
2016 AKAP12 scaffolds PKA to mediate phosphorylation of ATR at Ser435, a modification required for cAMP-enhanced nucleotide excision repair (NER); UV exposure promotes ATR-directed phosphorylation of AKAP12 at S732, driving nuclear translocation of the AKAP12-ATR-pS435 complex; this complex recruits XPA to UV-damaged DNA and enhances 5' strand incision; preventing AKAP12-PKA or AKAP12-ATR interaction abrogates ATR-pS435, delays XPA recruitment, impairs NER, and increases UV-induced mutagenesis. siRNA knockdown; AKAP12-PKA interaction-blocking mutants; AKAP12-ATR interaction mutants; NER assay (5' incision); XPA recruitment ChIP; phosphorylation site mutagenesis; UV mutagenesis assay Nucleic acids research High 27683220
2019 AKAP12 localizes to lamellipodia in migrating endothelial cells and to tip cells at the angiogenic front in postnatal retina; AKAP12 co-localizes with PKA type II-α regulatory subunit, Arp2/3 complex components, and VASP; AKAP12 deletion results in defective vascular plexus extension; VEGF-stimulated PKA-dependent phosphorylation of VASP at Ser157 requires AKAP12, demonstrated by co-localization of phospho-Ser157 VASP with AKAP12 at the leading edge. siRNA knockdown in human endothelial cells; AKAP12-/- mice; immunoprecipitation and mass spectrometry; postnatal retinal vascular imaging; VASP phosphorylation western blot; immunofluorescence co-localization Acta physiologica High 31162891
2020 AKAP12 loss in endothelial cells causes upregulation/activation of the Rho kinase pathway and increased endothelial permeability with dysregulation of ZO-1/Claudin-5; Rho kinase inhibitor Y-27632 reverses increased permeability in AKAP12-deficient cells and tightens the BBB in Akap12 knockout mice after stroke, placing AKAP12 upstream of the Rho kinase pathway in BBB maintenance. siRNA knockdown in cultured cerebral endothelial cells; Akap12 KO mice; stroke (focal ischemia) model; Rho kinase activity assay; permeability assay; Rho kinase inhibitor rescue; ZO-1/Claudin-5 western blot International journal of molecular sciences High 33260683
2020 Notch signaling suppresses Akap12 expression during renal tubule morphogenesis; loss of Notch signaling increases Akap12 expression and results in abnormally long primary cilia; ectopic Akap12 expression phenocopies Notch loss (long cilia, defective lumen formation); Akap12 inhibits Notch-mediated transcription, suggesting a negative feedback loop. Dominant-negative mastermind-like (dnMaml) expression in renal epithelia; Akap12 ectopic expression; primary cilia length measurement; organoid (spheroid) lumen formation assay; Notch transcriptional reporter assay FASEB journal Medium 32474964
2022 HDAC6 directly interacts with AKAP12 and deacetylates it at K526/K531; deacetylation of AKAP12 at K531 by HDAC6 increases its ubiquitination level, facilitating proteasome-dependent degradation; deletion of AKAP12 in HDAC6-knockdown cells restores cell motility defects and reactivates PKC isoforms, placing AKAP12 downstream of HDAC6-mediated degradation in colon cancer metastasis control. Proteomic analysis; co-immunoprecipitation of HDAC6-AKAP12; site-specific acetylation mapping (K526/K531); ubiquitination assay; AKAP12 deletion rescue in HDAC6-KD cells; PKC activity assays Cancer letters High 36122629
2024 AKAP12 overexpression in cardiac myocytes reduces total intracellular cAMP levels through PDE8 (not PDE4D); AKAP12-overexpressing mice show reduced cardiomyocyte contractility and impaired calcium handling in response to isoproterenol, reversed by selective PDE8 inhibitor (PF-04957325); AKAP12OX mice develop systolic dysfunction and left ventricular enlargement; patients with end-stage heart failure show upregulated AKAP12. Luciferase-based cAMP biosensor (GloSensor) in AC16 cardiomyocytes; adult primary cardiomyocyte contractility and calcium imaging; AKAP12 cardiac-specific overexpression mouse model; PDE8 inhibitor rescue; left ventricular function echocardiography Circulation research High 38506047
1999 SSeCKS/clone 72 contains a PKA RII-binding domain (aa 1495-1524) identified by deletion mutagenesis, confirming it is an AKAP; PKC-induced serine phosphorylation of SSeCKS causes rapid translocation to perinuclear sites, coincident with retraction of stellate processes in mesangial cells; ablation of SSeCKS by antisense retroviral vectors induces fibroblastic morphology, thick longitudinal stress fibers, and repositioning of vinculin-associated focal complexes. Deletion mutagenesis for RII binding; retroviral antisense vector knockdown; PKC activation with phorbol ester; bis-indolylmaleimide PKC inhibitor; immunofluorescence for SSeCKS, F-actin, vinculin Journal of cell science / European journal of biochemistry High 10469144 9885289
2002 SSeCKS tyrosine phosphorylation by mitogens (EGF, PDGF, serum) is FAK-dependent: FAK-deficient cells cannot phosphorylate SSeCKS upon EGF stimulation, rescued by re-expression of wild-type FAK but not FAK-Y397 mutant; purified FAK or Src fail to directly phosphorylate SSeCKS in vitro; phosphorylation is independent of Src/Fyn/Yes/Abl; unphosphorylated bacterially expressed SSeCKS co-sediments with F-actin; tyrosine phosphorylation modulates SSeCKS-actin interaction. FAK-/- MEF complementation; in vitro kinase assays with purified enzymes; [32P] metabolic labeling; F-actin co-sedimentation ultracentrifugation; immunofluorescence; coprecipitation with biotin-phalloidin Experimental cell research High 12083796
2008 AKAP12/gravin is selectively required for resensitization and recycling of the beta2-adrenergic receptor: AKAP12 knockdown in A431 or HEK293 cells abolishes receptor resensitization, while AKAP5 knockdown does not; AKAP5 knockdown abolishes Erk1/2 activation downstream of beta2AR while AKAP12 knockdown does not, demonstrating non-redundant pathway segregation between the two AKAPs. siRNA knockdown of AKAP5 or AKAP12 in A431 and HEK293 cells; beta2AR resensitization assay; ERK1/2 phosphorylation assay; receptor recycling assay Journal of molecular signaling High 19055733
2011 AKAP12 forms higher-order homo-oligomers (behaving as dimers or tetramers ~840 kDa by steric-exclusion chromatography); both N-terminal (aa 1-840) and C-terminal (aa 840-1782) regions independently form dimers; AKAP12 and AKAP5 form hetero-oligomers demonstrated by affinity chromatography and steric-exclusion chromatography; beta-adrenergic agonist stimulation increases AKAP5-AKAP12 docking 4-fold; AKAP12 overexpression potentiates AKAP5-mediated ERK1/2 activation. SDS-PAGE/urea denaturation; steric-exclusion chromatography; affinity chromatography with immobilized AKAPs; co-immunoprecipitation; ERK1/2 phosphorylation assay with agonist stimulation Journal of molecular signaling Medium 21554706 21831305
2017 Stromal SSeCKS/AKAP12 suppresses metastatic peritoneal colonization by attenuating secretion of Cxcl9/10 from peritoneal membrane fibroblasts; SSeCKS-null peritoneal fibroblasts exhibit senescence (SA-β-gal, p21, p16) and secrete elevated Cxcl10 in response to inflammatory mediators; Cxcr3 knockdown abrogates enhanced chemotaxis to KO peritoneal fluid; SSeCKS scaffolding-site mutants and kinase inhibitors show PKC, PKA, and PI3K/Akt pathways are responsible for Cxcl10 secretion control. SSeCKS-null mice; peritoneal fluid adoptive transfer; Cxcr3 knockdown; Cxcl10 neutralizing antibody; conditioned media from KO peritoneal membrane fibroblasts; SSeCKS scaffolding-site mutants; kinase inhibitors; senescence markers Oncotarget High 29050279
2018 SSeCKS/AKAP12 in lung fibroblasts suppresses metastatic melanoma colonization by attenuating Src/STAT3-dependent senescence-associated secretory phenotype; SSeCKS Src-scaffolding domain is required to attenuate IFNα-induced Stat3 activation in KO lung fibroblasts; KO lung endothelial cells exhibit increased E-Selectin levels facilitating melanoma adhesion. SSeCKS-null syngeneic mouse hosts; lung fibroblast conditioned media; co-injection of cancer cells with KO or WT lung fibroblasts; Stat3 activation assays; SSeCKS Src-scaffolding domain mutants; E-Selectin western blot Oncotarget Medium 30323895
2018 HDAC3 directly binds within the intron-1 region of AKAP12 and this binding is indispensable for HDAC3-mediated inhibition of AKAP12 expression; HDAC3 inhibitors (TSA, RGFP966) restore AKAP12 expression; AKAP12 knockdown increases PI3K/AKT signaling activity, establishing PI3K/AKT as downstream of AKAP12 in colorectal cancer cells. ChIP for HDAC3 binding at AKAP12 intron-1; HDAC3 inhibitor treatment (TSA, RGFP966); AKAP12 siRNA knockdown; PI3K/AKT pathway western blot; colony formation and migration assays International journal of oncology Medium 29484387
2015 SSeCKS expression is decreased in differentiated Schwann cells; long-term SSeCKS knockdown changes Schwann cell morphology, accelerates myelin gene expression induced by cAMP, and enhances myelination in Schwann cell-DRG co-culture; SSeCKS suppression promotes Akt (Ser473) phosphorylation in cAMP-treated Schwann cells, identifying SSeCKS as a negative regulator of Schwann cell myelination. SSeCKS siRNA/antisense knockdown in Schwann cells; DRG co-culture myelination assay; myelin gene expression (RT-PCR); Akt phosphorylation western blot Neurochemical research Medium 19757038

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nature medicine 388 12808449
2001 The Src-suppressed C kinase substrate, SSeCKS, is a potential metastasis inhibitor in prostate cancer. Cancer research 111 11454719
2000 SSeCKS, a major protein kinase C substrate with tumor suppressor activity, regulates G(1)-->S progression by controlling the expression and cellular compartmentalization of cyclin D. Molecular and cellular biology 107 10982843
2003 Protein kinase A regulates AKAP250 (gravin) scaffold binding to the beta2-adrenergic receptor. The EMBO journal 97 14657015
2010 Emerging Roles for SSeCKS/Gravin/AKAP12 in the Control of Cell Proliferation, Cancer Malignancy, and Barriergenesis. Genes & cancer 86 21779438
2007 AKAP12 regulates human blood-retinal barrier formation by downregulation of hypoxia-inducible factor-1alpha. The Journal of neuroscience : the official journal of the Society for Neuroscience 86 17442832
2004 AKAP12/Gravin is inactivated by epigenetic mechanism in human gastric carcinoma and shows growth suppressor activity. Oncogene 86 15258566
2009 SSeCKS/Gravin/AKAP12 inhibits cancer cell invasiveness and chemotaxis by suppressing a protein kinase C- Raf/MEK/ERK pathway. The Journal of biological chemistry 78 20018890
2018 Long noncoding RNA MALAT1 enhances the docetaxel resistance of prostate cancer cells via miR-145-5p-mediated regulation of AKAP12. Journal of cellular and molecular medicine 77 29633510
2002 The role of SSeCKS/gravin/AKAP12 scaffolding proteins in the spaciotemporal control of signaling pathways in oncogenesis and development . Frontiers in bioscience : a journal and virtual library 75 12133808
1998 Control of cytoskeletal architecture by the src-suppressed C kinase substrate, SSeCKS. Cell motility and the cytoskeleton 75 9744295
2012 Suppression of tumor and metastasis progression through the scaffolding functions of SSeCKS/Gravin/AKAP12. Cancer metastasis reviews 73 22684366
1997 Reexpression of the major protein kinase C substrate, SSeCKS, suppresses v-src-induced morphological transformation and tumorigenesis. Cancer research 69 9187136
2008 Loss of the SSeCKS/Gravin/AKAP12 gene results in prostatic hyperplasia. Cancer research 68 18593908
2006 SSeCKS metastasis-suppressing activity in MatLyLu prostate cancer cells correlates with vascular endothelial growth factor inhibition. Cancer research 67 16740695
2008 Hypermethylation of the AKAP12 promoter is a biomarker of Barrett's-associated esophageal neoplastic progression. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 65 18199717
2012 Pivotal Role of AKAP12 in the Regulation of Cellular Adhesion Dynamics: Control of Cytoskeletal Architecture, Cell Migration, and Mitogenic Signaling. Journal of signal transduction 63 22811901
2010 Rb-dependent cellular senescence, multinucleation and susceptibility to oncogenic transformation through PKC scaffolding by SSeCKS/AKAP12. Cell cycle (Georgetown, Tex.) 62 21099353
1999 Involvement of the protein kinase C substrate, SSeCKS, in the actin-based stellate morphology of mesangial cells. Journal of cell science 53 9885289
2000 A role for SSeCKS, a major protein kinase C substrate with tumour suppressor activity, in cytoskeletal architecture, formation of migratory processes, and cell migration during embryogenesis. The Histochemical journal 50 10805381
2015 Hypoxic induction of AKAP12 variant 2 shifts PKA-mediated protein phosphorylation to enhance migration and metastasis of melanoma cells. Proceedings of the National Academy of Sciences of the United States of America 47 25792458
2015 MiR-103 regulates hepatocellular carcinoma growth by targeting AKAP12. The international journal of biochemistry & cell biology 46 26646106
2004 Multiple promoters direct expression of three AKAP12 isoforms with distinct subcellular and tissue distribution profiles. The Journal of biological chemistry 45 15496411
2019 AKAP12 deficiency impairs VEGF-induced endothelial cell migration and sprouting. Acta physiologica (Oxford, England) 43 31162891
2012 The angiogenesis suppressor gene AKAP12 is under the epigenetic control of HDAC7 in endothelial cells. Angiogenesis 43 22584896
2012 Adhesion-mediated cytoskeletal remodeling is controlled by the direct scaffolding of Src from FAK complexes to lipid rafts by SSeCKS/AKAP12. Oncogene 43 22710722
2014 PKA compartmentalization via AKAP220 and AKAP12 contributes to endothelial barrier regulation. PloS one 42 25188285
2002 Calmodulin and cyclin D anchoring sites on the Src-suppressed C kinase substrate, SSeCKS. Biochemical and biophysical research communications 42 11820772
2001 Functional interaction between the SSeCKS scaffolding protein and the cytoplasmic domain of beta1,4-galactosyltransferase. Journal of cell science 41 11493668
1997 Cell-cycle regulated expression and serine phosphorylation of the myristylated protein kinase C substrate, SSeCKS: correlation with culture confluency, cell cycle phase and serum response. Molecular and cellular biochemistry 39 9350056
2007 AKAP12 induces apoptotic cell death in human fibrosarcoma cells by regulating CDKI-cyclin D1 and caspase-3 activity. Cancer letters 38 17442483
2011 Temporal profile of Src, SSeCKS, and angiogenic factors after focal cerebral ischemia: correlations with angiogenesis and cerebral edema. Neurochemistry international 37 21334414
2011 Identification of the A kinase anchor protein 12 (AKAP12) gene as a candidate tumor suppressor of hepatocellular carcinoma. Journal of surgical oncology 37 22052684
2006 G-Protein-coupled receptor-associated A-kinase anchoring proteins: AKAP79 and AKAP250 (gravin). European journal of cell biology 37 16442664
2006 SSeCKS/Gravin/AKAP12 metastasis suppressor inhibits podosome formation via RhoA- and Cdc42-dependent pathways. Molecular cancer research : MCR 37 16547152
2022 HDAC6-dependent deacetylation of AKAP12 dictates its ubiquitination and promotes colon cancer metastasis. Cancer letters 35 36122629
2007 v-Src-mediated down-regulation of SSeCKS metastasis suppressor gene promoter by the recruitment of HDAC1 into a USF1-Sp1-Sp3 complex. The Journal of biological chemistry 34 17626016
2012 SSeCKS sequesters cyclin D1 in glomerular parietal epithelial cells and influences proliferative injury in the glomerulus. Laboratory investigation; a journal of technical methods and pathology 33 22249313
2008 G-protein-coupled receptor-associated A-kinase anchoring proteins AKAP5 and AKAP12: differential signaling to MAPK and GPCR recycling. Journal of molecular signaling 33 19055733
2020 AKAP12 Signaling Complex: Impacts of Compartmentalizing cAMP-Dependent Signaling Pathways in the Heart and Various Signaling Systems. Journal of the American Heart Association 32 32573313
2012 AKAP12 regulates vascular integrity in zebrafish. Experimental & molecular medicine 32 22192928
2022 AKAP12 ameliorates liver injury via targeting PI3K/AKT/PCSK6 pathway. Redox biology 31 35576690
2018 Upregulation of AKAP12 with HDAC3 depletion suppresses the progression and migration of colorectal cancer. International journal of oncology 30 29484387
2014 AKAP12 mediates barrier functions of fibrotic scars during CNS repair. PloS one 30 24760034
2007 AKAP12, a gene with tumour suppressor properties, is a target of promoter DNA methylation in childhood myeloid malignancies. British journal of haematology 30 17686059
2014 Prompt meningeal reconstruction mediated by oxygen-sensitive AKAP12 scaffolding protein after central nervous system injury. Nature communications 29 25229625
2011 Control of protein kinase C activity, phorbol ester-induced cytoskeletal remodeling, and cell survival signals by the scaffolding protein SSeCKS/GRAVIN/AKAP12. The Journal of biological chemistry 28 21903576
2011 Re-expression of AKAP12 inhibits progression and metastasis potential of colorectal carcinoma in vivo and in vitro. PloS one 28 21918680
2002 Mitogen-induced, FAK-dependent tyrosine phosphorylation of the SSeCKS scaffolding protein. Experimental cell research 28 12083796
2019 MicroRNA-1251-5p promotes tumor growth and metastasis of hepatocellular carcinoma by targeting AKAP12. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 27 31918285
2018 Kinome and phosphoproteome of high-grade meningiomas reveal AKAP12 as a central regulator of aggressiveness and its possible role in progression. Scientific reports 27 29391485
2010 Rapid determination of AKAP12 promoter methylation levels in peripheral blood using methylation-sensitive high resolution melting (MS-HRM) analysis: application in colorectal cancer. Clinica chimica acta; international journal of clinical chemistry 27 20227403
2006 SSeCKS/Gravin/AKAP12 attenuates expression of proliferative and angiogenic genes during suppression of v-Src-induced oncogenesis. BMC cancer 27 16638134
2002 Induction of Src-suppressed C kinase substrate (SSeCKS) in vascular endothelial cells by bacterial lipopolysaccharide. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 26 11799143
1999 Developmental expression of the protein kinase C substrate/binding protein (clone 72/SSeCKS) in rat testis identification as a scaffolding protein containing an A-kinase-anchoring domain which is expressed during late-stage spermatogenesis. European journal of biochemistry 26 10469144
2020 AKAP12 Supports Blood-Brain Barrier Integrity against Ischemic Stroke. International journal of molecular sciences 25 33260683
2010 SERPINB5 and AKAP12 - expression and promoter methylation of metastasis suppressor genes in pancreatic ductal adenocarcinoma. BMC cancer 25 20939879
2001 Expression of a down-regulated target, SSeCKS, reverses v-Jun-induced transformation of 10T1/2 murine fibroblasts. Oncogene 25 11313943
2018 Altered AKAP12 expression in portal fibroblasts and liver sinusoids mediates transition from hepatic fibrogenesis to fibrosis resolution. Experimental & molecular medicine 24 29700280
2016 Epigenetic silencing of AKAP12 in juvenile myelomonocytic leukemia. Epigenetics 24 26891149
2010 Quantitative assessment of AKAP12 promoter methylation in colorectal cancer using methylation-sensitive high resolution melting: Correlation with Duke's stage. Cancer biology & therapy 23 20364105
2008 AKAP12 in astrocytes induces barrier functions in human endothelial cells through protein kinase Czeta. The FEBS journal 22 18397319
2020 Long Non-Coding RNA MEG3 Modifies Cell-Cycle, Migration, Invasion, and Proliferation Through AKAP12 by Sponging miR-29c in Meningioma Cells. Frontiers in oncology 21 33251130
2018 A-kinase anchor protein 12 (AKAP12) inhibits cell migration in breast cancer. Experimental and molecular pathology 21 30385176
2013 HIF-dependent regulation of AKAP12 (gravin) in the control of human vascular endothelial function. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 24029533
2016 AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair. Nucleic acids research 20 27683220
2009 Dexamethasone inhibits proliferation and stimulates SSeCKS expression in C6 rat glioma cell line. Brain research 20 19368818
2018 LipoxinA4 attenuates acute pancreatitis-associated acute lung injury by regulating AQP-5 and MMP-9 expression, anti-apoptosis and PKC/SSeCKS-mediated F-actin activation. Molecular immunology 19 30219663
2008 G-protein-coupled receptor-associated A-kinase anchoring proteins AKAP5 and AKAP12: differential trafficking and distribution. Cellular signalling 19 18950703
2005 Cross-species sequence analysis reveals multiple charged residue-rich domains that regulate nuclear/cytoplasmic partitioning and membrane localization of a kinase anchoring protein 12 (SSeCKS/Gravin). The Journal of biological chemistry 19 15923193
2023 Endothelial deletion of EPH receptor A4 alters single-cell profile and Tie2/Akap12 signaling to preserve blood-brain barrier integrity. Proceedings of the National Academy of Sciences of the United States of America 18 37796990
2020 LINC00163 inhibits the invasion and metastasis of gastric cancer cells as a ceRNA by sponging miR-183 to regulate the expression of AKAP12. International journal of clinical oncology 18 31894433
2024 AKAP12 positive fibroblast determines immunosuppressive contexture and immunotherapy response in patients with TNBC by promoting macrophage M2 polarization. Journal for immunotherapy of cancer 17 39448199
2019 Effect of the SSeCKS-TRAF6 interaction on gastrodin-mediated protection against 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced astrocyte activation and neuronal death. Chemosphere 17 30959452
2019 MiR-338-3p improved lung adenocarcinoma by AKAP12 suppression. Archives of medical science : AMS 17 33747281
2020 Notch signaling regulates Akap12 expression and primary cilia length during renal tubule morphogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 32474964
2014 2,3,7,8-Tetrachlorodibenzo-p-dioxin promotes astrocyte activation and the secretion of tumor necrosis factor-α via PKC/SSeCKS-dependent mechanisms. Journal of neurochemistry 16 24673440
2010 Examination of AKAP12 promoter methylation in skin cancer using methylation-sensitive high-resolution melting analysis. Clinical and experimental dermatology 16 21198787
2021 Goat AKAP12: Indel Mutation Detection, Association Analysis With Litter Size and Alternative Splicing Variant Expression. Frontiers in genetics 15 34093646
2018 Blockage of AKAP12 accelerates angiotensin II (Ang II)-induced cardiac injury in mice by regulating the transforming growth factor β1 (TGF-β1) pathway. Biochemical and biophysical research communications 15 29501491
2011 Quantitative assessment of AKAP12 promoter methylation in human prostate cancer using methylation-sensitive high-resolution melting: correlation with Gleason score. Urology 15 21310466
2022 Physiologic and pathophysiologic roles of AKAP12. Science progress 14 35775596
2011 Role for transcription factor TFII-I in the suppression of SSeCKS/Gravin/Akap12 transcription by Src. International journal of cancer 14 20568114
2011 AKAP12 and AKAP5 form higher-order hetero-oligomers. Journal of molecular signaling 14 21831305
2009 SSeCKS is a suppressor in Schwann cell differentiation and myelination. Neurochemical research 14 19757038
2007 Lipopolysaccharide induces expression of SSeCKS in rat lung microvascular endothelial cell. Molecular and cellular biochemistry 14 17551670
2001 Gene trap insertion reveals two open reading frames in the mouse SSeCKS gene: the form predominantly detected in the nervous system is suppressed by the insertion while the other, specific of the testis, remains expressed. Mechanisms of development 14 11429284
2021 Upregulated PPARG2 facilitates interaction with demethylated AKAP12 gene promoter and suppresses proliferation in prostate cancer. Cell death & disease 13 34023860
2021 Overexpression of miR-146a promotes cell proliferation and migration in a model of diabetic foot ulcers by regulating the AKAP12 axis. Endocrine journal 12 34483150
2017 SSeCKS/AKAP12 scaffolding functions suppress B16F10-induced peritoneal metastasis by attenuating CXCL9/10 secretion by resident fibroblasts. Oncotarget 12 29050279
2011 AKAP5 and AKAP12 Form Homo-oligomers. Journal of molecular signaling 12 21554706
2008 Spatiotemporal expression of SSeCKS in injured rat sciatic nerve. Anatomical record (Hoboken, N.J. : 2007) 11 18384053
2024 AKAP12 Upregulation Associates With PDE8A to Accelerate Cardiac Dysfunction. Circulation research 10 38506047
2004 The expression of src-suppressed C kinase substrate (SSeCKS) and uptake of exogenous particles in endothelial and reticular cells. Archives of histology and cytology 10 15468953
2002 SSeCKS immunolabeling in rat primary sensory neurons. Brain research 10 11814414
2021 Exploration of Genetic Variants within the Goat A-Kinase Anchoring Protein 12 (AKAP12) Gene and Their Effects on Growth Traits. Animals : an open access journal from MDPI 9 34359218
2019 AKAP12 Endogenous Transcripts Suppress The Proliferation, Migration And Invasion Of Colorectal Cancer Cells By Directly Targeting oncomiR-183-5p. OncoTargets and therapy 9 31632079
2014 Suppression of chemotaxis by SSeCKS via scaffolding of phosphoinositol phosphates and the recruitment of the Cdc42 GEF, Frabin, to the leading edge. PloS one 9 25356636
2018 SSeCKS/Akap12 suppresses metastatic melanoma lung colonization by attenuating Src-mediated pre-metastatic niche crosstalk. Oncotarget 8 30323895
2015 HSPA12B regulates SSeCKS-mediated astrocyte inflammatory activation in neuroinflammation. Experimental cell research 8 26428665

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