Gene Ontology annotation through association of InterPro records with GO terms
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Gene Ontology annotation based on curation of immunofluorescence data
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
AKAP12 PKC and calmodulin motif bioinformatics
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Human AKAP12 has three WSK calmodulin-binding motifs, and the two rodent PKC-binding motif matches overlap the first two human WSK motifs.
"So the human protein has **three** WSK motifs, of which **two** also match the PKC-binding consensus, and the third (801-821) does not."
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The scan supports motif presence and overlap but is not an activity or binding assay.
"Nothing here demonstrates human PKC binding or human CaM binding."
Gravin, an autoantigen recognized by serum from myasthenia gravis patients, is a kinase scaffold protein.
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Human gravin binds the RII regulatory subunit of PKA with high affinity through residues 1526-1780 and binds protein kinase C through residues 265-556; a PKA-gravin complex is isolable from human erythroleukemia cells.
"residues 1526-1780 of gravin bind the regulatory subunit (RII) of protein kinase A with high affinity, and residues 265-556 bind protein kinase C"
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Human gravin is concentrated at the cell periphery and enriched in filopodia, and its staining coincides with an AKAP detected by in situ RII overlay.
"gravin is concentrated at the cell periphery and is enriched in filopodia"
Molecular cloning and preliminary characterization of a novel cytoplasmic antigen recognized by myasthenia gravis sera.
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Gravin was cloned from an endothelial expression library using myasthenia gravis serum; it is a 250 kDa cytoplasmic protein of endothelial and adherent cells, absent from platelets and leukocytes, and inducible in HEL cells by phorbol ester.
"Gravin was not detected in platelets, leukocytes, U937, or human erythroleukemic (HEL) cell lines, but was expressed in HEL cells after induction with phorbol myristate acetate."
Gravin-mediated formation of signaling complexes in beta 2-adrenergic receptor desensitization and resensitization.
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Agonist stimulation drives assembly of a receptor-gravin complex containing PKA, PKC, GRK2, beta-arrestin and clathrin, and antisense suppression of gravin blocks both that assembly and receptor recovery from desensitisation.
"Suppression of gravin expression via antisense oligodeoxynucleotides disrupted agonist-induced association of the receptor with G-protein-linked receptor kinase-2, beta-arrestin, and clathrin as well as receptor recovery from desensitization."
An anchored PKA and PDE4 complex regulates subplasmalemmal cAMP dynamics.
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RNA interference against membrane-associated AKAPs in human HEK293 cells identified gravin as the organiser of a PDE4 complex that terminates subplasmalemmal cAMP transients.
"Knockdown of specific membrane-associated AKAPs using RNAi identified gravin (AKAP250) as the central organizer of the PDE4 complex."
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Co-immunoprecipitation confirms that gravin maintains a signalling complex containing PKA and PDE4D.
"Co-immunoprecipitation confirmed that gravin maintains a signaling complex that includes PKA and PDE4D."
Role of protein kinase C-dependent A-kinase anchoring proteins in lysophosphatidic acid-induced cAMP signaling in human diploid fibroblasts.
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In human diploid fibroblasts gravin co-immunoprecipitates adenylate cyclase types 4 and 6 but not type 2, and siRNA against gravin greatly reduces basal cAMP and reverses the cAMP response to lysophosphatidic acid.
"Co-immunoprecipitation experiments revealed that Gravin and AKAP79 do not associate with adenylyl cyclase type 2 (AC2) but bind to AC4/6"
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The authors conclude that gravin couples adenylate cyclase to inhibitory signals in young cells and to stimulatory signals in senescent cells - a bidirectional, age-dependent role.
"may play important roles in maintaining the basal AC activity and in coupling the AC systems to inhibitory signals such as Gialpha in young cells, and to stimulatory signals such as PKCs in senescent cells"
G-protein-coupled receptor-associated A-kinase anchoring proteins AKAP5 and AKAP12: differential signaling to MAPK and GPCR recycling.
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Knocking down AKAP12 in A431 or HEK293 cells abolishes beta2-adrenergic receptor resensitisation, whereas knocking down AKAP5 does not; the reciprocal readout, ERK1/2 activation, depends on AKAP5 and not AKAP12.
"Suppression of the expression of AKAP12 in either cell line leads to loss of the ability of these cells to resensitize the beta2-adrenergic receptor."
Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.
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A modified membrane yeast two-hybrid screen against ligand-unoccupied EGFR returned 87 candidate interactors; the paper follows up HDAC6 and does not discuss AKAP12.
"We used a modified membrane yeast two-hybrid system together with bioinformatics to identify 87 candidate proteins interacting with the ligand-unoccupied EGFR."
A comprehensive resource of interacting protein regions for refining human transcription factor networks.
Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation.
A directed protein interaction network for investigating intracellular signal transduction.
A human skeletal muscle interactome centered on proteins involved in muscular dystrophies: LGMD interactome.
Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).
OpenCell: Endogenous tagging for the cartography of human cellular organization.
Control of cytoskeletal architecture by the src-suppressed C kinase substrate, SSeCKS.
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Tetracycline-regulated induction of SSeCKS in NIH3T3 fibroblasts elaborates a detergent-resistant cortical cytoskeletal matrix, flattens cells, and transiently removes actin stress fibres and vinculin-associated adhesion plaques.
"The induction of SSeCKS (removal of tet) caused significant cell flattening and the elaboration of an SSeCKS-associated cortical cytoskeletal matrix resistant to Triton X-100 extraction."
Involvement of the protein kinase C substrate, SSeCKS, in the actin-based stellate morphology of mesangial cells.
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SSeCKS is enriched in mesangial cell podosomes and along a cytoskeletal network that the authors state is distinct from F-actin; antisense ablation repositions vinculin-associated focal complexes.
"enrichment of SSeCKS in mesangial cell podosomes and along a cytoskeletal network distinct from F-actin"
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.
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Deletion mutagenesis localises the RII-interacting element of rat clone 72/SSeCKS to residues 1495-1524, independently confirming the C-terminal AKAP helix.
"Deletion mutagenesis demonstrated that amino acids 1495-1524 of clone 72/SSeCKS had the ability to interact with RII."
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.
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Bacterially expressed SSeCKS CY motifs bind cyclins D1 and E, and lysine-to-serine mutation of either motif ablates binding; PKC activation releases cyclin D1 from cytoplasmic sequestration.
"Bacterially expressed SSeCKS-CY bound cyclins D1 and E, whereas K-->S mutations within either CY motif ablated binding."
Calmodulin and cyclin D anchoring sites on the Src-suppressed C kinase substrate, SSeCKS.
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Four calmodulin-binding sites conforming to the 1-5-10 motif were mapped in vitro on SSeCKS, and calmodulin binding is antagonised by prior PKC phosphorylation.
"Four CaM binding sites were identified by binding assays that conform to the so-called 1-5-10 motif."
Mitogen-induced, FAK-dependent tyrosine phosphorylation of the SSeCKS scaffolding protein.
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Bacterially expressed unphosphorylated SSeCKS co-sediments with F-actin, and in FAK+/+ cells the protein stains the cell edge and a cortical cytoskeletal matrix rather than stress fibres.
"in FAK-/- cells, SSeCKS costains along F-actin stress fibers, in contrast to FAK+/+ cells, where most SSeCKS stains at the cell edge and along a cortical cytoskeletal matrix"
SSeCKS immunolabeling in rat primary sensory neurons.
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Immunofluorescence of rat brain, spinal cord and dorsal root ganglia labels SSeCKS in neuronal cell bodies of a restricted nociceptive sensory population.
"A small portion of the SSeCKS-labeled cell bodies appeared to represent a subpopulation of substance P (4.8%) and CGRP (4.7%) containing neurons"
Src suppressed C kinase substrate regulates the lipopolysaccharide-induced TNF-alpha biosynthesis in rat astrocytes.
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siRNA knockdown of SSeCKS in rat astrocytes partly inhibits LPS-induced signalling, including ERK activation and TNF-alpha production.
"By using siRNA knockdown of SSeCKS expression, LPS-induced signaling events were partly inhibited"
A critical role of SRC-suppressed C kinase substrate in rat astrocytes after chronic constriction injury.
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Silencing SSeCKS in rat spinal astrocytes prevents the rise in phospho-ERK and pro-inflammatory cytokines after stimulation by damaged sensory neurons.
"SSeCKS gene silencing by siRNA inhibited the up-regulation of p-ERK and the pro-inflammation cytokines"
Involvement of Src-suppressed C kinase substrate in experimental autoimmune encephalomyelitis: a link between release of astrocyte proinflammatory factor and oligodendrocyte apoptosis.
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siRNA against SSeCKS in rat astrocytes blocks TNF-alpha and nitric oxide induction and prevents astrocyte-conditioned medium from killing oligodendrocytes.
"siRNA targeted to SSeCKS in astrocytes inhibited oligodendrocyte cell death"
Role of src-suppressed C kinase substrate in rat pulmonary microvascular endothelial hyperpermeability stimulated by inflammatory cytokines.
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Depleting SSeCKS in rat pulmonary microvascular endothelial cells attenuates the cytokine-induced fall in transendothelial resistance and rise in dextran flux; the authors conclude SSeCKS is involved in endothelial hyperpermeability.
"Depletion of endogenous SSeCKS in RPMVEC significantly attenuated cytokine-induced decrease in TER and increase in P (d), but not to the basal levels."
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IL-1beta and TNF-alpha applied directly to the same cells activate PKC signalling and up-regulate SSeCKS message and protein.
"IL-1β and TNF-α activated the PKC signaling pathway in RPMVEC, and up-regulated the gene and protein expression of SSeCKS."
Vagal efferent fiber stimulation ameliorates pulmonary microvascular endothelial cell injury by downregulating inflammatory responses.
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In LPS-induced rat acute lung injury, vagus nerve stimulation reduces lung injury markers and lowers SSeCKS protein in lung tissue.
"vagus nerve stimulation not only decreased the expressions of Src-suppressed C kinase substrate and E-selectin proteins in lung tissue"
Increased SSeCKS expression in rat hepatic stellate cells upon activation in vitro and in vivo.
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SSeCKS message and protein rise in CCl4-injured rat liver and in primary hepatic stellate cells activating in vitro; the functional interpretation is offered as a possibility rather than a result.
"The upregulation of SSeCKS protein expression in rat HSCs during activation in vitro and in vivo suggested the possibility of SSeCKS, an important part of function of the activated HSCs, perhaps through modulation of liver regeneration or formation of liver fibrosis after various injuries."
Control of protein kinase C activity, phorbol ester-induced cytoskeletal remodeling, and cell survival signals by the scaffolding protein SSeCKS/GRAVIN/AKAP12.
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Two homologous motifs mediate phosphatidylserine-independent binding of PKC by SSeCKS, and that binding lowers PKC-alpha kinase activity; SSeCKS-null fibroblasts show raised PKC activity, rescued by full-length but not PKC-binding-domain-deleted protein.
"SSeCKS binding to PKCα decreased kinase activity and was dependent on the two PKC-binding motifs."
PKA compartmentalization via AKAP220 and AKAP12 contributes to endothelial barrier regulation.
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siRNA-mediated AKAP12 knockdown impairs endothelial barrier function and abolishes cAMP-mediated barrier stabilisation; the knockdown used mouse-specific siRNA in MyEnd mouse endothelial cells.
"Down-regulation of mouse specific AKAP12- and AKAP220 mRNA was obtained by using ON-Target SMARTpool siRNA"
SSeCKS/Gravin/AKAP12 inhibits cancer cell invasiveness and chemotaxis by suppressing a protein kinase C- Raf/MEK/ERK pathway.
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SSeCKS suppresses serum-induced Raf/MEK/ERK activation with consequent loss of MMP-2 expression, and its suppression of phorbol-ester-induced ERK1/2 activity requires the PKC-binding domain (aa 553-900), implying the effect runs through direct PKC scaffolding.
"SSeCKS suppressed serum-induced activation of the Raf/MEK/ERK pathway, resulting in down-regulation of matrix metalloproteinase-2 expression."
SSeCKS/Gravin/AKAP12 metastasis suppressor inhibits podosome formation via RhoA- and Cdc42-dependent pathways.
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Re-expressing SSeCKS at physiological levels in v-Src-transformed NIH3T3 cells suppresses podosome formation and lowers RhoA and Cdc42 activity more than fivefold; activated RhoA or Cdc42 rescues podosomes.
"this correlated with the ability of SSeCKS to inhibit RhoA and Cdc42 activity levels by >5-fold"
AKAP12 Supports Blood-Brain Barrier Integrity against Ischemic Stroke.
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siRNA against AKAP12 in cultured cerebral endothelial cells raises permeability and dysregulates ZO-1 and claudin-5 through Rho kinase activation; Akap12 knockout mice sustain greater blood-brain barrier damage after stroke, mitigated by Y-27632.
"When AKAP12 expression was suppressed by an siRNA approach in cultured endothelial cells, endothelial permeability was increased along with the dysregulation of ZO-1/Claudin 5 expression."
AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair.
Retraction: AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair.
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The authors requested retraction of PMID:27683220 following a University of Kentucky investigation that found fabricated and/or falsified data.
"an internal investigation by a team of scientists at the University of Kentucky that recently determined it contains fabricated and/or falsified data"