{"gene":"RACK1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1998,"finding":"RACK1 interacts with integrin β subunit cytoplasmic domains via WD repeats 5–7; full-length RACK1 association with integrins in vivo requires phorbol ester treatment, suggesting RACK1 links PKC to integrins to regulate integrin function.","method":"Yeast two-hybrid, co-immunoprecipitation in 293T and JY cells, deletion mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP in two cell lines plus yeast two-hybrid domain mapping, single lab but multiple orthogonal methods","pmids":["9442085"],"is_preprint":false},{"year":2002,"finding":"RACK1 binds both the NR2B subunit of the NMDA receptor and Fyn tyrosine kinase, acting as an inhibitory scaffold; RACK1 inhibits Fyn-mediated phosphorylation of NR2B and decreases NMDA receptor-mediated currents in hippocampal slices. Disrupting RACK1–NR2B–Fyn interactions with peptides induces NR2B phosphorylation and potentiates NMDA currents.","method":"Co-immunoprecipitation, electrophysiology in CA1 hippocampal slices, cell-permeable peptide disruption assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional electrophysiology with peptide disruption, single lab but multiple orthogonal methods","pmids":["11943848"],"is_preprint":false},{"year":2002,"finding":"RACK1 is a substrate of Src tyrosine kinase; Src phosphorylates RACK1 on Tyr228 and/or Tyr246 (located in the sixth WD repeat), and this phosphorylation is required for RACK1 binding to Src's SH2 domain following PKC activation.","method":"In vitro kinase assay with various tyrosine kinases, in vivo kinase-active/inactive Src mutants, site-directed mutagenesis of RACK1 tyrosines","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay combined with mutagenesis and in vivo validation, single lab with orthogonal methods","pmids":["12400005"],"is_preprint":false},{"year":2003,"finding":"RACK1 regulates focal adhesion organization, cell protrusion, and chemotactic migration via its Src-binding site; a point mutant (Y246F) that does not bind Src abolishes RACK1-dependent regulation of protrusion and migration. RACK1 localizes to nascent focal complexes in protrusive regions.","method":"GFP-tagged RACK1 live-cell imaging, point-mutant expression, chemotaxis assay, focal adhesion morphology screen in CHO-K1 cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization by live imaging tied to functional consequence, mutagenesis, and quantitative migration assay, single lab multiple orthogonal methods","pmids":["12589061"],"is_preprint":false},{"year":2004,"finding":"RACK1 is a constituent of the eukaryotic 40S ribosomal subunit, localized by cryo-electron microscopy to the head region near the mRNA exit channel, where it recruits activated PKC to stimulate translation through phosphorylation of eIF6.","method":"Cryo-electron microscopy structural localization, biochemical reconstitution","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus biochemical reconstitution, replicated across subsequent structural studies","pmids":["15577927"],"is_preprint":false},{"year":2005,"finding":"RACK1 serves as an adaptor for PKC-mediated JNK activation; PKC phosphorylates JNK on Ser129 in a RACK1-dependent manner, and this phosphorylation augments subsequent MKK4/MKK7-mediated JNK activation. siRNA-mediated RACK1 depletion attenuates JNK activation by TPA, TNFα, UV, and PKC.","method":"Phospho-specific antibodies, in vitro kinase assays, siRNA knockdown, site-directed mutagenesis (Ser129)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay with mutagenesis plus siRNA KD and multiple stimuli tested, single lab multiple orthogonal methods","pmids":["16061178"],"is_preprint":false},{"year":2006,"finding":"RACK1 inhibits Src activity at G1 and mitotic cell cycle checkpoints to suppress colon cell growth; it suppresses Src-mediated Sam68 phosphorylation and maintains CDK1-cyclin B in an active state. Cell-permeable peptides disrupting RACK1–Src interaction abolish these effects.","method":"RACK1 overexpression and depletion, cell-permeable peptide disruption, cell cycle analysis, kinase activity assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD/OE with defined cell cycle phenotype and pathway placement, single lab","pmids":["17072338"],"is_preprint":false},{"year":2007,"finding":"RACK1 promotes O2/PHD/VHL-independent proteasomal degradation of HIF-1α by competing with HSP90 for binding to the HIF-1α PAS-A domain, then recruiting Elongin-C/B E3 ubiquitin ligase complex to HIF-1α to drive its ubiquitination and degradation.","method":"Co-immunoprecipitation, ubiquitination assays, competitive binding assays, overexpression/knockdown with HIF-1α stability readout","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assays with defined mechanism, single lab","pmids":["17361105"],"is_preprint":false},{"year":2010,"finding":"RACK1 and PKCα are recruited in a circadian manner into a nuclear BMAL1 complex during the negative feedback phase of the mammalian clock; RACK1 stimulates PKCα-mediated phosphorylation of BMAL1 in vitro, suppressing CLOCK-BMAL1 transcriptional activity. Depletion of RACK1 or PKCα shortens the circadian period.","method":"Co-immunoprecipitation from mouse liver, in vitro kinase assay, siRNA depletion in fibroblasts with period-length measurement, overexpression transcriptional reporter assay","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay plus reciprocal Co-IP, siRNA KD with defined circadian phenotype, multiple orthogonal methods","pmids":["20093473"],"is_preprint":false},{"year":2010,"finding":"Nuclear RACK1 associates with histone H3 and H4 at the BDNF gene promoter IV region following cAMP pathway activation, displaces the transcriptional repressor MeCP2, and promotes histone H4 acetylation, leading to exon IV-specific BDNF transcription.","method":"Chromatin immunoprecipitation (ChIP), co-immunoprecipitation, knockdown, RT-PCR for exon-specific BDNF expression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP with exon-specific transcriptional readout, single lab","pmids":["20410295"],"is_preprint":false},{"year":2011,"finding":"RACK1 interacts with Flt1 (VEGFR-1) in vitro and mediates VEGF/Flt1-driven cell migration through activation of the PI3K/Akt and Rac1 pathways; RACK1 siRNA suppresses VEGF-driven migration without affecting proliferation.","method":"In vitro binding assay, RNAi knockdown, PI3K/Akt pathway activation assays, migration assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus functional siRNA KD with signaling readout, single lab","pmids":["21212275"],"is_preprint":false},{"year":2011,"finding":"RACK1 promotes epithelial cell–cell adhesion by inhibiting Src-mediated E-cadherin phosphorylation, preventing Hakai-mediated E-cadherin ubiquitination and endocytosis, thereby stabilizing E-cadherin and catenins at cell–cell contacts and reducing invasive potential.","method":"RACK1 depletion/overexpression, Src activity assays, E-cadherin ubiquitination/endocytosis assays, calcium-switch assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic readouts (ubiquitination, endocytosis, Src phosphorylation) in single lab","pmids":["21685945"],"is_preprint":false},{"year":2011,"finding":"RACK1 interacts with components of the miRNA-induced silencing complex (miRISC) in C. elegans and mammals; RACK1 contributes to recruitment of miRISC to translating ribosomes and is required for miRNA-mediated gene repression (post-initiation mode).","method":"Co-immunoprecipitation of RACK1 with miRISC components in vivo, RACK1 overexpression/knockdown with miRNA reporter readouts, polysome fractionation","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated in two organisms (C. elegans and mammals), Co-IP and polysome fractionation with functional readout","pmids":["21525958"],"is_preprint":false},{"year":2012,"finding":"Ribosomal RACK1 couples with PKCβII to promote phosphorylation of eIF4E, leading to preferential cap-dependent translation of growth and survival factors and contributing to HCC chemoresistance; ribosome localization of RACK1 is required for this effect.","method":"Co-immunoprecipitation, eIF4E phosphorylation assays, ribosome-binding mutants, PKCβII inhibition, siRNA knockdown, in vivo xenograft","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, phospho-assays, ribosome-binding mutants, and in vivo validation, single lab multiple orthogonal methods","pmids":["22653060"],"is_preprint":false},{"year":2012,"finding":"RACK1 acts as a ribosomal scaffold protein for the β-actin mRNA/ZBP1 complex; RACK1 Y246 (Src phosphorylation/binding site) is required for binding to the β-actin mRNA/ZBP1 complex, contributing to release of β-actin mRNA from ZBP1 and its translation.","method":"Co-immunoprecipitation of RACK1 with ZBP1 on ribosomes, site-directed mutagenesis (Y246F), mRNA translation assay in neurons","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP on ribosomes with mutagenesis and translation readout, single lab","pmids":["22523568"],"is_preprint":false},{"year":2014,"finding":"RACK1 is an essential determinant for IRES-mediated viral translation (cricket paralysis virus, hepatitis C virus); RACK1 knockdown does not affect general translation or cell viability but specifically impairs IRES-dependent translation and viral infection.","method":"RNAi in Drosophila and human cells, viral IRES reporter translation assays, HCV infection assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated in two organisms with multiple viral IRES systems, specific vs. general translation discrimination","pmids":["25416947"],"is_preprint":false},{"year":2014,"finding":"TRIM45 directly interacts with RACK1 and downregulates PKC/MAPK signaling; TRIM45 expression is induced by MAPK pathway activation and attenuates signaling in a negative feedback manner.","method":"Co-immunoprecipitation, MAPK pathway reporter assays, TRIM45 overexpression/knockdown","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with functional pathway readout, single lab","pmids":["24681954"],"is_preprint":false},{"year":2014,"finding":"DJ-1 interacts with RACK1, increases RACK1 dimerization and protein stability, and the DJ-1–RACK1 complex protects cortical neurons from H2O2-induced apoptosis; disruption of this interaction by H2O2 or MPP+ sensitizes neurons to oxidative damage.","method":"Co-immunoprecipitation, crosslinking/dimerization assays, RACK1 knockdown with neuronal apoptosis readout","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional KD/OE with apoptosis phenotype, single lab","pmids":["24947010"],"is_preprint":false},{"year":2016,"finding":"RACK1 interacts with ATG5 and is a novel regulator of autophagy; classical autophagy inducers (starvation, mTOR blockade) stimulate RACK1–ATG5 interaction, and knockdown of RACK1 or prevention of its ATG5 binding by mutagenesis blocks autophagy activation.","method":"Co-immunoprecipitation, mutagenesis, multiple autophagy inducers, knockdown with LC3-II/autophagosome formation readout","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis and functional autophagy assays, single lab","pmids":["27325703"],"is_preprint":false},{"year":2017,"finding":"Yeast RACK1 ortholog Asc1p is phosphorylated at T143 and Y250; T143 phosphorylation is required for ribosome-binding stability (mutation to dephosphorylation-mimicking Ala destabilizes Asc1DEp), and Asc1p/RACK1 influences phosphorylation of ~90 proteins at 120 sites involved in translation, cytoskeleton, and signaling.","method":"Phospho-site mutagenesis (T143A, Y250F), ribosome-binding assays, quantitative phosphoproteomics","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with phosphoproteomics, yeast model system","pmids":["27821475"],"is_preprint":false},{"year":2018,"finding":"O-GlcNAcylation of RACK1 at Ser122 enhances its protein stability, ribosome binding, and interaction with PKCβII, leading to increased eIF4E phosphorylation and translation of oncogenes; genetic ablation of Ser122 O-GlcNAcylation suppresses HCC tumorigenesis in vivo.","method":"Mass spectrometry mapping of O-GlcNAc site, Ser122 knock-in mice, co-immunoprecipitation, eIF4E phosphorylation assay, in vivo DEN-induced HCC model","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — PTM site mapped by MS, genetic KI mouse model, multiple orthogonal in vitro and in vivo validations","pmids":["29454068"],"is_preprint":false},{"year":2018,"finding":"RACK1 interacts with VISA (MAVS) and attenuates RIG-I/VISA-mediated antiviral signaling by disrupting VISA-TRAF2, VISA-TRAF3, and VISA-TRAF6 complexes; RACK1 promotes K48-linked ubiquitination of VISA and reduces its K63-linked ubiquitination, decreasing VISA-mediated IFN-β production.","method":"Co-immunoprecipitation, overexpression/siRNA knockdown, IFN-β promoter reporter assays, IRF3 dimerization assay, ubiquitination assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IPs, ubiquitination assays with defined K48/K63 linkages, single lab","pmids":["30527812"],"is_preprint":false},{"year":2019,"finding":"RACK1 interaction with c-Src via RACK1 Tyr228/Tyr246 is essential for osteoclast function; a RACK1 Y228F/Y246F double mutant retains osteoclast differentiation but abolishes cytoskeletal integrity, bone resorption, and c-Src phosphorylation. Lys152 in the Src SH2 domain mediates RACK1 binding.","method":"Site-directed mutagenesis of RACK1 and c-Src, co-immunoprecipitation, osteoclast bone resorption assay, cytoskeleton imaging","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis on both binding partners with functional osteoclast phenotype, single lab","pmids":["31358728"],"is_preprint":false},{"year":2019,"finding":"RACK1 mediates HCV-induced rewiring of subcellular membranes and autophagy induction; RACK1 binds HCV NS5A protein and promotes NS5A interaction with ATG14L in a RACK1-dependent manner, facilitating formation of the ATG14L-Beclin1-Vps34-Vps15 autophagosome-initiation complex and HCV double-membrane vesicle replication organelles.","method":"Yeast two-hybrid screening, co-immunoprecipitation, RACK1 depletion with HCV RNA replication readout, electron microscopy of DMVs","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP and functional replication assay, single lab","pmids":["31525236"],"is_preprint":false},{"year":2020,"finding":"Mycobacterium tuberculosis EST12 binds RACK1 in macrophages; the EST12–RACK1 complex recruits deubiquitinase UCHL5 to promote K48-linked deubiquitination of NLRP3, leading to NLRP3 inflammasome activation and pyroptosis. Crystal structure of EST12 reveals Y80 as the critical RACK1-binding residue.","method":"Co-immunoprecipitation, crystal structure of EST12, mutagenesis (Y80), ubiquitination assays, pyroptosis/caspase-1 activation assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis and biochemical ubiquitination assays and functional pyroptosis readout, single study multiple orthogonal methods","pmids":["33097533"],"is_preprint":false},{"year":2020,"finding":"RACK1 is a component of NLRP3 inflammasome complexes; RACK1 interacts with NLRP3 and NEK7 (but not ASC), promotes the active conformation of NLRP3 upon activating stimuli, and facilitates subsequent inflammasome assembly. RACK1 suppression abolishes caspase-1 activation and IL-1β release specifically in response to NLRP3- but not NLRC4- or AIM2-activating stimuli. This function is independent of ribosomal binding.","method":"Co-immunoprecipitation, siRNA knockdown with stimulus-specific caspase-1/IL-1β readout, conformational assay, ribosomal binding mutant","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP with specificity controls across three inflammasome types, mutagenesis separating ribosomal from inflammasome function, single lab multiple orthogonal methods","pmids":["33207200"],"is_preprint":false},{"year":2020,"finding":"UBE2T promotes ubiquitination and degradation of RACK1 at Lys172, Lys225, and Lys257 independently of an E3 ligase, leading to Wnt/β-catenin pathway hyperactivation and gastric cancer progression; pharmacological UBE2T inhibition blocks RACK1 degradation.","method":"Co-immunoprecipitation, ubiquitination site mapping by mutagenesis, in vivo tumor models, UBE2T inhibitor","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, mutagenesis of ubiquitin sites, and functional tumor assays, single lab","pmids":["33323973"],"is_preprint":false},{"year":2020,"finding":"Rack1 is required for Hedgehog signaling through dual mechanisms: in the absence of Hh, Rack1 promotes formation of a Ci–Rack1–Cos2 complex leading to Slimb-mediated Ci proteolysis; in the presence of Hh, Rack1 dissociates from this complex, forms a trimeric complex with Smo and Usp8 leading to Smo deubiquitination and cell surface accumulation. This regulation is conserved from Drosophila to mammals.","method":"Co-immunoprecipitation, genetic epistasis in Drosophila, cell surface accumulation assays, deubiquitination assays, mammalian cell validation","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis plus biochemical Co-IP and ubiquitination assays, replicated in two organisms","pmids":["32467643"],"is_preprint":false},{"year":2021,"finding":"Rack1 directly interacts with Smad3 to suppress TGF-β/Smad signaling and downstream p21-mediated senescence in neural stem cells; conditional deletion of Rack1 in cortical progenitors causes microcephaly via p21-dependent NSC senescence, and removal of p21 rescues the Rack1-KO phenotype in vivo.","method":"Conditional knockout mice, genetic rescue (p21 deletion), co-immunoprecipitation of Rack1–Smad3, p21 pathway analysis, in vivo cortical development phenotype","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (double KO rescue) plus Co-IP and in vivo cortical phenotype, multiple orthogonal methods","pmids":["34469723"],"is_preprint":false},{"year":2022,"finding":"RACK1 associates with RNA-binding proteins Vigilin and SERBP1 at the 40S ribosomal subunit to facilitate dengue virus (DENV) replication; Vigilin and SERBP1 interact with the DENV genome, and mutants lacking RACK1-binding but retaining viral RNA-binding cannot mediate DENV infection.","method":"RACK1 interactome by mass spectrometry, RNAi screen, genetic ablation of Vigilin/SERBP1, RACK1-binding mutants of Vigilin/SERBP1 with viral replication readout","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interactome MS plus functional mutagenesis and RNAi screen with viral replication readout, single lab","pmids":["35266803"],"is_preprint":false},{"year":2023,"finding":"SMURF2 is an E3 ubiquitin ligase for RACK1, adding K6, K33, and K48 polyubiquitin chains to RACK1; PCAF-mediated acetylation of RACK1 at K130 inhibits SMURF2-mediated ubiquitination. Loss of SMURF2 increases RACK1 stability and promotes ovarian cancer progression.","method":"Co-immunoprecipitation, ubiquitination assays with K-linkage specific antibodies, acetylation assays, mutagenesis of K130","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — E3-substrate Co-IP and ubiquitination assays with acetylation crosstalk mutagenesis, single lab","pmids":["37828084"],"is_preprint":false},{"year":2023,"finding":"TRIM26 interacts with RACK1 and promotes its proteasomal degradation, thereby inactivating MEK/ERK signaling and suppressing osteosarcoma progression; overexpression of RACK1 rescues the inhibitory effect of TRIM26 overexpression on p-MEK/p-ERK.","method":"Co-immunoprecipitation, gain/loss-of-function with MEK/ERK readout, rescue experiments with RACK1 overexpression","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with epistasis rescue experiments and signaling readout, single lab","pmids":["37591850"],"is_preprint":false},{"year":2023,"finding":"FMRP maintains RACK1 protein levels in human prenatal neurons by interacting with CNOT1 to regulate RACK1 as a species-specific target; genetic reduction of RACK1 reproduces FXS-like mitochondrial dysfunction and hyperexcitability.","method":"Multiomics (FMRP-bound mRNA/protein interactome), RACK1 knockdown in human fetal cortical neurons with mitochondrial function and electrophysiology readouts","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiomics plus functional KD in human neurons, single study","pmids":["37820724"],"is_preprint":false},{"year":2025,"finding":"RACK1 is MARylated by PARP14 in ovarian cancer cells; MARylation promotes RACK1 association with stress granules (colocalizing with G3BP1, eIF3η, 40S proteins) and reduces translation of a subset of mRNAs including AKT. TARG1 deMARylates RACK1 to dissolve stress granules and restore translation. PARP14 inhibition or mutation of MARylation sites on RACK1 blocks stress granule formation and reduces tumor growth.","method":"ADP-ribosylation assays, PARP14 inhibitor, RACK1 MARylation-site mutagenesis, stress granule imaging with colocalization, polysome profiling, in vivo tumor growth assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct PTM assay with site mutagenesis, functional stress granule imaging, translation readout, and in vivo validation, single lab multiple orthogonal methods","pmids":["39760726"],"is_preprint":false},{"year":2009,"finding":"RACK1 physically interacts with WRN helicase/exonuclease via the WRN RQC domain; purified RACK1 selectively inhibits WRN exonuclease activity in vitro without affecting helicase activity. Depletion of WRN causes nuclear RACK1 to translocate to the membrane fraction where it activates PKCδ and PKCβII.","method":"Tandem affinity purification, in vitro exonuclease/helicase assays, domain-mapping, cellular fractionation with PKC activation readout","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic assay with domain mapping plus cellular fractionation, single lab","pmids":["19966859"],"is_preprint":false},{"year":2013,"finding":"MCM7 interacts with RACK1 in vivo and in vitro via MCM7 amino acids 221–248; RACK1 scaffolds Akt in proximity to MCM7, promoting Akt-dependent MCM7 phosphorylation, which increases MCM7 chromatin association and DNA replication. MCM7 mutants that do not bind RACK1 lack DNA replication licensing activity.","method":"Co-immunoprecipitation in vivo and in vitro, domain mapping, MCM7 binding-deficient mutant, chromatin fractionation, DNA synthesis assay","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo/in vitro Co-IP with mutagenesis and functional DNA replication readout, single lab","pmids":["23313748"],"is_preprint":false},{"year":2001,"finding":"RACK1 interacts with the PH domain of p120GAP (RasGAP) in vivo and in vitro; deletion of the PH or C2/CaLB domain of p120GAP abolishes the interaction, and serine/threonine phosphorylation regulates this association.","method":"Co-immunoprecipitation, GST pulldown with recombinant RACK1, domain-deletion mutants of p120GAP","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus direct pulldown with domain mapping, single lab","pmids":["11350068"],"is_preprint":false},{"year":2001,"finding":"HIV-1 Nef binds the C-terminal moiety of RACK1 in yeast two-hybrid and cell-free pulldown assays; Nef and RACK1 partially colocalize on the trans-Golgi network and plasma membrane; RACK1 doubles Nef phosphorylation by PKC in vitro, suggesting RACK1 acts as a Nef–PKC docking adaptor.","method":"Yeast two-hybrid, cell-free pulldown, co-purification, in vitro PKC phosphorylation assay, colocalization by microscopy","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple in vitro binding methods plus in vitro kinase assay, single lab","pmids":["11312657"],"is_preprint":false},{"year":2006,"finding":"RACK1 binds the BKCa (large conductance Ca2+-activated K+) channel intracellular C-terminal tail; interaction confirmed by GST pulldown and co-immunoprecipitation; co-localization observed in vascular smooth muscle cells; RACK1 affects BKCa channel biophysical properties, suggesting RACK1 forms part of a BKCa regulatory complex.","method":"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, immunocytochemistry, electrophysiology","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid plus GST pulldown, Co-IP, and electrophysiology, single lab","pmids":["17166942"],"is_preprint":false},{"year":2023,"finding":"SPOP recognizes Ser/Thr-rich motifs on RACK1 and promotes its ubiquitination and proteasomal degradation via the CUL3/RING E3 ligase complex, leading to Smad3-mediated cardiac fibroblast activation and exacerbated cardiac fibrosis after myocardial infarction.","method":"Co-immunoprecipitation, ubiquitination assays, lentiviral knockdown/overexpression, RACK1 forced expression rescue in SPOP-overexpressing CFs, in vivo MI mouse model","journal":"Cell chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assays, and rescue experiments with in vivo validation, single lab","pmids":["37442135"],"is_preprint":false},{"year":2024,"finding":"c-Abl kinase maintains RACK1 protein stability at focal adhesions, where RACK1 serves as a scaffold for c-Abl and FAK, driving fibroblast activation and myofibroblast differentiation during renal fibrosis; c-Abl deletion reduces RACK1 expression and diminishes fibrosis.","method":"Fibroblast-specific c-Abl conditional KO mice, co-immunoprecipitation, western blot, fibrosis readouts in vivo","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse model plus Co-IP, single lab","pmids":["38689280"],"is_preprint":false},{"year":2022,"finding":"RACK1 is required for vaccinia virus postreplicative mRNA translation (via 5′ polyA leaders) independently of its role in ribosome-based stress signaling; RACK1 KO blunts JNK activation during infection only as an indirect consequence of reduced viral protein accumulation, not through direct RSR-mediated signaling.","method":"RACK1 knockout cells, viral protein synthesis assays, JNK inhibitors vs. RACK1 KO comparison, RSR activation assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with mechanistic dissection using inhibitors, single lab","pmids":["36098514"],"is_preprint":false},{"year":2019,"finding":"RACK1 stably reassociates with the human 40S ribosomal subunit, displays limited conformational dynamics, and remains bound for hours in vitro; fluorescently labeled RACK1 can be used as a stable ribosome tag for single-molecule translation studies.","method":"Bulk and single-molecule FRET/fluorescence biochemical assays, engineered fluorescent human RACK1–ribosome complexes","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — single-molecule biochemical analysis of ribosome binding kinetics, single lab","pmids":["31023766"],"is_preprint":false}],"current_model":"RACK1 is a seven-bladed WD40 β-propeller scaffold protein that constitutively occupies the head of the 40S ribosomal subunit and simultaneously recruits activated PKC isoforms, Src family kinases, and multiple signaling proteins to the ribosome, enabling stimulus-dependent phosphorylation of eIF4E and selective IRES-dependent or cap-dependent mRNA translation; off the ribosome, RACK1 acts as an adaptor that links PKC to integrins, scaffolds PKC-mediated JNK activation (via Ser129 phosphorylation), inhibits Src at cell cycle checkpoints to regulate proliferation and E-cadherin stability, suppresses NMDA receptor activity by sequestering Fyn away from NR2B, promotes HIF-1α proteasomal degradation by competing with HSP90 and recruiting the Elongin-C/B E3 ligase, facilitates NLRP3 inflammasome assembly by stabilizing NLRP3's active conformation, regulates circadian period by scaffolding PKCα-mediated BMAL1 phosphorylation, controls NSC senescence by suppressing Smad3/TGF-β/p21 signaling, and is itself regulated by post-translational modifications including Src-mediated phosphorylation (Tyr228/246), O-GlcNAcylation (Ser122), MARylation (by PARP14), and polyubiquitination by SMURF2, TRIM26, TRIM45, SPOP, and UBE2T that control its stability and subcellular localization."},"narrative":{"mechanistic_narrative":"RACK1 is a WD40 β-propeller scaffold that constitutively occupies the head of the 40S ribosomal subunit near the mRNA exit channel, where it recruits activated PKC to couple signaling to translational control [PMID:15577927, PMID:31023766]. On the ribosome it pairs with PKCβII to drive eIF4E phosphorylation and preferential cap-dependent translation of growth and survival factors, a function exploited in hepatocellular carcinoma and tuned by O-GlcNAcylation at Ser122, which strengthens ribosome binding and PKCβII engagement [PMID:22653060, PMID:29454068]. RACK1 is also required for IRES-dependent translation of viral mRNAs and serves as a ribosomal platform for mRNA-specific factors, recruiting miRISC for miRNA-mediated repression, scaffolding the β-actin mRNA/ZBP1 complex, and partnering with Vigilin/SERBP1 to support flaviviral replication [PMID:25416947, PMID:21525958, PMID:22523568, PMID:35266803]. Beyond the ribosome, RACK1 functions as a multivalent signaling adaptor: it links PKC to integrins, scaffolds PKC-dependent JNK activation through Ser129 phosphorylation, and binds Src family kinases via phosphorylated Tyr228/Tyr246 to control focal adhesion dynamics, migration, osteoclast cytoskeletal integrity, and E-cadherin–based cell adhesion [PMID:9442085, PMID:16061178, PMID:12400005, PMID:12589061, PMID:31358728, PMID:21685945]. It additionally acts as a conformational and degradative regulator of innate immune and stress pathways — promoting the active conformation of NLRP3 to license inflammasome assembly, attenuating RIG-I/MAVS antiviral signaling, and competing with HSP90 to drive HIF-1α degradation via the Elongin-C/B ligase [PMID:33207200, PMID:30527812, PMID:17361105]. RACK1 scaffolds developmental and stress signaling including PKCα-mediated BMAL1 phosphorylation in the circadian clock, Hedgehog pathway control of Ci and Smo, and suppression of TGF-β/Smad3/p21 signaling that prevents neural stem cell senescence during cortical development [PMID:20093473, PMID:32467643, PMID:34469723]. RACK1 abundance and localization are themselves controlled by an extensive set of post-translational modifications, including PARP14-mediated MARylation that drives stress granule association and translational repression, and polyubiquitination by multiple ligases (SMURF2, TRIM26, SPOP) and the E3-independent conjugating enzyme UBE2T [PMID:39760726, PMID:37828084, PMID:37591850, PMID:37442135, PMID:33323973].","teleology":[{"year":1998,"claim":"Established RACK1 as a PKC-dependent adaptor linking signaling kinases to membrane receptors, defining its core scaffold function before any ribosomal role was known.","evidence":"Yeast two-hybrid and reciprocal Co-IP with integrin β cytoplasmic tails in 293T/JY cells","pmids":["9442085"],"confidence":"High","gaps":["Did not resolve whether integrin binding occurs on or off the ribosome","Structural basis of the WD5–7 interaction surface not determined"]},{"year":2002,"claim":"Defined RACK1 as both a Src substrate and an inhibitory scaffold for tyrosine kinases, showing it can suppress rather than only relay kinase activity.","evidence":"In vitro kinase assays with Src mutants and Tyr228/246 mutagenesis; Co-IP and hippocampal electrophysiology with peptide disruption of RACK1–NR2B–Fyn","pmids":["12400005","11943848"],"confidence":"High","gaps":["Mechanism by which a single scaffold both binds and inhibits Src/Fyn not structurally resolved","Tissue-specific selection between activating and inhibitory outputs unclear"]},{"year":2004,"claim":"Placed RACK1 physically on the 40S ribosome head near the mRNA exit channel, transforming it from a cytoplasmic adaptor into a structural link between signaling and translation.","evidence":"Cryo-EM localization and biochemical reconstitution","pmids":["15577927"],"confidence":"High","gaps":["How ribosomal versus extra-ribosomal pools are partitioned not defined","Direct evidence of eIF6 phosphorylation in cells limited"]},{"year":2005,"claim":"Showed RACK1 acts as a priming scaffold for the JNK cascade, demonstrating it organizes MAPK signaling and not only PKC localization.","evidence":"Phospho-specific antibodies, in vitro kinase assays, Ser129 mutagenesis, and siRNA knockdown across multiple stimuli","pmids":["16061178"],"confidence":"High","gaps":["Whether JNK priming occurs on the ribosome not addressed","Stoichiometry of the PKC–JNK–RACK1 assembly unknown"]},{"year":2006,"claim":"Connected RACK1's Src inhibition to cell-cycle checkpoint control and growth suppression, expanding its role into proliferation regulation.","evidence":"Overexpression/depletion, cell-permeable peptide disruption, and cell-cycle/kinase assays in colon cells","pmids":["17072338"],"confidence":"Medium","gaps":["Single lab; in vivo cell-cycle relevance not established","Link between Sam68 phosphorylation and CDK1-cyclin B regulation indirect"]},{"year":2007,"claim":"Revealed an O2/VHL-independent route to HIF-1α turnover in which RACK1 acts as a degradation adaptor competing with a chaperone.","evidence":"Competitive binding, Co-IP, and ubiquitination/stability assays with the Elongin-C/B complex","pmids":["17361105"],"confidence":"Medium","gaps":["Physiological conditions favoring RACK1 over HSP90 binding undefined","In vivo contribution to hypoxic signaling not tested"]},{"year":2010,"claim":"Extended RACK1 to nuclear scaffolding of clock and chromatin machinery, showing it times PKCα-mediated transcriptional repression and gene-specific transcription.","evidence":"Co-IP from mouse liver, in vitro kinase assays, siRNA period-length measurement; ChIP at BDNF promoter IV with MeCP2 displacement readout","pmids":["20093473","20410295"],"confidence":"Medium","gaps":["How RACK1 is targeted to specific nuclear loci unresolved","Relationship between nuclear and ribosomal pools not defined"]},{"year":2012,"claim":"Established that ribosomal RACK1 couples PKCβII to eIF4E phosphorylation for selective mRNA translation and recruits mRNA-specific factors, mechanistically tying its scaffold role to translational selectivity.","evidence":"Ribosome-binding mutants, eIF4E phospho-assays, Co-IP with ZBP1 and miRISC, polysome fractionation, and xenograft validation","pmids":["22653060","22523568","21525958"],"confidence":"High","gaps":["Rules governing which mRNAs are selected not fully defined","Direct contacts between RACK1 and individual mRNP factors not structurally mapped"]},{"year":2014,"claim":"Demonstrated RACK1 is specifically required for IRES-dependent viral translation without affecting bulk translation, distinguishing a dedicated translational function.","evidence":"RNAi in Drosophila and human cells with CrPV/HCV IRES reporters and HCV infection assays","pmids":["25416947"],"confidence":"High","gaps":["Molecular basis for IRES vs. cap-dependent discrimination not resolved","Whether host IRES mRNAs share this dependence unknown"]},{"year":2018,"claim":"Identified O-GlcNAcylation at Ser122 as a regulatory switch enhancing ribosome binding and oncogenic translation, providing a genetic in vivo link to tumorigenesis.","evidence":"MS site mapping, Ser122 knock-in mice, Co-IP, eIF4E phospho-assay, and DEN-induced HCC model","pmids":["29454068"],"confidence":"High","gaps":["Upstream signals controlling RACK1 O-GlcNAcylation unknown","Interplay with other RACK1 PTMs not examined"]},{"year":2020,"claim":"Defined a ribosome-independent role for RACK1 as a conformational chaperone for NLRP3 inflammasome activation, including a pathogen-driven deubiquitination axis.","evidence":"Co-IP with NLRP3/NEK7, ribosomal-binding mutant, stimulus-specific caspase-1/IL-1β readouts; EST12 crystal structure and UCHL5-mediated NLRP3 deubiquitination","pmids":["33207200","33097533"],"confidence":"High","gaps":["Structural basis of RACK1 stabilizing active NLRP3 conformation not solved","How RACK1 partitions between inflammasome and ribosome pools unresolved"]},{"year":2021,"claim":"Established a developmental in vivo requirement for RACK1 in suppressing TGF-β/Smad3/p21-driven neural stem cell senescence, with genetic rescue confirming the pathway.","evidence":"Conditional knockout mice, p21-deletion rescue, Rack1–Smad3 Co-IP, and cortical development phenotyping","pmids":["34469723"],"confidence":"High","gaps":["Direct mechanism of Smad3 inhibition by RACK1 not structurally defined","Whether ribosomal RACK1 contributes to this phenotype untested"]},{"year":2023,"claim":"Mapped a network of E3 ligases and conjugating enzymes that control RACK1 stability through distinct ubiquitin linkages and acetylation crosstalk, explaining context-dependent RACK1 abundance.","evidence":"Co-IP, K-linkage-specific ubiquitination assays, site mutagenesis, and rescue experiments for SMURF2, TRIM26, SPOP, and UBE2T across multiple cancer/fibrosis models","pmids":["37828084","37591850","37442135","33323973"],"confidence":"Medium","gaps":["Whether these ligases act on distinct RACK1 pools is unknown","Hierarchy and combinatorial logic among the modifications undefined"]},{"year":2025,"claim":"Showed PARP14-mediated MARylation redirects RACK1 into stress granules to repress translation of specific mRNAs, defining a reversible PTM that toggles RACK1 between active translation and sequestration.","evidence":"ADP-ribosylation assays, MARylation-site mutagenesis, stress granule imaging, polysome profiling, and in vivo tumor growth in ovarian cancer cells","pmids":["39760726"],"confidence":"High","gaps":["MARylated residues and their structural effect on the propeller not fully mapped","Interplay with O-GlcNAcylation and ubiquitination during stress not tested"]},{"year":null,"claim":"How the cell partitions a single RACK1 scaffold among its ribosomal, nuclear, inflammasome, focal-adhesion, and stress-granule functions, and how the various PTMs are integrated to dictate this partitioning, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model for spatial allocation of RACK1 pools","Stoichiometry and competition among the many partners not measured","Combinatorial PTM logic governing localization and stability undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,5,4,13,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,6,7,25]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[12,14,29]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,42]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[4,13,42]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[25,33]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,9,28]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,37]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,12,13,15,33]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,2,6,16,31]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[25,24,21]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,26,30,39]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[18,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[27,28]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[8]}],"complexes":["40S ribosomal subunit","NLRP3 inflammasome","miRISC","stress granule"],"partners":["PKC","SRC","NLRP3","NEK7","FYN","ATG5","SMAD3","BMAL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P63244","full_name":"Small ribosomal subunit protein RACK1","aliases":["Cell proliferation-inducing gene 21 protein","Guanine nucleotide-binding protein subunit beta-2-like 1","Guanine nucleotide-binding protein subunit beta-like protein 12.3","Human lung cancer oncogene 7 protein","HLC-7","Receptor for activated C kinase","Receptor for activated C kinase 1","Receptor of activated protein C kinase 1"],"length_aa":317,"mass_kda":35.1,"function":"Scaffolding protein involved in the recruitment, assembly and/or regulation of a variety of signaling molecules. Interacts with a wide variety of proteins and plays a role in many cellular processes. Component of the 40S ribosomal subunit involved in translational repression (PubMed:23636399). Involved in the initiation of the ribosome quality control (RQC), a pathway that takes place when a ribosome has stalled during translation, by promoting ubiquitination of a subset of 40S ribosomal subunits (PubMed:28132843). Binds to and stabilizes activated protein kinase C (PKC), increasing PKC-mediated phosphorylation. May recruit activated PKC to the ribosome, leading to phosphorylation of EIF6. Inhibits the activity of SRC kinases including SRC, LCK and YES1. Inhibits cell growth by prolonging the G0/G1 phase of the cell cycle. Enhances phosphorylation of BMAL1 by PRKCA and inhibits transcriptional activity of the BMAL1-CLOCK heterodimer. Facilitates ligand-independent nuclear translocation of AR following PKC activation, represses AR transactivation activity and is required for phosphorylation of AR by SRC. Modulates IGF1R-dependent integrin signaling and promotes cell spreading and contact with the extracellular matrix. Involved in PKC-dependent translocation of ADAM12 to the cell membrane. Promotes the ubiquitination and proteasome-mediated degradation of proteins such as CLEC1B and HIF1A. Required for VANGL2 membrane localization, inhibits Wnt signaling, and regulates cellular polarization and oriented cell division during gastrulation. Required for PTK2/FAK1 phosphorylation and dephosphorylation. Regulates internalization of the muscarinic receptor CHRM2. Promotes apoptosis by increasing oligomerization of BAX and disrupting the interaction of BAX with the anti-apoptotic factor BCL2L. Inhibits TRPM6 channel activity. Regulates cell surface expression of some GPCRs such as TBXA2R. Plays a role in regulation of FLT1-mediated cell migration. Involved in the transport of ABCB4 from the Golgi to the apical bile canalicular membrane (PubMed:19674157). Promotes migration of breast carcinoma cells by binding to and activating RHOA (PubMed:20499158). Acts as an adapter for the dephosphorylation and inactivation of AKT1 by promoting recruitment of PP2A phosphatase to AKT1 (By similarity) (Microbial infection) Binds to Y.pseudotuberculosis yopK which leads to inhibition of phagocytosis and survival of bacteria following infection of host cells (Microbial infection) Enhances phosphorylation of HIV-1 Nef by PKCs (Microbial infection) In case of poxvirus infection, remodels the ribosomes so that they become optimal for the viral mRNAs (containing poly-A leaders) translation but not for host mRNAs (Microbial infection) Contributes to the cap-independent internal ribosome entry site (IRES)-mediated translation by some RNA viruses","subcellular_location":"Cell membrane; Cytoplasm; Cytoplasm, perinuclear region; Nucleus; Perikaryon; Cell projection, dendrite; Cell projection, phagocytic cup","url":"https://www.uniprot.org/uniprotkb/P63244/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RACK1","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000204628","cell_line_id":"CID001172","localizations":[{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"RPLP0;RPLP0P6","stoichiometry":10.0},{"gene":"RPLP2","stoichiometry":10.0},{"gene":"RPLP1","stoichiometry":10.0},{"gene":"RPS15","stoichiometry":10.0},{"gene":"RPL13A;RPL13A","stoichiometry":10.0},{"gene":"RPL3","stoichiometry":10.0},{"gene":"RPS19","stoichiometry":10.0},{"gene":"RPL4","stoichiometry":10.0},{"gene":"RPL35","stoichiometry":10.0},{"gene":"RPL22","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001172","total_profiled":1310},"omim":[{"mim_id":"618957","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 27; ANKRD27","url":"https://www.omim.org/entry/618957"},{"mim_id":"618657","title":"La RIBONUCLEOPROTEIN 4; LARP4","url":"https://www.omim.org/entry/618657"},{"mim_id":"617508","title":"ZINC FINGER PROTEIN 598; ZNF598","url":"https://www.omim.org/entry/617508"},{"mim_id":"617424","title":"WD REPEAT-CONTAINING PROTEIN 26; WDR26","url":"https://www.omim.org/entry/617424"},{"mim_id":"616513","title":"La RIBONUCLEOPROTEIN 4B; LARP4B","url":"https://www.omim.org/entry/616513"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RACK1"},"hgnc":{"alias_symbol":["Gnb2-rs1","H12.3"],"prev_symbol":["GNB2L1"]},"alphafold":{"accession":"P63244","domains":[{"cath_id":"2.130.10.10","chopping":"1-314","consensus_level":"high","plddt":92.2968,"start":1,"end":314}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P63244","model_url":"https://alphafold.ebi.ac.uk/files/AF-P63244-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P63244-F1-predicted_aligned_error_v6.png","plddt_mean":92.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RACK1","jax_strain_url":"https://www.jax.org/strain/search?query=RACK1"},"sequence":{"accession":"P63244","fasta_url":"https://rest.uniprot.org/uniprotkb/P63244.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P63244/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P63244"}},"corpus_meta":[{"pmid":"21978545","id":"PMC_21978545","title":"RACK1, A 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\"finding\": \"RACK1 interacts with integrin β subunit cytoplasmic domains via WD repeats 5–7; full-length RACK1 association with integrins in vivo requires phorbol ester treatment, suggesting RACK1 links PKC to integrins to regulate integrin function.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in 293T and JY cells, deletion mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP in two cell lines plus yeast two-hybrid domain mapping, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"9442085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RACK1 binds both the NR2B subunit of the NMDA receptor and Fyn tyrosine kinase, acting as an inhibitory scaffold; RACK1 inhibits Fyn-mediated phosphorylation of NR2B and decreases NMDA receptor-mediated currents in hippocampal slices. Disrupting RACK1–NR2B–Fyn interactions with peptides induces NR2B phosphorylation and potentiates NMDA currents.\",\n      \"method\": \"Co-immunoprecipitation, electrophysiology in CA1 hippocampal slices, cell-permeable peptide disruption assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional electrophysiology with peptide disruption, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"11943848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RACK1 is a substrate of Src tyrosine kinase; Src phosphorylates RACK1 on Tyr228 and/or Tyr246 (located in the sixth WD repeat), and this phosphorylation is required for RACK1 binding to Src's SH2 domain following PKC activation.\",\n      \"method\": \"In vitro kinase assay with various tyrosine kinases, in vivo kinase-active/inactive Src mutants, site-directed mutagenesis of RACK1 tyrosines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay combined with mutagenesis and in vivo validation, single lab with orthogonal methods\",\n      \"pmids\": [\"12400005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RACK1 regulates focal adhesion organization, cell protrusion, and chemotactic migration via its Src-binding site; a point mutant (Y246F) that does not bind Src abolishes RACK1-dependent regulation of protrusion and migration. RACK1 localizes to nascent focal complexes in protrusive regions.\",\n      \"method\": \"GFP-tagged RACK1 live-cell imaging, point-mutant expression, chemotaxis assay, focal adhesion morphology screen in CHO-K1 cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by live imaging tied to functional consequence, mutagenesis, and quantitative migration assay, single lab multiple orthogonal methods\",\n      \"pmids\": [\"12589061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RACK1 is a constituent of the eukaryotic 40S ribosomal subunit, localized by cryo-electron microscopy to the head region near the mRNA exit channel, where it recruits activated PKC to stimulate translation through phosphorylation of eIF6.\",\n      \"method\": \"Cryo-electron microscopy structural localization, biochemical reconstitution\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus biochemical reconstitution, replicated across subsequent structural studies\",\n      \"pmids\": [\"15577927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RACK1 serves as an adaptor for PKC-mediated JNK activation; PKC phosphorylates JNK on Ser129 in a RACK1-dependent manner, and this phosphorylation augments subsequent MKK4/MKK7-mediated JNK activation. siRNA-mediated RACK1 depletion attenuates JNK activation by TPA, TNFα, UV, and PKC.\",\n      \"method\": \"Phospho-specific antibodies, in vitro kinase assays, siRNA knockdown, site-directed mutagenesis (Ser129)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay with mutagenesis plus siRNA KD and multiple stimuli tested, single lab multiple orthogonal methods\",\n      \"pmids\": [\"16061178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RACK1 inhibits Src activity at G1 and mitotic cell cycle checkpoints to suppress colon cell growth; it suppresses Src-mediated Sam68 phosphorylation and maintains CDK1-cyclin B in an active state. Cell-permeable peptides disrupting RACK1–Src interaction abolish these effects.\",\n      \"method\": \"RACK1 overexpression and depletion, cell-permeable peptide disruption, cell cycle analysis, kinase activity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD/OE with defined cell cycle phenotype and pathway placement, single lab\",\n      \"pmids\": [\"17072338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RACK1 promotes O2/PHD/VHL-independent proteasomal degradation of HIF-1α by competing with HSP90 for binding to the HIF-1α PAS-A domain, then recruiting Elongin-C/B E3 ubiquitin ligase complex to HIF-1α to drive its ubiquitination and degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, competitive binding assays, overexpression/knockdown with HIF-1α stability readout\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assays with defined mechanism, single lab\",\n      \"pmids\": [\"17361105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RACK1 and PKCα are recruited in a circadian manner into a nuclear BMAL1 complex during the negative feedback phase of the mammalian clock; RACK1 stimulates PKCα-mediated phosphorylation of BMAL1 in vitro, suppressing CLOCK-BMAL1 transcriptional activity. Depletion of RACK1 or PKCα shortens the circadian period.\",\n      \"method\": \"Co-immunoprecipitation from mouse liver, in vitro kinase assay, siRNA depletion in fibroblasts with period-length measurement, overexpression transcriptional reporter assay\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay plus reciprocal Co-IP, siRNA KD with defined circadian phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"20093473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Nuclear RACK1 associates with histone H3 and H4 at the BDNF gene promoter IV region following cAMP pathway activation, displaces the transcriptional repressor MeCP2, and promotes histone H4 acetylation, leading to exon IV-specific BDNF transcription.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), co-immunoprecipitation, knockdown, RT-PCR for exon-specific BDNF expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP with exon-specific transcriptional readout, single lab\",\n      \"pmids\": [\"20410295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RACK1 interacts with Flt1 (VEGFR-1) in vitro and mediates VEGF/Flt1-driven cell migration through activation of the PI3K/Akt and Rac1 pathways; RACK1 siRNA suppresses VEGF-driven migration without affecting proliferation.\",\n      \"method\": \"In vitro binding assay, RNAi knockdown, PI3K/Akt pathway activation assays, migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus functional siRNA KD with signaling readout, single lab\",\n      \"pmids\": [\"21212275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RACK1 promotes epithelial cell–cell adhesion by inhibiting Src-mediated E-cadherin phosphorylation, preventing Hakai-mediated E-cadherin ubiquitination and endocytosis, thereby stabilizing E-cadherin and catenins at cell–cell contacts and reducing invasive potential.\",\n      \"method\": \"RACK1 depletion/overexpression, Src activity assays, E-cadherin ubiquitination/endocytosis assays, calcium-switch assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic readouts (ubiquitination, endocytosis, Src phosphorylation) in single lab\",\n      \"pmids\": [\"21685945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RACK1 interacts with components of the miRNA-induced silencing complex (miRISC) in C. elegans and mammals; RACK1 contributes to recruitment of miRISC to translating ribosomes and is required for miRNA-mediated gene repression (post-initiation mode).\",\n      \"method\": \"Co-immunoprecipitation of RACK1 with miRISC components in vivo, RACK1 overexpression/knockdown with miRNA reporter readouts, polysome fractionation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated in two organisms (C. elegans and mammals), Co-IP and polysome fractionation with functional readout\",\n      \"pmids\": [\"21525958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Ribosomal RACK1 couples with PKCβII to promote phosphorylation of eIF4E, leading to preferential cap-dependent translation of growth and survival factors and contributing to HCC chemoresistance; ribosome localization of RACK1 is required for this effect.\",\n      \"method\": \"Co-immunoprecipitation, eIF4E phosphorylation assays, ribosome-binding mutants, PKCβII inhibition, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, phospho-assays, ribosome-binding mutants, and in vivo validation, single lab multiple orthogonal methods\",\n      \"pmids\": [\"22653060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RACK1 acts as a ribosomal scaffold protein for the β-actin mRNA/ZBP1 complex; RACK1 Y246 (Src phosphorylation/binding site) is required for binding to the β-actin mRNA/ZBP1 complex, contributing to release of β-actin mRNA from ZBP1 and its translation.\",\n      \"method\": \"Co-immunoprecipitation of RACK1 with ZBP1 on ribosomes, site-directed mutagenesis (Y246F), mRNA translation assay in neurons\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP on ribosomes with mutagenesis and translation readout, single lab\",\n      \"pmids\": [\"22523568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RACK1 is an essential determinant for IRES-mediated viral translation (cricket paralysis virus, hepatitis C virus); RACK1 knockdown does not affect general translation or cell viability but specifically impairs IRES-dependent translation and viral infection.\",\n      \"method\": \"RNAi in Drosophila and human cells, viral IRES reporter translation assays, HCV infection assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated in two organisms with multiple viral IRES systems, specific vs. general translation discrimination\",\n      \"pmids\": [\"25416947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM45 directly interacts with RACK1 and downregulates PKC/MAPK signaling; TRIM45 expression is induced by MAPK pathway activation and attenuates signaling in a negative feedback manner.\",\n      \"method\": \"Co-immunoprecipitation, MAPK pathway reporter assays, TRIM45 overexpression/knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with functional pathway readout, single lab\",\n      \"pmids\": [\"24681954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DJ-1 interacts with RACK1, increases RACK1 dimerization and protein stability, and the DJ-1–RACK1 complex protects cortical neurons from H2O2-induced apoptosis; disruption of this interaction by H2O2 or MPP+ sensitizes neurons to oxidative damage.\",\n      \"method\": \"Co-immunoprecipitation, crosslinking/dimerization assays, RACK1 knockdown with neuronal apoptosis readout\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional KD/OE with apoptosis phenotype, single lab\",\n      \"pmids\": [\"24947010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RACK1 interacts with ATG5 and is a novel regulator of autophagy; classical autophagy inducers (starvation, mTOR blockade) stimulate RACK1–ATG5 interaction, and knockdown of RACK1 or prevention of its ATG5 binding by mutagenesis blocks autophagy activation.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis, multiple autophagy inducers, knockdown with LC3-II/autophagosome formation readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis and functional autophagy assays, single lab\",\n      \"pmids\": [\"27325703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Yeast RACK1 ortholog Asc1p is phosphorylated at T143 and Y250; T143 phosphorylation is required for ribosome-binding stability (mutation to dephosphorylation-mimicking Ala destabilizes Asc1DEp), and Asc1p/RACK1 influences phosphorylation of ~90 proteins at 120 sites involved in translation, cytoskeleton, and signaling.\",\n      \"method\": \"Phospho-site mutagenesis (T143A, Y250F), ribosome-binding assays, quantitative phosphoproteomics\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with phosphoproteomics, yeast model system\",\n      \"pmids\": [\"27821475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"O-GlcNAcylation of RACK1 at Ser122 enhances its protein stability, ribosome binding, and interaction with PKCβII, leading to increased eIF4E phosphorylation and translation of oncogenes; genetic ablation of Ser122 O-GlcNAcylation suppresses HCC tumorigenesis in vivo.\",\n      \"method\": \"Mass spectrometry mapping of O-GlcNAc site, Ser122 knock-in mice, co-immunoprecipitation, eIF4E phosphorylation assay, in vivo DEN-induced HCC model\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — PTM site mapped by MS, genetic KI mouse model, multiple orthogonal in vitro and in vivo validations\",\n      \"pmids\": [\"29454068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RACK1 interacts with VISA (MAVS) and attenuates RIG-I/VISA-mediated antiviral signaling by disrupting VISA-TRAF2, VISA-TRAF3, and VISA-TRAF6 complexes; RACK1 promotes K48-linked ubiquitination of VISA and reduces its K63-linked ubiquitination, decreasing VISA-mediated IFN-β production.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/siRNA knockdown, IFN-β promoter reporter assays, IRF3 dimerization assay, ubiquitination assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IPs, ubiquitination assays with defined K48/K63 linkages, single lab\",\n      \"pmids\": [\"30527812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RACK1 interaction with c-Src via RACK1 Tyr228/Tyr246 is essential for osteoclast function; a RACK1 Y228F/Y246F double mutant retains osteoclast differentiation but abolishes cytoskeletal integrity, bone resorption, and c-Src phosphorylation. Lys152 in the Src SH2 domain mediates RACK1 binding.\",\n      \"method\": \"Site-directed mutagenesis of RACK1 and c-Src, co-immunoprecipitation, osteoclast bone resorption assay, cytoskeleton imaging\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis on both binding partners with functional osteoclast phenotype, single lab\",\n      \"pmids\": [\"31358728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RACK1 mediates HCV-induced rewiring of subcellular membranes and autophagy induction; RACK1 binds HCV NS5A protein and promotes NS5A interaction with ATG14L in a RACK1-dependent manner, facilitating formation of the ATG14L-Beclin1-Vps34-Vps15 autophagosome-initiation complex and HCV double-membrane vesicle replication organelles.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, RACK1 depletion with HCV RNA replication readout, electron microscopy of DMVs\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP and functional replication assay, single lab\",\n      \"pmids\": [\"31525236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Mycobacterium tuberculosis EST12 binds RACK1 in macrophages; the EST12–RACK1 complex recruits deubiquitinase UCHL5 to promote K48-linked deubiquitination of NLRP3, leading to NLRP3 inflammasome activation and pyroptosis. Crystal structure of EST12 reveals Y80 as the critical RACK1-binding residue.\",\n      \"method\": \"Co-immunoprecipitation, crystal structure of EST12, mutagenesis (Y80), ubiquitination assays, pyroptosis/caspase-1 activation assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis and biochemical ubiquitination assays and functional pyroptosis readout, single study multiple orthogonal methods\",\n      \"pmids\": [\"33097533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RACK1 is a component of NLRP3 inflammasome complexes; RACK1 interacts with NLRP3 and NEK7 (but not ASC), promotes the active conformation of NLRP3 upon activating stimuli, and facilitates subsequent inflammasome assembly. RACK1 suppression abolishes caspase-1 activation and IL-1β release specifically in response to NLRP3- but not NLRC4- or AIM2-activating stimuli. This function is independent of ribosomal binding.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with stimulus-specific caspase-1/IL-1β readout, conformational assay, ribosomal binding mutant\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with specificity controls across three inflammasome types, mutagenesis separating ribosomal from inflammasome function, single lab multiple orthogonal methods\",\n      \"pmids\": [\"33207200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UBE2T promotes ubiquitination and degradation of RACK1 at Lys172, Lys225, and Lys257 independently of an E3 ligase, leading to Wnt/β-catenin pathway hyperactivation and gastric cancer progression; pharmacological UBE2T inhibition blocks RACK1 degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination site mapping by mutagenesis, in vivo tumor models, UBE2T inhibitor\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mutagenesis of ubiquitin sites, and functional tumor assays, single lab\",\n      \"pmids\": [\"33323973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rack1 is required for Hedgehog signaling through dual mechanisms: in the absence of Hh, Rack1 promotes formation of a Ci–Rack1–Cos2 complex leading to Slimb-mediated Ci proteolysis; in the presence of Hh, Rack1 dissociates from this complex, forms a trimeric complex with Smo and Usp8 leading to Smo deubiquitination and cell surface accumulation. This regulation is conserved from Drosophila to mammals.\",\n      \"method\": \"Co-immunoprecipitation, genetic epistasis in Drosophila, cell surface accumulation assays, deubiquitination assays, mammalian cell validation\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis plus biochemical Co-IP and ubiquitination assays, replicated in two organisms\",\n      \"pmids\": [\"32467643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rack1 directly interacts with Smad3 to suppress TGF-β/Smad signaling and downstream p21-mediated senescence in neural stem cells; conditional deletion of Rack1 in cortical progenitors causes microcephaly via p21-dependent NSC senescence, and removal of p21 rescues the Rack1-KO phenotype in vivo.\",\n      \"method\": \"Conditional knockout mice, genetic rescue (p21 deletion), co-immunoprecipitation of Rack1–Smad3, p21 pathway analysis, in vivo cortical development phenotype\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (double KO rescue) plus Co-IP and in vivo cortical phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"34469723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RACK1 associates with RNA-binding proteins Vigilin and SERBP1 at the 40S ribosomal subunit to facilitate dengue virus (DENV) replication; Vigilin and SERBP1 interact with the DENV genome, and mutants lacking RACK1-binding but retaining viral RNA-binding cannot mediate DENV infection.\",\n      \"method\": \"RACK1 interactome by mass spectrometry, RNAi screen, genetic ablation of Vigilin/SERBP1, RACK1-binding mutants of Vigilin/SERBP1 with viral replication readout\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interactome MS plus functional mutagenesis and RNAi screen with viral replication readout, single lab\",\n      \"pmids\": [\"35266803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SMURF2 is an E3 ubiquitin ligase for RACK1, adding K6, K33, and K48 polyubiquitin chains to RACK1; PCAF-mediated acetylation of RACK1 at K130 inhibits SMURF2-mediated ubiquitination. Loss of SMURF2 increases RACK1 stability and promotes ovarian cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays with K-linkage specific antibodies, acetylation assays, mutagenesis of K130\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — E3-substrate Co-IP and ubiquitination assays with acetylation crosstalk mutagenesis, single lab\",\n      \"pmids\": [\"37828084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM26 interacts with RACK1 and promotes its proteasomal degradation, thereby inactivating MEK/ERK signaling and suppressing osteosarcoma progression; overexpression of RACK1 rescues the inhibitory effect of TRIM26 overexpression on p-MEK/p-ERK.\",\n      \"method\": \"Co-immunoprecipitation, gain/loss-of-function with MEK/ERK readout, rescue experiments with RACK1 overexpression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with epistasis rescue experiments and signaling readout, single lab\",\n      \"pmids\": [\"37591850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FMRP maintains RACK1 protein levels in human prenatal neurons by interacting with CNOT1 to regulate RACK1 as a species-specific target; genetic reduction of RACK1 reproduces FXS-like mitochondrial dysfunction and hyperexcitability.\",\n      \"method\": \"Multiomics (FMRP-bound mRNA/protein interactome), RACK1 knockdown in human fetal cortical neurons with mitochondrial function and electrophysiology readouts\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiomics plus functional KD in human neurons, single study\",\n      \"pmids\": [\"37820724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RACK1 is MARylated by PARP14 in ovarian cancer cells; MARylation promotes RACK1 association with stress granules (colocalizing with G3BP1, eIF3η, 40S proteins) and reduces translation of a subset of mRNAs including AKT. TARG1 deMARylates RACK1 to dissolve stress granules and restore translation. PARP14 inhibition or mutation of MARylation sites on RACK1 blocks stress granule formation and reduces tumor growth.\",\n      \"method\": \"ADP-ribosylation assays, PARP14 inhibitor, RACK1 MARylation-site mutagenesis, stress granule imaging with colocalization, polysome profiling, in vivo tumor growth assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct PTM assay with site mutagenesis, functional stress granule imaging, translation readout, and in vivo validation, single lab multiple orthogonal methods\",\n      \"pmids\": [\"39760726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RACK1 physically interacts with WRN helicase/exonuclease via the WRN RQC domain; purified RACK1 selectively inhibits WRN exonuclease activity in vitro without affecting helicase activity. Depletion of WRN causes nuclear RACK1 to translocate to the membrane fraction where it activates PKCδ and PKCβII.\",\n      \"method\": \"Tandem affinity purification, in vitro exonuclease/helicase assays, domain-mapping, cellular fractionation with PKC activation readout\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic assay with domain mapping plus cellular fractionation, single lab\",\n      \"pmids\": [\"19966859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MCM7 interacts with RACK1 in vivo and in vitro via MCM7 amino acids 221–248; RACK1 scaffolds Akt in proximity to MCM7, promoting Akt-dependent MCM7 phosphorylation, which increases MCM7 chromatin association and DNA replication. MCM7 mutants that do not bind RACK1 lack DNA replication licensing activity.\",\n      \"method\": \"Co-immunoprecipitation in vivo and in vitro, domain mapping, MCM7 binding-deficient mutant, chromatin fractionation, DNA synthesis assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo/in vitro Co-IP with mutagenesis and functional DNA replication readout, single lab\",\n      \"pmids\": [\"23313748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"RACK1 interacts with the PH domain of p120GAP (RasGAP) in vivo and in vitro; deletion of the PH or C2/CaLB domain of p120GAP abolishes the interaction, and serine/threonine phosphorylation regulates this association.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown with recombinant RACK1, domain-deletion mutants of p120GAP\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus direct pulldown with domain mapping, single lab\",\n      \"pmids\": [\"11350068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HIV-1 Nef binds the C-terminal moiety of RACK1 in yeast two-hybrid and cell-free pulldown assays; Nef and RACK1 partially colocalize on the trans-Golgi network and plasma membrane; RACK1 doubles Nef phosphorylation by PKC in vitro, suggesting RACK1 acts as a Nef–PKC docking adaptor.\",\n      \"method\": \"Yeast two-hybrid, cell-free pulldown, co-purification, in vitro PKC phosphorylation assay, colocalization by microscopy\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple in vitro binding methods plus in vitro kinase assay, single lab\",\n      \"pmids\": [\"11312657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RACK1 binds the BKCa (large conductance Ca2+-activated K+) channel intracellular C-terminal tail; interaction confirmed by GST pulldown and co-immunoprecipitation; co-localization observed in vascular smooth muscle cells; RACK1 affects BKCa channel biophysical properties, suggesting RACK1 forms part of a BKCa regulatory complex.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, immunocytochemistry, electrophysiology\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid plus GST pulldown, Co-IP, and electrophysiology, single lab\",\n      \"pmids\": [\"17166942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SPOP recognizes Ser/Thr-rich motifs on RACK1 and promotes its ubiquitination and proteasomal degradation via the CUL3/RING E3 ligase complex, leading to Smad3-mediated cardiac fibroblast activation and exacerbated cardiac fibrosis after myocardial infarction.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, lentiviral knockdown/overexpression, RACK1 forced expression rescue in SPOP-overexpressing CFs, in vivo MI mouse model\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assays, and rescue experiments with in vivo validation, single lab\",\n      \"pmids\": [\"37442135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"c-Abl kinase maintains RACK1 protein stability at focal adhesions, where RACK1 serves as a scaffold for c-Abl and FAK, driving fibroblast activation and myofibroblast differentiation during renal fibrosis; c-Abl deletion reduces RACK1 expression and diminishes fibrosis.\",\n      \"method\": \"Fibroblast-specific c-Abl conditional KO mice, co-immunoprecipitation, western blot, fibrosis readouts in vivo\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse model plus Co-IP, single lab\",\n      \"pmids\": [\"38689280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RACK1 is required for vaccinia virus postreplicative mRNA translation (via 5′ polyA leaders) independently of its role in ribosome-based stress signaling; RACK1 KO blunts JNK activation during infection only as an indirect consequence of reduced viral protein accumulation, not through direct RSR-mediated signaling.\",\n      \"method\": \"RACK1 knockout cells, viral protein synthesis assays, JNK inhibitors vs. RACK1 KO comparison, RSR activation assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with mechanistic dissection using inhibitors, single lab\",\n      \"pmids\": [\"36098514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RACK1 stably reassociates with the human 40S ribosomal subunit, displays limited conformational dynamics, and remains bound for hours in vitro; fluorescently labeled RACK1 can be used as a stable ribosome tag for single-molecule translation studies.\",\n      \"method\": \"Bulk and single-molecule FRET/fluorescence biochemical assays, engineered fluorescent human RACK1–ribosome complexes\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-molecule biochemical analysis of ribosome binding kinetics, single lab\",\n      \"pmids\": [\"31023766\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RACK1 is a seven-bladed WD40 β-propeller scaffold protein that constitutively occupies the head of the 40S ribosomal subunit and simultaneously recruits activated PKC isoforms, Src family kinases, and multiple signaling proteins to the ribosome, enabling stimulus-dependent phosphorylation of eIF4E and selective IRES-dependent or cap-dependent mRNA translation; off the ribosome, RACK1 acts as an adaptor that links PKC to integrins, scaffolds PKC-mediated JNK activation (via Ser129 phosphorylation), inhibits Src at cell cycle checkpoints to regulate proliferation and E-cadherin stability, suppresses NMDA receptor activity by sequestering Fyn away from NR2B, promotes HIF-1α proteasomal degradation by competing with HSP90 and recruiting the Elongin-C/B E3 ligase, facilitates NLRP3 inflammasome assembly by stabilizing NLRP3's active conformation, regulates circadian period by scaffolding PKCα-mediated BMAL1 phosphorylation, controls NSC senescence by suppressing Smad3/TGF-β/p21 signaling, and is itself regulated by post-translational modifications including Src-mediated phosphorylation (Tyr228/246), O-GlcNAcylation (Ser122), MARylation (by PARP14), and polyubiquitination by SMURF2, TRIM26, TRIM45, SPOP, and UBE2T that control its stability and subcellular localization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RACK1 is a WD40 β-propeller scaffold that constitutively occupies the head of the 40S ribosomal subunit near the mRNA exit channel, where it recruits activated PKC to couple signaling to translational control [#4, #42]. On the ribosome it pairs with PKCβII to drive eIF4E phosphorylation and preferential cap-dependent translation of growth and survival factors, a function exploited in hepatocellular carcinoma and tuned by O-GlcNAcylation at Ser122, which strengthens ribosome binding and PKCβII engagement [#13, #20]. RACK1 is also required for IRES-dependent translation of viral mRNAs and serves as a ribosomal platform for mRNA-specific factors, recruiting miRISC for miRNA-mediated repression, scaffolding the β-actin mRNA/ZBP1 complex, and partnering with Vigilin/SERBP1 to support flaviviral replication [#15, #12, #14, #29]. Beyond the ribosome, RACK1 functions as a multivalent signaling adaptor: it links PKC to integrins, scaffolds PKC-dependent JNK activation through Ser129 phosphorylation, and binds Src family kinases via phosphorylated Tyr228/Tyr246 to control focal adhesion dynamics, migration, osteoclast cytoskeletal integrity, and E-cadherin–based cell adhesion [#0, #5, #2, #3, #22, #11]. It additionally acts as a conformational and degradative regulator of innate immune and stress pathways — promoting the active conformation of NLRP3 to license inflammasome assembly, attenuating RIG-I/MAVS antiviral signaling, and competing with HSP90 to drive HIF-1α degradation via the Elongin-C/B ligase [#25, #21, #7]. RACK1 scaffolds developmental and stress signaling including PKCα-mediated BMAL1 phosphorylation in the circadian clock, Hedgehog pathway control of Ci and Smo, and suppression of TGF-β/Smad3/p21 signaling that prevents neural stem cell senescence during cortical development [#8, #27, #28]. RACK1 abundance and localization are themselves controlled by an extensive set of post-translational modifications, including PARP14-mediated MARylation that drives stress granule association and translational repression, and polyubiquitination by multiple ligases (SMURF2, TRIM26, SPOP) and the E3-independent conjugating enzyme UBE2T [#33, #30, #31, #39, #26].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established RACK1 as a PKC-dependent adaptor linking signaling kinases to membrane receptors, defining its core scaffold function before any ribosomal role was known.\",\n      \"evidence\": \"Yeast two-hybrid and reciprocal Co-IP with integrin β cytoplasmic tails in 293T/JY cells\",\n      \"pmids\": [\"9442085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether integrin binding occurs on or off the ribosome\", \"Structural basis of the WD5–7 interaction surface not determined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined RACK1 as both a Src substrate and an inhibitory scaffold for tyrosine kinases, showing it can suppress rather than only relay kinase activity.\",\n      \"evidence\": \"In vitro kinase assays with Src mutants and Tyr228/246 mutagenesis; Co-IP and hippocampal electrophysiology with peptide disruption of RACK1–NR2B–Fyn\",\n      \"pmids\": [\"12400005\", \"11943848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which a single scaffold both binds and inhibits Src/Fyn not structurally resolved\", \"Tissue-specific selection between activating and inhibitory outputs unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Placed RACK1 physically on the 40S ribosome head near the mRNA exit channel, transforming it from a cytoplasmic adaptor into a structural link between signaling and translation.\",\n      \"evidence\": \"Cryo-EM localization and biochemical reconstitution\",\n      \"pmids\": [\"15577927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ribosomal versus extra-ribosomal pools are partitioned not defined\", \"Direct evidence of eIF6 phosphorylation in cells limited\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed RACK1 acts as a priming scaffold for the JNK cascade, demonstrating it organizes MAPK signaling and not only PKC localization.\",\n      \"evidence\": \"Phospho-specific antibodies, in vitro kinase assays, Ser129 mutagenesis, and siRNA knockdown across multiple stimuli\",\n      \"pmids\": [\"16061178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether JNK priming occurs on the ribosome not addressed\", \"Stoichiometry of the PKC–JNK–RACK1 assembly unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected RACK1's Src inhibition to cell-cycle checkpoint control and growth suppression, expanding its role into proliferation regulation.\",\n      \"evidence\": \"Overexpression/depletion, cell-permeable peptide disruption, and cell-cycle/kinase assays in colon cells\",\n      \"pmids\": [\"17072338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; in vivo cell-cycle relevance not established\", \"Link between Sam68 phosphorylation and CDK1-cyclin B regulation indirect\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed an O2/VHL-independent route to HIF-1α turnover in which RACK1 acts as a degradation adaptor competing with a chaperone.\",\n      \"evidence\": \"Competitive binding, Co-IP, and ubiquitination/stability assays with the Elongin-C/B complex\",\n      \"pmids\": [\"17361105\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological conditions favoring RACK1 over HSP90 binding undefined\", \"In vivo contribution to hypoxic signaling not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended RACK1 to nuclear scaffolding of clock and chromatin machinery, showing it times PKCα-mediated transcriptional repression and gene-specific transcription.\",\n      \"evidence\": \"Co-IP from mouse liver, in vitro kinase assays, siRNA period-length measurement; ChIP at BDNF promoter IV with MeCP2 displacement readout\",\n      \"pmids\": [\"20093473\", \"20410295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How RACK1 is targeted to specific nuclear loci unresolved\", \"Relationship between nuclear and ribosomal pools not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that ribosomal RACK1 couples PKCβII to eIF4E phosphorylation for selective mRNA translation and recruits mRNA-specific factors, mechanistically tying its scaffold role to translational selectivity.\",\n      \"evidence\": \"Ribosome-binding mutants, eIF4E phospho-assays, Co-IP with ZBP1 and miRISC, polysome fractionation, and xenograft validation\",\n      \"pmids\": [\"22653060\", \"22523568\", \"21525958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rules governing which mRNAs are selected not fully defined\", \"Direct contacts between RACK1 and individual mRNP factors not structurally mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated RACK1 is specifically required for IRES-dependent viral translation without affecting bulk translation, distinguishing a dedicated translational function.\",\n      \"evidence\": \"RNAi in Drosophila and human cells with CrPV/HCV IRES reporters and HCV infection assays\",\n      \"pmids\": [\"25416947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for IRES vs. cap-dependent discrimination not resolved\", \"Whether host IRES mRNAs share this dependence unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified O-GlcNAcylation at Ser122 as a regulatory switch enhancing ribosome binding and oncogenic translation, providing a genetic in vivo link to tumorigenesis.\",\n      \"evidence\": \"MS site mapping, Ser122 knock-in mice, Co-IP, eIF4E phospho-assay, and DEN-induced HCC model\",\n      \"pmids\": [\"29454068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling RACK1 O-GlcNAcylation unknown\", \"Interplay with other RACK1 PTMs not examined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a ribosome-independent role for RACK1 as a conformational chaperone for NLRP3 inflammasome activation, including a pathogen-driven deubiquitination axis.\",\n      \"evidence\": \"Co-IP with NLRP3/NEK7, ribosomal-binding mutant, stimulus-specific caspase-1/IL-1β readouts; EST12 crystal structure and UCHL5-mediated NLRP3 deubiquitination\",\n      \"pmids\": [\"33207200\", \"33097533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RACK1 stabilizing active NLRP3 conformation not solved\", \"How RACK1 partitions between inflammasome and ribosome pools unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a developmental in vivo requirement for RACK1 in suppressing TGF-β/Smad3/p21-driven neural stem cell senescence, with genetic rescue confirming the pathway.\",\n      \"evidence\": \"Conditional knockout mice, p21-deletion rescue, Rack1–Smad3 Co-IP, and cortical development phenotyping\",\n      \"pmids\": [\"34469723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism of Smad3 inhibition by RACK1 not structurally defined\", \"Whether ribosomal RACK1 contributes to this phenotype untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped a network of E3 ligases and conjugating enzymes that control RACK1 stability through distinct ubiquitin linkages and acetylation crosstalk, explaining context-dependent RACK1 abundance.\",\n      \"evidence\": \"Co-IP, K-linkage-specific ubiquitination assays, site mutagenesis, and rescue experiments for SMURF2, TRIM26, SPOP, and UBE2T across multiple cancer/fibrosis models\",\n      \"pmids\": [\"37828084\", \"37591850\", \"37442135\", \"33323973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these ligases act on distinct RACK1 pools is unknown\", \"Hierarchy and combinatorial logic among the modifications undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed PARP14-mediated MARylation redirects RACK1 into stress granules to repress translation of specific mRNAs, defining a reversible PTM that toggles RACK1 between active translation and sequestration.\",\n      \"evidence\": \"ADP-ribosylation assays, MARylation-site mutagenesis, stress granule imaging, polysome profiling, and in vivo tumor growth in ovarian cancer cells\",\n      \"pmids\": [\"39760726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MARylated residues and their structural effect on the propeller not fully mapped\", \"Interplay with O-GlcNAcylation and ubiquitination during stress not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the cell partitions a single RACK1 scaffold among its ribosomal, nuclear, inflammasome, focal-adhesion, and stress-granule functions, and how the various PTMs are integrated to dictate this partitioning, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model for spatial allocation of RACK1 pools\", \"Stoichiometry and competition among the many partners not measured\", \"Combinatorial PTM logic governing localization and stability undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 5, 4, 13, 25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 6, 7, 25]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [12, 14, 29]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 42]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [4, 13, 42]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [25, 33]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 9, 28]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 37]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 12, 13, 15, 33]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 2, 6, 16, 31]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [25, 24, 21]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 26, 30, 39]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [18, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [27, 28]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"40S ribosomal subunit\", \"NLRP3 inflammasome\", \"miRISC\", \"stress granule\"],\n    \"partners\": [\"PKC\", \"SRC\", \"NLRP3\", \"NEK7\", \"FYN\", \"ATG5\", \"SMAD3\", \"BMAL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}