{"gene":"STRAP","run_date":"2026-04-28T21:42:57","timeline":{"discoveries":[{"year":1998,"finding":"STRAP (serine-threonine kinase receptor-associated protein) was identified as a novel WD40-domain protein that interacts with TGF-β type I receptor (TβR-I) in a yeast two-hybrid system and associates with both functional TβR-I and TβR-II in vivo. Overexpression of STRAP inhibits TGF-β-mediated transcriptional activation and shows synergistic inhibition with Smad7 but not Smad6.","method":"Yeast two-hybrid, co-immunoprecipitation, transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and functional reporter assays; foundational discovery paper replicated by subsequent studies","pmids":["9856985"],"is_preprint":false},{"year":2000,"finding":"STRAP synergizes specifically with Smad7 (not Smad6) to inhibit TGF-β-induced transcriptional responses by recruiting Smad7 to the activated type I receptor and stabilizing the Smad7-receptor complex, thereby preventing Smad2 and Smad3 access to the receptor. STRAP associates stably with Smad7 but not with a C-terminal deletion mutant of Smad7 that lacks receptor-binding activity. The C terminus of STRAP is required for its phosphorylation in vivo, which depends on TGF-β receptor kinases.","method":"Co-immunoprecipitation, transcriptional reporter assays, deletion mutagenesis, in vivo phosphorylation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, mutagenesis, functional reporters) in a single rigorous study","pmids":["10757800"],"is_preprint":false},{"year":2006,"finding":"STRAP is localized in both cytoplasm and nucleus, and its stable expression activates the MEK/ERK pathway and downregulates the CDK inhibitor p21(Cip1), resulting in retinoblastoma protein hyperphosphorylation. STRAP-knockout mouse embryonic fibroblasts show enhanced Smad2/3 phosphorylation, TGF-β-mediated transcription, and growth inhibition compared to wild-type cells.","method":"Stable overexpression, knockdown by siRNA, western blotting, STRAP-knockout MEFs, subcellular fractionation/localization","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — complementary gain- and loss-of-function experiments with defined molecular readouts","pmids":["16778189"],"is_preprint":false},{"year":2007,"finding":"NM23-H1 and STRAP directly interact with the central DNA-binding domain of p53 (residues 113–290). Specific cysteine residues mediate binding: Cys145 of NM23-H1 and Cys152/Cys270 of STRAP bind p53 at Cys176 and Cys135, respectively. NM23-H1 and STRAP potentiate p53 transcriptional activity and p53-induced apoptosis by removing Mdm2 from the p53-Mdm2 complex.","method":"Co-immunoprecipitation, mutagenesis, transcriptional reporter assays, apoptosis assays, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, mutagenesis of binding residues, and functional validation across multiple endpoints","pmids":["17916563"],"is_preprint":false},{"year":2008,"finding":"ATM kinase directly phosphorylates Strap, prompting its nuclear accumulation by impeding nuclear export. Subsequently, Chk2 kinase phosphorylates Strap to augment protein stability once Strap has attained a nuclear location. These two kinase-dependent events cooperate to regulate Strap during the DNA damage response.","method":"In vitro kinase assays, mutational analysis, nuclear/cytoplasmic fractionation, live-cell imaging","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 — direct kinase assays combined with localization experiments and mutagenesis","pmids":["18833288"],"is_preprint":false},{"year":2008,"finding":"p49/STRAP (SRFBP1) was identified as a cofactor of serum response factor (SRF) and interacts with NDUFAB1, a subunit of NADH dehydrogenase, via yeast two-hybrid. The two proteins co-localize in the cell. Overexpression of p49/STRAP alters intracellular NAD levels, reduces the NAD/NADH ratio, and induces deacetylation of SRF.","method":"Yeast two-hybrid, co-immunoprecipitation, co-localization, NAD/NADH measurement, SRF deacetylation assay","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 3 — yeast two-hybrid and single Co-IP with functional metabolic readout but limited orthogonal validation","pmids":["18230186"],"is_preprint":false},{"year":2009,"finding":"Deletion of STRAP from mouse embryonic fibroblasts (MEFs) results in loss of mesenchymal morphology and acquisition of epithelial features, upregulation of E-cadherin and formation of adherens junctions, β-catenin relocalization to the cell membrane, and downregulation of the mesenchymal marker LEF1. Upregulation of WT1 in STRAP-null MEFs drives E-cadherin induction. Stable re-expression of STRAP reverses this phenotype.","method":"STRAP-knockout MEFs, gene expression profiling, western blotting, immunofluorescence, stable re-expression","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 2 — knockout plus rescue with multiple orthogonal readouts defines pathway placement","pmids":["19781628"],"is_preprint":false},{"year":2010,"finding":"B-MYB is a STRAP-interacting protein; the N-terminal DNA-binding domain and a region (aa 373–468) of B-MYB mediate the interaction. B-MYB enhances STRAP-mediated inhibition of TGF-β signaling by modulating complex formation between the TGF-β receptor and SMAD3 or SMAD7, and stimulates STRAP-mediated p53-induced apoptosis and cell cycle arrest. B-MYB prevents Smad3 nuclear translocation and promotes p53 nuclear translocation.","method":"Co-immunoprecipitation, deletion mapping, transcriptional reporter assays, confocal microscopy, apoptosis assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — mapping of interaction domains combined with functional pathway assays","pmids":["21148321"],"is_preprint":false},{"year":2011,"finding":"STRAP binds GSK3β through its WD40 domains, and STRAP, GSK3β, and Axin form a ternary complex. The intracellular fragment of Notch3 (ICN3) binds GSK3β through its ankyrin repeat domain and also binds STRAP through the ankyrin repeat region. STRAP reduces ubiquitination of ICN3, stabilizing it. Small-molecule GSK3β inhibitors reduce the STRAP-GSK3β interaction.","method":"Co-immunoprecipitation, deletion mapping, in vivo ubiquitination assay, small-molecule inhibitor treatment","journal":"Cell cycle","confidence":"High","confidence_rationale":"Tier 2 — multiple Co-IPs defining a ternary complex plus functional ubiquitination assay","pmids":["21502811"],"is_preprint":false},{"year":2011,"finding":"STRAP regulates c-Jun stability by decreasing its ubiquitylation and proteasomal degradation. Loss of STRAP in MEFs reduces phospho-c-Jun and total c-Jun, decreases cyclin D1 expression, and reduces cell growth. Overexpression of STRAP in STRAP-null fibroblasts restores c-Jun expression, and STRAP overexpression decreases ubiquitylation of c-Jun in 293T cells.","method":"STRAP-knockout MEFs, proteasome inhibition assay, ubiquitylation assay, stable re-expression, western blotting","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function and gain-of-function with direct ubiquitylation assay","pmids":["21397588"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of full-length Strap (stress-responsive activator of p300) was solved at 2.05 Å resolution, revealing an atypical six-tetratricopeptide repeat (TPR) protein that also contains an unexpected oligonucleotide/oligosaccharide-binding (OB)-fold domain. This domain organization provides an extended superhelical scaffold for protein-protein and protein-DNA interactions. Both TPR and OB-fold domains localize to chromatin of p53 target genes and exhibit intrinsic regulatory activity necessary for the Strap-dependent p53 response.","method":"X-ray crystallography, chromatin immunoprecipitation (ChIP), functional reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structure at high resolution with functional chromatin validation","pmids":["22362889"],"is_preprint":false},{"year":2013,"finding":"STRAP is tethered to collagen α1(I) and α2(I) mRNAs via interaction with LARP6 (which directly binds the 5' stem-loop of collagen mRNAs) through LARP6's C-terminal domain. Tethered STRAP restrains translation of collagen α2(I) mRNA by interacting with eIF4A. In the absence of STRAP, collagen α2(I) mRNA is unrestrictedly loaded onto polysomes, causing imbalanced synthesis of α1(I) and α2(I) polypeptides, hypermodification of α1(I), and inefficient assembly of the collagen trimer. Supplementing STRAP partially restores these defects.","method":"RNA pulldown, polysome profiling, co-immunoprecipitation, siRNA knockdown, rescue experiment, collagen secretion assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing STRAP's role in translation regulation of collagen mRNAs","pmids":["23918805"],"is_preprint":false},{"year":2014,"finding":"MPK38 (murine protein serine/threonine kinase 38) directly phosphorylates STRAP at Ser188 via direct interaction. The STRAP-MPK38 complex is formed through Cys152 and Cys270 of STRAP and Cys339 and Cys377 of MPK38, suggesting redox-dependent interaction. MPK38-mediated Ser188 phosphorylation converts STRAP from an anti-apoptotic to a pro-apoptotic regulator, modulating ASK1, TGF-β, p53, and PI3K/PDK1 signaling pathways.","method":"In vitro kinase assay, mutagenesis, inducible shRNA knockdown, adenoviral delivery in mice, cell death assays","journal":"Cell cycle","confidence":"High","confidence_rationale":"Tier 1–2 — direct in vitro kinase assay, mutagenesis of interaction residues, in vivo adenoviral validation","pmids":["25485581"],"is_preprint":false},{"year":2014,"finding":"Strap localizes to mitochondria where it interacts with ATP synthase. This interaction downregulates mitochondrial ATP production. Under glucose-limiting conditions, mitochondrial Strap sensitizes cancer cells to apoptosis. Strap also augments the apoptotic effects of mitochondrial p53.","method":"Subcellular fractionation, co-immunoprecipitation, ATP production assay, apoptosis assays, extracellular ATP rescue","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — fractionation with functional consequence, Co-IP, and rescue experiment","pmids":["25168243"],"is_preprint":false},{"year":2014,"finding":"STRAP downregulates E-cadherin and p21(Cip1) by abrogating the binding of transcription factor Sp1 to its consensus binding sites on these promoters. STRAP recruits HDAC1 to Sp1 binding sites in the p21(Cip1) promoter. Loss of STRAP stabilizes Sp1 by repressing its ubiquitination in G1 phase, leading to enhanced p21(Cip1) expression and cell cycle arrest.","method":"ChIP assay, STRAP-knockout MEFs, siRNA knockdown, luciferase reporter assay, ubiquitination assay, cell cycle analysis","journal":"Cell cycle","confidence":"High","confidence_rationale":"Tier 2 — ChIP + ubiquitination assay + knockout/knockdown with multiple functional readouts","pmids":["25483064"],"is_preprint":false},{"year":2014,"finding":"p49/STRAP overexpression reduces actin content in cultured cells, results in smaller cell size, and causes malformations in transgenic mice including asymmetric abdominal/thoracic cavities and cardiac morphology changes. p49/STRAP co-localizes with nucleolin in the nucleolus and has a BUD22 domain at its C-terminus. p49/STRAP alters expression of muscle-specific genes including the SRF gene.","method":"Transgenic mouse model, GFP co-localization, actin content measurement, gene expression analysis","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — transgenic overexpression with defined morphological phenotype but limited mechanistic depth","pmids":["25183317"],"is_preprint":false},{"year":2016,"finding":"STRAP binds GSK-3β and reduces phosphorylation, ubiquitylation, and degradation of β-catenin by preventing its binding to the destruction complex, thereby activating Wnt/β-catenin signaling and upregulating downstream targets including Cyclin D1, MMP2, MMP9, and β-TrCP. This promotes colorectal cancer invasion and metastasis.","method":"Co-immunoprecipitation, siRNA knockdown, western blotting, in vitro invasion assay, in vivo metastasis model, human CRC specimens","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 — mechanistic Co-IP defining complex disruption plus in vivo validation","pmids":["26910283"],"is_preprint":false},{"year":2016,"finding":"STRAP acts as a scaffold protein in TLR2/4-mediated innate immune signaling by binding TAK1 and IKKα along with NF-κB subunit p65, enhancing TAK1-IKKα-p65 association, and facilitating p65 phosphorylation and nuclear translocation. STRAP depletion severely impairs IL-6, TNF-α, and IL-1β production in macrophages stimulated with TLR2 or TLR4 agonists. The C-terminal region of STRAP is essential for this activity. STRAP also translocates to the nucleus at later times after LPS stimulation to prolong IL-6 mRNA production.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, cytokine ELISA, nuclear translocation assay, C-terminus deletion","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — scaffold function defined by multiple Co-IPs, domain mapping, and cytokine functional assays","pmids":["27934954"],"is_preprint":false},{"year":2017,"finding":"STRAP acts as a scaffold protein in TLR3-triggered signaling by interacting with TBK1 and IRF3, enhancing IFN-β production. STRAP knockdown reduces both pro-inflammatory cytokine and IFN production in TLR3 agonist-stimulated macrophages. The C-terminus of STRAP is essential for its function in TLR3-mediated IL-6 and IFN-β production.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, cytokine ELISA, C-terminus deletion","journal":"Cellular immunology","confidence":"High","confidence_rationale":"Tier 2 — interaction mapped and confirmed by functional assays with domain requirements established","pmids":["28651742"],"is_preprint":false},{"year":2017,"finding":"STRAP antagonizes formation of the PRC2 chromatin modifier complex by competitively disrupting the association of PRC2 subunits EZH2 and SUZ12, thereby inhibiting PRC2 assembly and reducing H3K27me3 marks on NOTCH pathway gene promoters. This epigenetically activates NOTCH signaling and maintains cancer stem cell subpopulations in colorectal cancer. Restoring the NOTCH pathway by expressing NICD1 or HES1 in STRAP-depleted cells reverses the CSC phenotype.","method":"Co-immunoprecipitation, ChIP-seq, siRNA knockdown, lentiviral rescue, in vitro and in vivo tumor assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — mechanistic epigenetic pathway placement with rescue experiment and in vivo validation","pmids":["28827371"],"is_preprint":false},{"year":2018,"finding":"STRAP interacts with MELK (maternal embryonic leucine zipper kinase) and their association is phosphorylation-dependent. Sanguinarine dephosphorylates STRAP and MELK and disrupts their interaction, triggering Bax-dependent intrinsic apoptosis in colorectal cancer cells.","method":"Co-immunoprecipitation, immunofluorescence, in vitro kinase activity assay, western blotting, in vivo orthotopic model","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus functional apoptosis assays, but mechanistic link is pharmacological rather than genetic","pmids":["29783958"],"is_preprint":false},{"year":2018,"finding":"Strap associates with Csde1 (Cold shock domain protein e1/Unr) in erythroblasts and is the most strongly associated protein with Csde1. Reduced Strap expression alters mRNA and/or protein expression of several Csde1-bound transcripts involved in translational regulation during hypoxia (Hmbs, eIF4g3, Pabpc4), as well as Vim and Elavl1, without altering the overall pool of Csde1-bound transcripts.","method":"Co-immunoprecipitation, mass spectrometry, RIP (RNA immunoprecipitation), siRNA knockdown, proteomics","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — proteomic identification of complex plus RIP-based functional follow-up, single lab","pmids":["30138317"],"is_preprint":false},{"year":2019,"finding":"During autophagy, TTC5/STRAP binds JMY and antagonizes JMY's actin nucleation activity. LC3 recruits JMY to the phagophore and promotes its actin nucleation activity. An in vitro reconstitution system demonstrated that membrane-bound LC3 is sufficient to recruit JMY and stimulate JMY-mediated actin filament assembly, while STRAP acts as a negative autophagy regulator by competing with this activation.","method":"In vitro reconstitution, co-immunoprecipitation, actin nucleation assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with membrane-bound LC3 plus functional actin nucleation assay","pmids":["30593260"],"is_preprint":false},{"year":2020,"finding":"STRAP was identified as a spliceosome-associated factor. Upon Strap deletion, numerous alternative splicing events occur in mouse embryoid bodies undergoing neuroectoderm-like differentiation. Global mapping by eCLIP-seq in mouse embryos reveals STRAP preferentially targets transcripts for nervous system development and regulates alternative splicing through preferred binding positions. STRAP is involved in the assembly of 17S U2 snRNP proteins. In Xenopus, loss of Strap impedes lineage differentiation, delays neural tube closure, and alters exon skipping.","method":"eCLIP-seq, STRAP-knockout mouse embryoid bodies, Xenopus loss-of-function, U2 snRNP assembly assay, RNA-seq splicing analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — eCLIP-seq genome-wide binding mapping plus snRNP assembly assay and orthologous Xenopus validation","pmids":["33230114"],"is_preprint":false},{"year":2020,"finding":"GDF5 increases expression of STRAP and NME1 in SH-SY5Y neuronal cells. Expression of both STRAP and NME1 is necessary and sufficient for the promotion of neurite growth by GDF5 in SH-SY5Y cells and in cultured midbrain dopaminergic neurons.","method":"Proteomics, siRNA knockdown, overexpression, neurite length quantification","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — loss- and gain-of-function for neurite growth, but pathway mechanism downstream of STRAP not fully resolved","pmids":["32853992"],"is_preprint":false},{"year":2020,"finding":"STRAP is acetylated at lysines 147, 148, and 156 by the acetyltransferases CBP. The deacetylase SIRT7 reverses this acetylation. Hypo- or hyperacetylation mutations (3KR or 3KQ) of STRAP influence its activation and stabilization of p53. Following 5-FU treatment, STRAP is mobilized from the cytoplasm to the nucleus and promotes STRAP acetylation.","method":"Mass spectrometry identification of acetylation sites, mutagenesis, co-immunoprecipitation, subcellular fractionation, p53 functional assays","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 — site identification with mutagenesis and identification of writer (CBP) and eraser (SIRT7)","pmids":["32527012"],"is_preprint":false},{"year":2024,"finding":"circPCNXL2 directly binds STRAP and induces interaction between STRAP and MEK1/2, resulting in activation of ERK/MAPK pathways and tumor promotion in intrahepatic cholangiocarcinoma.","method":"RNA pulldown, mass spectrometry, RIP (RNA immunoprecipitation), co-immunoprecipitation, luciferase reporter, xenograft model","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-protein interaction confirmed by pulldown and RIP plus co-IP for protein complex, single lab","pmids":["38365721"],"is_preprint":false},{"year":2025,"finding":"The deubiquitinase USP38 stabilizes STRAP via deubiquitination, thereby enhancing TGF-β/SMAD signaling and promoting atrial fibrosis in chronic kidney disease-associated atrial fibrillation. STRAP knockdown reverses the pro-fibrotic effects induced by USP38 overexpression.","method":"Co-immunoprecipitation, ubiquitination assay, cardiomyocyte-specific knockout/overexpression mice, immunofluorescence, STRAP knockdown rescue","journal":"Molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — direct deubiquitination assay, genetic mouse models, and rescue experiment","pmids":["40514673"],"is_preprint":false},{"year":2025,"finding":"The Csde1-Strap complex binds Bach2 mRNA and couples its decay with translation to control the magnitude and duration of Bach2 protein expression during B cell differentiation. In the absence of Csde1 or Strap, Bach2 translation is decoupled from mRNA decay, leading to elevated and prolonged Bach2 protein expression and impaired plasma cell differentiation.","method":"RNA interactome capture, CRISPR/Cas9 screening, RIP, co-immunoprecipitation, mRNA decay assays, polysome profiling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — CRISPR functional screen plus RIP and mRNA decay/translation coupling assays","pmids":["40133358"],"is_preprint":false},{"year":2026,"finding":"iNOS mediates S-nitrosylation of STRAP specifically at Cys152 and Cys270. S-nitrosylation disrupts the STRAP-ASK1 interaction, increases ASK1 activity, activates the MKK3-p38 pathway, and enhances hydrogen peroxide-induced apoptosis. Mutation of Cys152/270 to serine abolishes the STRAP-ASK1 interaction and constitutively activates the ASK1-MKK3-p38 pathway. STRAP specifically interacts with iNOS but not eNOS or nNOS.","method":"S-nitrosylation assay (biotin switch), co-immunoprecipitation, mutagenesis, kinase activity assay, apoptosis assays, iNOS overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct PTM identification with site-specific mutagenesis and in vitro kinase functional validation","pmids":["41519199"],"is_preprint":false},{"year":2005,"finding":"Unrip (STRAP) is integrated into the SMN complex via a stable interaction with Gemin7. It is also found in a mutually exclusive complex with Unr. Unrip is absent from nuclear gems/Cajal bodies and localizes predominantly to the cytoplasm. RNAi-induced reduction of Unrip leads to enhanced accumulation of SMN in the nucleus and increased formation of nuclear gems/Cajal bodies.","method":"Co-immunoprecipitation, RNAi knockdown, immunofluorescence localization, biochemical fractionation","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — biochemical complex characterization with localization plus functional knockdown phenotype","pmids":["16159890"],"is_preprint":false},{"year":2005,"finding":"Unrip (STRAP) directly interacts with Gemin6 and Gemin7 within the SMN complex, also binds a subset of Sm proteins, and unrip-containing SMN complexes are necessary and sufficient to mediate the assembly of spliceosomal snRNPs in vitro.","method":"Biochemical reconstitution of snRNP assembly, co-immunoprecipitation, pulldown assays","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro snRNP assembly reconstitution with defined complex components","pmids":["15848170"],"is_preprint":false},{"year":2009,"finding":"p49/STRAP interacts with the β-sandwich domain of Hsp70. It reduces ATP-hydrolytic activity of Hsp70 stimulated by Hsp40 and inhibits the refolding activity of the Hsp70/Hsp40 chaperone system, functioning as a co-chaperone.","method":"Co-immunoprecipitation, ATPase assay, protein refolding assay, domain mapping","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro enzymatic assay with domain-mapping pulldown, single lab","pmids":["19751705"],"is_preprint":false},{"year":2022,"finding":"STRAP overexpression in neuroblastoma cell lines activates focal adhesion kinase (FAK) downstream targets as measured by kinomic peptide microarray. FAK inhibitor treatment selectively decreased growth of STRAP-overexpressing neuroblastoma cells compared to controls, placing STRAP upstream of FAK in a signaling pathway.","method":"Kinomic peptide microarray (PamChip), stable overexpression, FAK inhibitor (PF-573,228) treatment, proliferation assay","journal":"Journal of pediatric surgery","confidence":"Medium","confidence_rationale":"Tier 2 — kinomic assay plus pharmacological rescue establishing pathway relationship, single lab","pmids":["35272839"],"is_preprint":false}],"current_model":"STRAP is a WD40/TPR-OB fold scaffold protein that functions as a multifunctional regulator: it inhibits TGF-β signaling by recruiting Smad7 to stabilize its complex with activated type I receptors (blocking Smad2/3 access), activates Wnt/β-catenin and ERK/MAPK pathways, regulates p53 activity through interactions with NM23-H1 and by disrupting the p53-Mdm2 complex (and is itself phosphorylated by ATM/Chk2 to accumulate in the nucleus and acetylated by CBP/deacetylated by SIRT7), controls collagen mRNA translation through LARP6 and eIF4A interactions, participates in spliceosomal snRNP assembly via the SMN complex, inhibits JMY-mediated actin nucleation during autophagy, stabilizes proteins such as c-Jun, Notch3/ICN3, and β-catenin by reducing their ubiquitylation, acts as a scaffold for TLR2/4 and TLR3 innate immune signaling through TAK1-IKKα-p65 and TBK1-IRF3 complexes, localizes to mitochondria where it interacts with ATP synthase to suppress oxidative phosphorylation, and is post-translationally regulated by MPK38 phosphorylation at Ser188, USP38-mediated deubiquitination, and iNOS-mediated S-nitrosylation at Cys152/270 which disrupts its interaction with ASK1 to promote apoptosis."},"narrative":{"teleology":[{"year":1998,"claim":"The discovery that STRAP is a WD40-domain protein interacting with TGF-β receptors and inhibiting TGF-β transcription established STRAP as a negative regulator of TGF-β signaling, opening the question of its mechanism of inhibition.","evidence":"Yeast two-hybrid screen and co-IP with TβR-I/TβR-II plus transcriptional reporter assays in mammalian cells","pmids":["9856985"],"confidence":"High","gaps":["Mechanism of inhibition not yet defined","No structural information","Physiological relevance in vivo unknown"]},{"year":2000,"claim":"Demonstrating that STRAP recruits Smad7 to the activated type I receptor and stabilizes the inhibitory complex—blocking Smad2/3 access—defined the molecular mechanism of STRAP-mediated TGF-β pathway inhibition.","evidence":"Co-IP, deletion mutagenesis, and reporter assays showing STRAP–Smad7 cooperativity and receptor complex formation","pmids":["10757800"],"confidence":"High","gaps":["In vivo requirement not yet demonstrated","Post-translational regulation of STRAP unknown","Structural basis of Smad7 interaction unresolved"]},{"year":2005,"claim":"Identification of STRAP (Unrip) as a stable subunit of the SMN complex—binding Gemin6/7 and mediating spliceosomal snRNP assembly in vitro—revealed a second major function distinct from TGF-β signaling and raised the question of how one scaffold serves both pathways.","evidence":"Biochemical reconstitution of snRNP assembly, co-IP defining Gemin6/7 interaction, and RNAi-mediated knockdown showing altered SMN nuclear accumulation","pmids":["16159890","15848170"],"confidence":"High","gaps":["No structural detail of STRAP within the SMN complex","How STRAP partitions between SMN and receptor signaling complexes unknown","Whether snRNP assembly role is relevant to disease phenotypes not tested"]},{"year":2006,"claim":"Using STRAP-knockout MEFs and stable overexpression, STRAP was shown to activate the MEK/ERK pathway and suppress p21 and TGF-β-mediated growth arrest, establishing its role as a proliferative signal beyond TGF-β receptor inhibition.","evidence":"STRAP-knockout MEFs showing enhanced Smad2/3 phosphorylation; overexpression activating ERK and downregulating p21","pmids":["16778189"],"confidence":"High","gaps":["Direct ERK pathway target of STRAP unidentified","Whether STRAP is an oncogene in vivo not addressed"]},{"year":2007,"claim":"Identifying that STRAP and NM23-H1 potentiate p53 activity by displacing Mdm2 from the p53 complex—mapping interaction to specific cysteine residues—established STRAP as a p53 co-activator and connected TGF-β and p53 pathways through a shared scaffold.","evidence":"Co-IP with cysteine mutagenesis, transcriptional reporters, and apoptosis assays","pmids":["17916563"],"confidence":"High","gaps":["No in vivo p53 tumor suppression phenotype for STRAP","Whether STRAP-p53 interaction is constitutive or damage-dependent unknown"]},{"year":2008,"claim":"ATM-dependent phosphorylation driving STRAP nuclear accumulation, followed by Chk2-dependent stabilization, defined how the DNA damage response regulates STRAP subcellular distribution to enhance its nuclear p53 co-activator function.","evidence":"In vitro kinase assays, mutational analysis, and nuclear/cytoplasmic fractionation with live-cell imaging","pmids":["18833288"],"confidence":"High","gaps":["Phosphorylation sites on STRAP not all mapped","Whether nuclear STRAP engages chromatin directly was unknown at this point"]},{"year":2009,"claim":"STRAP deletion caused mesenchymal-to-epithelial transition in MEFs with E-cadherin upregulation and β-catenin membrane relocalization, revealing STRAP as a master regulator of epithelial–mesenchymal identity beyond individual signaling pathways.","evidence":"STRAP-knockout MEFs with gene expression profiling, immunofluorescence, and phenotypic rescue by STRAP re-expression","pmids":["19781628"],"confidence":"High","gaps":["Whether STRAP controls EMT in vivo during development or cancer progression not shown","Upstream signals controlling STRAP in this context unknown"]},{"year":2011,"claim":"Demonstrating that STRAP binds GSK-3β/Axin and stabilizes Notch3 ICN and c-Jun by reducing their ubiquitylation established STRAP as a general protein stabilizer acting through the GSK-3β–destruction complex axis and ubiquitin-proteasome modulation.","evidence":"Co-IP defining STRAP–GSK-3β–Axin ternary complex, ubiquitination assays for ICN3 and c-Jun, and STRAP-knockout/rescue MEFs","pmids":["21502811","21397588"],"confidence":"High","gaps":["Whether STRAP directly inhibits an E3 ligase or acts indirectly through GSK-3β unclear","Structural basis of STRAP–GSK-3β interaction unresolved"]},{"year":2012,"claim":"The crystal structure at 2.05 Å revealed an unexpected TPR–OB-fold architecture rather than a canonical WD40 domain, redefining STRAP's structural classification and explaining its capacity for diverse protein and chromatin interactions.","evidence":"X-ray crystallography of full-length Strap, ChIP on p53 target genes, and functional reporter assays","pmids":["22362889"],"confidence":"High","gaps":["Structures of STRAP in complex with any partner remain unsolved","How the OB-fold domain contacts DNA specifically unknown"]},{"year":2013,"claim":"STRAP was shown to control collagen mRNA translation by being tethered via LARP6 to collagen 5′ stem-loops and restraining eIF4A-dependent ribosome loading, revealing a post-transcriptional regulatory function critical for balanced collagen trimer assembly.","evidence":"RNA pulldown, polysome profiling, co-IP, siRNA knockdown, and collagen secretion rescue","pmids":["23918805"],"confidence":"High","gaps":["How STRAP inhibits eIF4A helicase activity mechanistically unknown","Whether this function operates in fibrotic disease contexts not tested"]},{"year":2014,"claim":"Multiple studies converged to define STRAP's post-translational regulation: MPK38 phosphorylation at Ser188 switches STRAP from anti-apoptotic to pro-apoptotic, STRAP recruits HDAC1 to repress Sp1-dependent transcription, and mitochondrial STRAP suppresses ATP synthase to modulate energy metabolism and apoptosis.","evidence":"In vitro kinase assays with Ser188 mutagenesis, ChIP for HDAC1/Sp1 at p21 promoter, mitochondrial fractionation with ATP production assays","pmids":["25485581","25483064","25168243"],"confidence":"High","gaps":["Whether MPK38–STRAP axis operates in vivo under physiological stress unknown","How STRAP is targeted to mitochondria undefined","Relationship between mitochondrial and nuclear STRAP pools unexplored"]},{"year":2016,"claim":"STRAP was established as a scaffold for innate immune signaling: it bridges TAK1–IKKα–p65 downstream of TLR2/4 and promotes cytokine production, while also activating Wnt/β-catenin signaling by binding GSK-3β to prevent β-catenin destruction complex formation in colorectal cancer.","evidence":"Co-IP defining TAK1–IKKα–p65 scaffolding, cytokine ELISAs with STRAP knockdown in macrophages, and GSK-3β/β-catenin interaction studies with in vivo metastasis model","pmids":["27934954","26910283"],"confidence":"High","gaps":["Whether STRAP scaffold function in immunity requires the same domains as in TGF-β inhibition not fully mapped","No structural model of STRAP immune signaling complexes"]},{"year":2017,"claim":"Extension of STRAP's innate immune scaffold function to TLR3 signaling via TBK1–IRF3 interaction and STRAP's disruption of PRC2 assembly to epigenetically activate NOTCH signaling broadened the scope of STRAP from a receptor-proximal scaffold to a chromatin-level regulatory platform.","evidence":"Co-IP and cytokine assays for TLR3/TBK1/IRF3; ChIP-seq showing reduced H3K27me3 at NOTCH gene promoters upon STRAP expression with rescue experiments","pmids":["28651742","28827371"],"confidence":"High","gaps":["Whether STRAP directly contacts EZH2 or acts through an intermediary not fully resolved","In vivo immune phenotype of STRAP loss not established"]},{"year":2019,"claim":"Reconstitution experiments showed that STRAP/TTC5 inhibits JMY-mediated actin nucleation at phagophore membranes, identifying STRAP as a negative regulator of autophagy that acts by competing with LC3-dependent JMY activation.","evidence":"In vitro reconstitution with membrane-bound LC3, actin nucleation assay, and co-IP","pmids":["30593260"],"confidence":"High","gaps":["Physiological relevance of STRAP autophagy inhibition in vivo unknown","Whether this connects to STRAP's other cytoplasmic functions unaddressed"]},{"year":2020,"claim":"Genome-wide eCLIP-seq in mouse embryos and snRNP assembly assays revealed that STRAP directly binds RNA, preferentially targets neurodevelopmental transcripts, regulates U2 snRNP assembly and alternative splicing, and is required for neural tube closure in Xenopus—unifying its SMN complex role with a direct RNA-binding and splicing regulatory function.","evidence":"eCLIP-seq, STRAP-knockout embryoid bodies, U2 snRNP assembly assay, Xenopus morpholino knockdown, RNA-seq splicing analysis","pmids":["33230114"],"confidence":"High","gaps":["Whether STRAP binds RNA through the OB-fold domain not determined","Human neurodevelopmental disease association not established"]},{"year":2020,"claim":"Identification of CBP as the acetyltransferase and SIRT7 as the deacetylase for STRAP at Lys147/148/156 provided a regulatory PTM code that tunes STRAP's p53 co-activator function, complementing the earlier ATM/Chk2 phosphorylation axis.","evidence":"Mass spectrometry acetylation site mapping, mutagenesis (3KR/3KQ), co-IP for CBP and SIRT7, p53 functional assays","pmids":["32527012"],"confidence":"High","gaps":["How acetylation and phosphorylation are coordinated on STRAP unclear","Whether acetylation affects non-p53 functions of STRAP unknown"]},{"year":2025,"claim":"The Csde1–Strap complex was shown to couple Bach2 mRNA decay with translation to control plasma cell differentiation, and USP38 was identified as the deubiquitinase stabilizing STRAP to enhance TGF-β/SMAD-dependent atrial fibrosis, revealing tissue-specific post-translational and RNA-level regulatory circuits centered on STRAP.","evidence":"CRISPR screen, RIP, mRNA decay/polysome assays for Csde1–Strap–Bach2; deubiquitination assay and cardiomyocyte-specific mouse genetics for USP38–STRAP","pmids":["40133358","40514673"],"confidence":"High","gaps":["Whether USP38 regulation of STRAP is relevant outside cardiac fibrosis not tested","Structural basis of Csde1–Strap complex unknown"]},{"year":2026,"claim":"iNOS-mediated S-nitrosylation of STRAP at Cys152/270 disrupts its interaction with ASK1, activating the ASK1–MKK3–p38 apoptotic axis—demonstrating that the same cysteine residues used for multiple protein interactions are also redox-regulated switches.","evidence":"Biotin switch S-nitrosylation assay, cysteine-to-serine mutagenesis, kinase activity assays, apoptosis assays","pmids":["41519199"],"confidence":"High","gaps":["Whether S-nitrosylation also disrupts STRAP–p53 or STRAP–MPK38 interactions not tested","In vivo relevance in inflammatory or ischemic contexts not established"]},{"year":null,"claim":"Key unresolved questions include: how STRAP partitions among its many complexes (SMN, TGF-β receptor, TLR, mitochondria, chromatin) in a cell-type-specific manner; whether high-resolution structures of STRAP bound to its partners will reveal allosteric mechanisms; and whether STRAP mutations cause human developmental or immune disease.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of any STRAP–partner complex","No Mendelian disease linked to STRAP mutations","Cell-type-specific partitioning mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,17,18]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[23,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,12,22,29]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[14,19]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,30]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,4,10]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,8,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,18]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[23,30,31]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,12,13,29]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[22]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[14,19]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11,25]}],"complexes":["SMN complex","Csde1-Strap complex","TAK1-IKKα-p65 signaling complex"],"partners":["SMAD7","GSK3B","TP53","GEMIN7","CSDE1","LARP6","JMY","TBK1"],"other_free_text":[]},"mechanistic_narrative":"STRAP (serine-threonine kinase receptor-associated protein/TTC5/Unrip) is a multifunctional scaffold protein that integrates TGF-β, Wnt/β-catenin, p53, innate immune, and spliceosomal pathways. Structurally, STRAP adopts a six-TPR plus OB-fold architecture that provides an extended superhelical surface for diverse protein–protein and protein–nucleic acid interactions [PMID:22362889]. In TGF-β signaling, STRAP recruits Smad7 to activated type I receptors, stabilizing the inhibitory Smad7–receptor complex and blocking Smad2/3 access [PMID:10757800]; it activates Wnt/β-catenin signaling by binding GSK-3β and preventing β-catenin phosphorylation and degradation [PMID:26910283]; it potentiates p53 transcriptional activity by displacing Mdm2 from p53, a function modulated by ATM/Chk2-dependent nuclear accumulation and CBP/SIRT7-regulated acetylation [PMID:17916563, PMID:18833288, PMID:32527012]. Additionally, STRAP is an integral subunit of the SMN complex—interacting with Gemin6/7 to mediate spliceosomal snRNP assembly [PMID:15848170]—regulates collagen mRNA translation through LARP6 and eIF4A [PMID:23918805], couples Bach2 mRNA decay with translation via the Csde1–Strap complex to control B cell differentiation [PMID:40133358], inhibits JMY-mediated actin nucleation during autophagy [PMID:30593260], scaffolds TLR2/4 and TLR3 innate immune signaling through TAK1–IKKα–p65 and TBK1–IRF3 complexes [PMID:27934954, PMID:28651742], and localizes to mitochondria where it suppresses ATP synthase-dependent oxidative phosphorylation [PMID:25168243]."},"prefetch_data":{"uniprot":{"accession":"Q9Y3F4","full_name":"Serine-threonine kinase receptor-associated protein","aliases":["MAP activator with WD repeats","UNR-interacting protein","WD-40 repeat protein PT-WD"],"length_aa":350,"mass_kda":38.4,"function":"The SMN complex catalyzes the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome, and thereby plays an important role in the splicing of cellular pre-mRNAs. Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (Sm core). In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP. To assemble core snRNPs, the SMN complex accepts the trapped 5Sm proteins from CLNS1A forming an intermediate. Binding of snRNA inside 5Sm triggers eviction of the SMN complex, thereby allowing binding of SNRPD3 and SNRPB to complete assembly of the core snRNP. STRAP plays a role in the cellular distribution of the SMN complex. Negatively regulates TGF-beta signaling but positively regulates the PDPK1 kinase activity by enhancing its autophosphorylation and by significantly reducing the association of PDPK1 with 14-3-3 protein","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y3F4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/STRAP","classification":"Common 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GEMIN7","url":"https://www.omim.org/entry/607419"},{"mim_id":"607006","title":"GEM NUCLEAR ORGANELLE-ASSOCIATED PROTEIN 6; GEMIN6","url":"https://www.omim.org/entry/607006"},{"mim_id":"605986","title":"SERINE/THREONINE KINASE RECEPTOR-ASSOCIATED PROTEIN; STRAP","url":"https://www.omim.org/entry/605986"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/STRAP"},"hgnc":{"alias_symbol":["UNRIP","pt-wd","MAWD"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y3F4","domains":[{"cath_id":"2.130.10.10","chopping":"16-181","consensus_level":"medium","plddt":97.6925,"start":16,"end":181},{"cath_id":"2.130.10.10","chopping":"193-295","consensus_level":"medium","plddt":96.7245,"start":193,"end":295}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3F4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3F4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3F4-F1-predicted_aligned_error_v6.png","plddt_mean":89.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STRAP","jax_strain_url":"https://www.jax.org/strain/search?query=STRAP"},"sequence":{"accession":"Q9Y3F4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y3F4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y3F4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3F4"}},"corpus_meta":[{"pmid":"24678027","id":"PMC_24678027","title":"Suspension 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Overexpression of STRAP inhibits TGF-β-mediated transcriptional activation and shows synergistic inhibition with Smad7 but not Smad6.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and functional reporter assays; foundational discovery paper replicated by subsequent studies\",\n      \"pmids\": [\"9856985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"STRAP synergizes specifically with Smad7 (not Smad6) to inhibit TGF-β-induced transcriptional responses by recruiting Smad7 to the activated type I receptor and stabilizing the Smad7-receptor complex, thereby preventing Smad2 and Smad3 access to the receptor. STRAP associates stably with Smad7 but not with a C-terminal deletion mutant of Smad7 that lacks receptor-binding activity. The C terminus of STRAP is required for its phosphorylation in vivo, which depends on TGF-β receptor kinases.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assays, deletion mutagenesis, in vivo phosphorylation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, mutagenesis, functional reporters) in a single rigorous study\",\n      \"pmids\": [\"10757800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"STRAP is localized in both cytoplasm and nucleus, and its stable expression activates the MEK/ERK pathway and downregulates the CDK inhibitor p21(Cip1), resulting in retinoblastoma protein hyperphosphorylation. STRAP-knockout mouse embryonic fibroblasts show enhanced Smad2/3 phosphorylation, TGF-β-mediated transcription, and growth inhibition compared to wild-type cells.\",\n      \"method\": \"Stable overexpression, knockdown by siRNA, western blotting, STRAP-knockout MEFs, subcellular fractionation/localization\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — complementary gain- and loss-of-function experiments with defined molecular readouts\",\n      \"pmids\": [\"16778189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NM23-H1 and STRAP directly interact with the central DNA-binding domain of p53 (residues 113–290). Specific cysteine residues mediate binding: Cys145 of NM23-H1 and Cys152/Cys270 of STRAP bind p53 at Cys176 and Cys135, respectively. NM23-H1 and STRAP potentiate p53 transcriptional activity and p53-induced apoptosis by removing Mdm2 from the p53-Mdm2 complex.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis, transcriptional reporter assays, apoptosis assays, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, mutagenesis of binding residues, and functional validation across multiple endpoints\",\n      \"pmids\": [\"17916563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ATM kinase directly phosphorylates Strap, prompting its nuclear accumulation by impeding nuclear export. Subsequently, Chk2 kinase phosphorylates Strap to augment protein stability once Strap has attained a nuclear location. These two kinase-dependent events cooperate to regulate Strap during the DNA damage response.\",\n      \"method\": \"In vitro kinase assays, mutational analysis, nuclear/cytoplasmic fractionation, live-cell imaging\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct kinase assays combined with localization experiments and mutagenesis\",\n      \"pmids\": [\"18833288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"p49/STRAP (SRFBP1) was identified as a cofactor of serum response factor (SRF) and interacts with NDUFAB1, a subunit of NADH dehydrogenase, via yeast two-hybrid. The two proteins co-localize in the cell. Overexpression of p49/STRAP alters intracellular NAD levels, reduces the NAD/NADH ratio, and induces deacetylation of SRF.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-localization, NAD/NADH measurement, SRF deacetylation assay\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid and single Co-IP with functional metabolic readout but limited orthogonal validation\",\n      \"pmids\": [\"18230186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Deletion of STRAP from mouse embryonic fibroblasts (MEFs) results in loss of mesenchymal morphology and acquisition of epithelial features, upregulation of E-cadherin and formation of adherens junctions, β-catenin relocalization to the cell membrane, and downregulation of the mesenchymal marker LEF1. Upregulation of WT1 in STRAP-null MEFs drives E-cadherin induction. Stable re-expression of STRAP reverses this phenotype.\",\n      \"method\": \"STRAP-knockout MEFs, gene expression profiling, western blotting, immunofluorescence, stable re-expression\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockout plus rescue with multiple orthogonal readouts defines pathway placement\",\n      \"pmids\": [\"19781628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"B-MYB is a STRAP-interacting protein; the N-terminal DNA-binding domain and a region (aa 373–468) of B-MYB mediate the interaction. B-MYB enhances STRAP-mediated inhibition of TGF-β signaling by modulating complex formation between the TGF-β receptor and SMAD3 or SMAD7, and stimulates STRAP-mediated p53-induced apoptosis and cell cycle arrest. B-MYB prevents Smad3 nuclear translocation and promotes p53 nuclear translocation.\",\n      \"method\": \"Co-immunoprecipitation, deletion mapping, transcriptional reporter assays, confocal microscopy, apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mapping of interaction domains combined with functional pathway assays\",\n      \"pmids\": [\"21148321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STRAP binds GSK3β through its WD40 domains, and STRAP, GSK3β, and Axin form a ternary complex. The intracellular fragment of Notch3 (ICN3) binds GSK3β through its ankyrin repeat domain and also binds STRAP through the ankyrin repeat region. STRAP reduces ubiquitination of ICN3, stabilizing it. Small-molecule GSK3β inhibitors reduce the STRAP-GSK3β interaction.\",\n      \"method\": \"Co-immunoprecipitation, deletion mapping, in vivo ubiquitination assay, small-molecule inhibitor treatment\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple Co-IPs defining a ternary complex plus functional ubiquitination assay\",\n      \"pmids\": [\"21502811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STRAP regulates c-Jun stability by decreasing its ubiquitylation and proteasomal degradation. Loss of STRAP in MEFs reduces phospho-c-Jun and total c-Jun, decreases cyclin D1 expression, and reduces cell growth. Overexpression of STRAP in STRAP-null fibroblasts restores c-Jun expression, and STRAP overexpression decreases ubiquitylation of c-Jun in 293T cells.\",\n      \"method\": \"STRAP-knockout MEFs, proteasome inhibition assay, ubiquitylation assay, stable re-expression, western blotting\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and gain-of-function with direct ubiquitylation assay\",\n      \"pmids\": [\"21397588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of full-length Strap (stress-responsive activator of p300) was solved at 2.05 Å resolution, revealing an atypical six-tetratricopeptide repeat (TPR) protein that also contains an unexpected oligonucleotide/oligosaccharide-binding (OB)-fold domain. This domain organization provides an extended superhelical scaffold for protein-protein and protein-DNA interactions. Both TPR and OB-fold domains localize to chromatin of p53 target genes and exhibit intrinsic regulatory activity necessary for the Strap-dependent p53 response.\",\n      \"method\": \"X-ray crystallography, chromatin immunoprecipitation (ChIP), functional reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure at high resolution with functional chromatin validation\",\n      \"pmids\": [\"22362889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"STRAP is tethered to collagen α1(I) and α2(I) mRNAs via interaction with LARP6 (which directly binds the 5' stem-loop of collagen mRNAs) through LARP6's C-terminal domain. Tethered STRAP restrains translation of collagen α2(I) mRNA by interacting with eIF4A. In the absence of STRAP, collagen α2(I) mRNA is unrestrictedly loaded onto polysomes, causing imbalanced synthesis of α1(I) and α2(I) polypeptides, hypermodification of α1(I), and inefficient assembly of the collagen trimer. Supplementing STRAP partially restores these defects.\",\n      \"method\": \"RNA pulldown, polysome profiling, co-immunoprecipitation, siRNA knockdown, rescue experiment, collagen secretion assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing STRAP's role in translation regulation of collagen mRNAs\",\n      \"pmids\": [\"23918805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MPK38 (murine protein serine/threonine kinase 38) directly phosphorylates STRAP at Ser188 via direct interaction. The STRAP-MPK38 complex is formed through Cys152 and Cys270 of STRAP and Cys339 and Cys377 of MPK38, suggesting redox-dependent interaction. MPK38-mediated Ser188 phosphorylation converts STRAP from an anti-apoptotic to a pro-apoptotic regulator, modulating ASK1, TGF-β, p53, and PI3K/PDK1 signaling pathways.\",\n      \"method\": \"In vitro kinase assay, mutagenesis, inducible shRNA knockdown, adenoviral delivery in mice, cell death assays\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct in vitro kinase assay, mutagenesis of interaction residues, in vivo adenoviral validation\",\n      \"pmids\": [\"25485581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Strap localizes to mitochondria where it interacts with ATP synthase. This interaction downregulates mitochondrial ATP production. Under glucose-limiting conditions, mitochondrial Strap sensitizes cancer cells to apoptosis. Strap also augments the apoptotic effects of mitochondrial p53.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, ATP production assay, apoptosis assays, extracellular ATP rescue\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — fractionation with functional consequence, Co-IP, and rescue experiment\",\n      \"pmids\": [\"25168243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STRAP downregulates E-cadherin and p21(Cip1) by abrogating the binding of transcription factor Sp1 to its consensus binding sites on these promoters. STRAP recruits HDAC1 to Sp1 binding sites in the p21(Cip1) promoter. Loss of STRAP stabilizes Sp1 by repressing its ubiquitination in G1 phase, leading to enhanced p21(Cip1) expression and cell cycle arrest.\",\n      \"method\": \"ChIP assay, STRAP-knockout MEFs, siRNA knockdown, luciferase reporter assay, ubiquitination assay, cell cycle analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + ubiquitination assay + knockout/knockdown with multiple functional readouts\",\n      \"pmids\": [\"25483064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"p49/STRAP overexpression reduces actin content in cultured cells, results in smaller cell size, and causes malformations in transgenic mice including asymmetric abdominal/thoracic cavities and cardiac morphology changes. p49/STRAP co-localizes with nucleolin in the nucleolus and has a BUD22 domain at its C-terminus. p49/STRAP alters expression of muscle-specific genes including the SRF gene.\",\n      \"method\": \"Transgenic mouse model, GFP co-localization, actin content measurement, gene expression analysis\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic overexpression with defined morphological phenotype but limited mechanistic depth\",\n      \"pmids\": [\"25183317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"STRAP binds GSK-3β and reduces phosphorylation, ubiquitylation, and degradation of β-catenin by preventing its binding to the destruction complex, thereby activating Wnt/β-catenin signaling and upregulating downstream targets including Cyclin D1, MMP2, MMP9, and β-TrCP. This promotes colorectal cancer invasion and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, western blotting, in vitro invasion assay, in vivo metastasis model, human CRC specimens\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic Co-IP defining complex disruption plus in vivo validation\",\n      \"pmids\": [\"26910283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"STRAP acts as a scaffold protein in TLR2/4-mediated innate immune signaling by binding TAK1 and IKKα along with NF-κB subunit p65, enhancing TAK1-IKKα-p65 association, and facilitating p65 phosphorylation and nuclear translocation. STRAP depletion severely impairs IL-6, TNF-α, and IL-1β production in macrophages stimulated with TLR2 or TLR4 agonists. The C-terminal region of STRAP is essential for this activity. STRAP also translocates to the nucleus at later times after LPS stimulation to prolong IL-6 mRNA production.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, cytokine ELISA, nuclear translocation assay, C-terminus deletion\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — scaffold function defined by multiple Co-IPs, domain mapping, and cytokine functional assays\",\n      \"pmids\": [\"27934954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STRAP acts as a scaffold protein in TLR3-triggered signaling by interacting with TBK1 and IRF3, enhancing IFN-β production. STRAP knockdown reduces both pro-inflammatory cytokine and IFN production in TLR3 agonist-stimulated macrophages. The C-terminus of STRAP is essential for its function in TLR3-mediated IL-6 and IFN-β production.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, cytokine ELISA, C-terminus deletion\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — interaction mapped and confirmed by functional assays with domain requirements established\",\n      \"pmids\": [\"28651742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STRAP antagonizes formation of the PRC2 chromatin modifier complex by competitively disrupting the association of PRC2 subunits EZH2 and SUZ12, thereby inhibiting PRC2 assembly and reducing H3K27me3 marks on NOTCH pathway gene promoters. This epigenetically activates NOTCH signaling and maintains cancer stem cell subpopulations in colorectal cancer. Restoring the NOTCH pathway by expressing NICD1 or HES1 in STRAP-depleted cells reverses the CSC phenotype.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, siRNA knockdown, lentiviral rescue, in vitro and in vivo tumor assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic epigenetic pathway placement with rescue experiment and in vivo validation\",\n      \"pmids\": [\"28827371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"STRAP interacts with MELK (maternal embryonic leucine zipper kinase) and their association is phosphorylation-dependent. Sanguinarine dephosphorylates STRAP and MELK and disrupts their interaction, triggering Bax-dependent intrinsic apoptosis in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, in vitro kinase activity assay, western blotting, in vivo orthotopic model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional apoptosis assays, but mechanistic link is pharmacological rather than genetic\",\n      \"pmids\": [\"29783958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Strap associates with Csde1 (Cold shock domain protein e1/Unr) in erythroblasts and is the most strongly associated protein with Csde1. Reduced Strap expression alters mRNA and/or protein expression of several Csde1-bound transcripts involved in translational regulation during hypoxia (Hmbs, eIF4g3, Pabpc4), as well as Vim and Elavl1, without altering the overall pool of Csde1-bound transcripts.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, RIP (RNA immunoprecipitation), siRNA knockdown, proteomics\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomic identification of complex plus RIP-based functional follow-up, single lab\",\n      \"pmids\": [\"30138317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"During autophagy, TTC5/STRAP binds JMY and antagonizes JMY's actin nucleation activity. LC3 recruits JMY to the phagophore and promotes its actin nucleation activity. An in vitro reconstitution system demonstrated that membrane-bound LC3 is sufficient to recruit JMY and stimulate JMY-mediated actin filament assembly, while STRAP acts as a negative autophagy regulator by competing with this activation.\",\n      \"method\": \"In vitro reconstitution, co-immunoprecipitation, actin nucleation assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with membrane-bound LC3 plus functional actin nucleation assay\",\n      \"pmids\": [\"30593260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STRAP was identified as a spliceosome-associated factor. Upon Strap deletion, numerous alternative splicing events occur in mouse embryoid bodies undergoing neuroectoderm-like differentiation. Global mapping by eCLIP-seq in mouse embryos reveals STRAP preferentially targets transcripts for nervous system development and regulates alternative splicing through preferred binding positions. STRAP is involved in the assembly of 17S U2 snRNP proteins. In Xenopus, loss of Strap impedes lineage differentiation, delays neural tube closure, and alters exon skipping.\",\n      \"method\": \"eCLIP-seq, STRAP-knockout mouse embryoid bodies, Xenopus loss-of-function, U2 snRNP assembly assay, RNA-seq splicing analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — eCLIP-seq genome-wide binding mapping plus snRNP assembly assay and orthologous Xenopus validation\",\n      \"pmids\": [\"33230114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GDF5 increases expression of STRAP and NME1 in SH-SY5Y neuronal cells. Expression of both STRAP and NME1 is necessary and sufficient for the promotion of neurite growth by GDF5 in SH-SY5Y cells and in cultured midbrain dopaminergic neurons.\",\n      \"method\": \"Proteomics, siRNA knockdown, overexpression, neurite length quantification\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss- and gain-of-function for neurite growth, but pathway mechanism downstream of STRAP not fully resolved\",\n      \"pmids\": [\"32853992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STRAP is acetylated at lysines 147, 148, and 156 by the acetyltransferases CBP. The deacetylase SIRT7 reverses this acetylation. Hypo- or hyperacetylation mutations (3KR or 3KQ) of STRAP influence its activation and stabilization of p53. Following 5-FU treatment, STRAP is mobilized from the cytoplasm to the nucleus and promotes STRAP acetylation.\",\n      \"method\": \"Mass spectrometry identification of acetylation sites, mutagenesis, co-immunoprecipitation, subcellular fractionation, p53 functional assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — site identification with mutagenesis and identification of writer (CBP) and eraser (SIRT7)\",\n      \"pmids\": [\"32527012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"circPCNXL2 directly binds STRAP and induces interaction between STRAP and MEK1/2, resulting in activation of ERK/MAPK pathways and tumor promotion in intrahepatic cholangiocarcinoma.\",\n      \"method\": \"RNA pulldown, mass spectrometry, RIP (RNA immunoprecipitation), co-immunoprecipitation, luciferase reporter, xenograft model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-protein interaction confirmed by pulldown and RIP plus co-IP for protein complex, single lab\",\n      \"pmids\": [\"38365721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The deubiquitinase USP38 stabilizes STRAP via deubiquitination, thereby enhancing TGF-β/SMAD signaling and promoting atrial fibrosis in chronic kidney disease-associated atrial fibrillation. STRAP knockdown reverses the pro-fibrotic effects induced by USP38 overexpression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, cardiomyocyte-specific knockout/overexpression mice, immunofluorescence, STRAP knockdown rescue\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct deubiquitination assay, genetic mouse models, and rescue experiment\",\n      \"pmids\": [\"40514673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The Csde1-Strap complex binds Bach2 mRNA and couples its decay with translation to control the magnitude and duration of Bach2 protein expression during B cell differentiation. In the absence of Csde1 or Strap, Bach2 translation is decoupled from mRNA decay, leading to elevated and prolonged Bach2 protein expression and impaired plasma cell differentiation.\",\n      \"method\": \"RNA interactome capture, CRISPR/Cas9 screening, RIP, co-immunoprecipitation, mRNA decay assays, polysome profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — CRISPR functional screen plus RIP and mRNA decay/translation coupling assays\",\n      \"pmids\": [\"40133358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"iNOS mediates S-nitrosylation of STRAP specifically at Cys152 and Cys270. S-nitrosylation disrupts the STRAP-ASK1 interaction, increases ASK1 activity, activates the MKK3-p38 pathway, and enhances hydrogen peroxide-induced apoptosis. Mutation of Cys152/270 to serine abolishes the STRAP-ASK1 interaction and constitutively activates the ASK1-MKK3-p38 pathway. STRAP specifically interacts with iNOS but not eNOS or nNOS.\",\n      \"method\": \"S-nitrosylation assay (biotin switch), co-immunoprecipitation, mutagenesis, kinase activity assay, apoptosis assays, iNOS overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct PTM identification with site-specific mutagenesis and in vitro kinase functional validation\",\n      \"pmids\": [\"41519199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Unrip (STRAP) is integrated into the SMN complex via a stable interaction with Gemin7. It is also found in a mutually exclusive complex with Unr. Unrip is absent from nuclear gems/Cajal bodies and localizes predominantly to the cytoplasm. RNAi-induced reduction of Unrip leads to enhanced accumulation of SMN in the nucleus and increased formation of nuclear gems/Cajal bodies.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, immunofluorescence localization, biochemical fractionation\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical complex characterization with localization plus functional knockdown phenotype\",\n      \"pmids\": [\"16159890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Unrip (STRAP) directly interacts with Gemin6 and Gemin7 within the SMN complex, also binds a subset of Sm proteins, and unrip-containing SMN complexes are necessary and sufficient to mediate the assembly of spliceosomal snRNPs in vitro.\",\n      \"method\": \"Biochemical reconstitution of snRNP assembly, co-immunoprecipitation, pulldown assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro snRNP assembly reconstitution with defined complex components\",\n      \"pmids\": [\"15848170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"p49/STRAP interacts with the β-sandwich domain of Hsp70. It reduces ATP-hydrolytic activity of Hsp70 stimulated by Hsp40 and inhibits the refolding activity of the Hsp70/Hsp40 chaperone system, functioning as a co-chaperone.\",\n      \"method\": \"Co-immunoprecipitation, ATPase assay, protein refolding assay, domain mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro enzymatic assay with domain-mapping pulldown, single lab\",\n      \"pmids\": [\"19751705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STRAP overexpression in neuroblastoma cell lines activates focal adhesion kinase (FAK) downstream targets as measured by kinomic peptide microarray. FAK inhibitor treatment selectively decreased growth of STRAP-overexpressing neuroblastoma cells compared to controls, placing STRAP upstream of FAK in a signaling pathway.\",\n      \"method\": \"Kinomic peptide microarray (PamChip), stable overexpression, FAK inhibitor (PF-573,228) treatment, proliferation assay\",\n      \"journal\": \"Journal of pediatric surgery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — kinomic assay plus pharmacological rescue establishing pathway relationship, single lab\",\n      \"pmids\": [\"35272839\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STRAP is a WD40/TPR-OB fold scaffold protein that functions as a multifunctional regulator: it inhibits TGF-β signaling by recruiting Smad7 to stabilize its complex with activated type I receptors (blocking Smad2/3 access), activates Wnt/β-catenin and ERK/MAPK pathways, regulates p53 activity through interactions with NM23-H1 and by disrupting the p53-Mdm2 complex (and is itself phosphorylated by ATM/Chk2 to accumulate in the nucleus and acetylated by CBP/deacetylated by SIRT7), controls collagen mRNA translation through LARP6 and eIF4A interactions, participates in spliceosomal snRNP assembly via the SMN complex, inhibits JMY-mediated actin nucleation during autophagy, stabilizes proteins such as c-Jun, Notch3/ICN3, and β-catenin by reducing their ubiquitylation, acts as a scaffold for TLR2/4 and TLR3 innate immune signaling through TAK1-IKKα-p65 and TBK1-IRF3 complexes, localizes to mitochondria where it interacts with ATP synthase to suppress oxidative phosphorylation, and is post-translationally regulated by MPK38 phosphorylation at Ser188, USP38-mediated deubiquitination, and iNOS-mediated S-nitrosylation at Cys152/270 which disrupts its interaction with ASK1 to promote apoptosis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"STRAP (serine-threonine kinase receptor-associated protein/TTC5/Unrip) is a multifunctional scaffold protein that integrates TGF-β, Wnt/β-catenin, p53, innate immune, and spliceosomal pathways. Structurally, STRAP adopts a six-TPR plus OB-fold architecture that provides an extended superhelical surface for diverse protein–protein and protein–nucleic acid interactions [PMID:22362889]. In TGF-β signaling, STRAP recruits Smad7 to activated type I receptors, stabilizing the inhibitory Smad7–receptor complex and blocking Smad2/3 access [PMID:10757800]; it activates Wnt/β-catenin signaling by binding GSK-3β and preventing β-catenin phosphorylation and degradation [PMID:26910283]; it potentiates p53 transcriptional activity by displacing Mdm2 from p53, a function modulated by ATM/Chk2-dependent nuclear accumulation and CBP/SIRT7-regulated acetylation [PMID:17916563, PMID:18833288, PMID:32527012]. Additionally, STRAP is an integral subunit of the SMN complex—interacting with Gemin6/7 to mediate spliceosomal snRNP assembly [PMID:15848170]—regulates collagen mRNA translation through LARP6 and eIF4A [PMID:23918805], couples Bach2 mRNA decay with translation via the Csde1–Strap complex to control B cell differentiation [PMID:40133358], inhibits JMY-mediated actin nucleation during autophagy [PMID:30593260], scaffolds TLR2/4 and TLR3 innate immune signaling through TAK1–IKKα–p65 and TBK1–IRF3 complexes [PMID:27934954, PMID:28651742], and localizes to mitochondria where it suppresses ATP synthase-dependent oxidative phosphorylation [PMID:25168243].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"The discovery that STRAP is a WD40-domain protein interacting with TGF-β receptors and inhibiting TGF-β transcription established STRAP as a negative regulator of TGF-β signaling, opening the question of its mechanism of inhibition.\",\n      \"evidence\": \"Yeast two-hybrid screen and co-IP with TβR-I/TβR-II plus transcriptional reporter assays in mammalian cells\",\n      \"pmids\": [\"9856985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of inhibition not yet defined\", \"No structural information\", \"Physiological relevance in vivo unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that STRAP recruits Smad7 to the activated type I receptor and stabilizes the inhibitory complex—blocking Smad2/3 access—defined the molecular mechanism of STRAP-mediated TGF-β pathway inhibition.\",\n      \"evidence\": \"Co-IP, deletion mutagenesis, and reporter assays showing STRAP–Smad7 cooperativity and receptor complex formation\",\n      \"pmids\": [\"10757800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo requirement not yet demonstrated\", \"Post-translational regulation of STRAP unknown\", \"Structural basis of Smad7 interaction unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of STRAP (Unrip) as a stable subunit of the SMN complex—binding Gemin6/7 and mediating spliceosomal snRNP assembly in vitro—revealed a second major function distinct from TGF-β signaling and raised the question of how one scaffold serves both pathways.\",\n      \"evidence\": \"Biochemical reconstitution of snRNP assembly, co-IP defining Gemin6/7 interaction, and RNAi-mediated knockdown showing altered SMN nuclear accumulation\",\n      \"pmids\": [\"16159890\", \"15848170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural detail of STRAP within the SMN complex\", \"How STRAP partitions between SMN and receptor signaling complexes unknown\", \"Whether snRNP assembly role is relevant to disease phenotypes not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Using STRAP-knockout MEFs and stable overexpression, STRAP was shown to activate the MEK/ERK pathway and suppress p21 and TGF-β-mediated growth arrest, establishing its role as a proliferative signal beyond TGF-β receptor inhibition.\",\n      \"evidence\": \"STRAP-knockout MEFs showing enhanced Smad2/3 phosphorylation; overexpression activating ERK and downregulating p21\",\n      \"pmids\": [\"16778189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ERK pathway target of STRAP unidentified\", \"Whether STRAP is an oncogene in vivo not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying that STRAP and NM23-H1 potentiate p53 activity by displacing Mdm2 from the p53 complex—mapping interaction to specific cysteine residues—established STRAP as a p53 co-activator and connected TGF-β and p53 pathways through a shared scaffold.\",\n      \"evidence\": \"Co-IP with cysteine mutagenesis, transcriptional reporters, and apoptosis assays\",\n      \"pmids\": [\"17916563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in vivo p53 tumor suppression phenotype for STRAP\", \"Whether STRAP-p53 interaction is constitutive or damage-dependent unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"ATM-dependent phosphorylation driving STRAP nuclear accumulation, followed by Chk2-dependent stabilization, defined how the DNA damage response regulates STRAP subcellular distribution to enhance its nuclear p53 co-activator function.\",\n      \"evidence\": \"In vitro kinase assays, mutational analysis, and nuclear/cytoplasmic fractionation with live-cell imaging\",\n      \"pmids\": [\"18833288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation sites on STRAP not all mapped\", \"Whether nuclear STRAP engages chromatin directly was unknown at this point\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"STRAP deletion caused mesenchymal-to-epithelial transition in MEFs with E-cadherin upregulation and β-catenin membrane relocalization, revealing STRAP as a master regulator of epithelial–mesenchymal identity beyond individual signaling pathways.\",\n      \"evidence\": \"STRAP-knockout MEFs with gene expression profiling, immunofluorescence, and phenotypic rescue by STRAP re-expression\",\n      \"pmids\": [\"19781628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STRAP controls EMT in vivo during development or cancer progression not shown\", \"Upstream signals controlling STRAP in this context unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that STRAP binds GSK-3β/Axin and stabilizes Notch3 ICN and c-Jun by reducing their ubiquitylation established STRAP as a general protein stabilizer acting through the GSK-3β–destruction complex axis and ubiquitin-proteasome modulation.\",\n      \"evidence\": \"Co-IP defining STRAP–GSK-3β–Axin ternary complex, ubiquitination assays for ICN3 and c-Jun, and STRAP-knockout/rescue MEFs\",\n      \"pmids\": [\"21502811\", \"21397588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STRAP directly inhibits an E3 ligase or acts indirectly through GSK-3β unclear\", \"Structural basis of STRAP–GSK-3β interaction unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The crystal structure at 2.05 Å revealed an unexpected TPR–OB-fold architecture rather than a canonical WD40 domain, redefining STRAP's structural classification and explaining its capacity for diverse protein and chromatin interactions.\",\n      \"evidence\": \"X-ray crystallography of full-length Strap, ChIP on p53 target genes, and functional reporter assays\",\n      \"pmids\": [\"22362889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of STRAP in complex with any partner remain unsolved\", \"How the OB-fold domain contacts DNA specifically unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"STRAP was shown to control collagen mRNA translation by being tethered via LARP6 to collagen 5′ stem-loops and restraining eIF4A-dependent ribosome loading, revealing a post-transcriptional regulatory function critical for balanced collagen trimer assembly.\",\n      \"evidence\": \"RNA pulldown, polysome profiling, co-IP, siRNA knockdown, and collagen secretion rescue\",\n      \"pmids\": [\"23918805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How STRAP inhibits eIF4A helicase activity mechanistically unknown\", \"Whether this function operates in fibrotic disease contexts not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Multiple studies converged to define STRAP's post-translational regulation: MPK38 phosphorylation at Ser188 switches STRAP from anti-apoptotic to pro-apoptotic, STRAP recruits HDAC1 to repress Sp1-dependent transcription, and mitochondrial STRAP suppresses ATP synthase to modulate energy metabolism and apoptosis.\",\n      \"evidence\": \"In vitro kinase assays with Ser188 mutagenesis, ChIP for HDAC1/Sp1 at p21 promoter, mitochondrial fractionation with ATP production assays\",\n      \"pmids\": [\"25485581\", \"25483064\", \"25168243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MPK38–STRAP axis operates in vivo under physiological stress unknown\", \"How STRAP is targeted to mitochondria undefined\", \"Relationship between mitochondrial and nuclear STRAP pools unexplored\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"STRAP was established as a scaffold for innate immune signaling: it bridges TAK1–IKKα–p65 downstream of TLR2/4 and promotes cytokine production, while also activating Wnt/β-catenin signaling by binding GSK-3β to prevent β-catenin destruction complex formation in colorectal cancer.\",\n      \"evidence\": \"Co-IP defining TAK1–IKKα–p65 scaffolding, cytokine ELISAs with STRAP knockdown in macrophages, and GSK-3β/β-catenin interaction studies with in vivo metastasis model\",\n      \"pmids\": [\"27934954\", \"26910283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STRAP scaffold function in immunity requires the same domains as in TGF-β inhibition not fully mapped\", \"No structural model of STRAP immune signaling complexes\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extension of STRAP's innate immune scaffold function to TLR3 signaling via TBK1–IRF3 interaction and STRAP's disruption of PRC2 assembly to epigenetically activate NOTCH signaling broadened the scope of STRAP from a receptor-proximal scaffold to a chromatin-level regulatory platform.\",\n      \"evidence\": \"Co-IP and cytokine assays for TLR3/TBK1/IRF3; ChIP-seq showing reduced H3K27me3 at NOTCH gene promoters upon STRAP expression with rescue experiments\",\n      \"pmids\": [\"28651742\", \"28827371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STRAP directly contacts EZH2 or acts through an intermediary not fully resolved\", \"In vivo immune phenotype of STRAP loss not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reconstitution experiments showed that STRAP/TTC5 inhibits JMY-mediated actin nucleation at phagophore membranes, identifying STRAP as a negative regulator of autophagy that acts by competing with LC3-dependent JMY activation.\",\n      \"evidence\": \"In vitro reconstitution with membrane-bound LC3, actin nucleation assay, and co-IP\",\n      \"pmids\": [\"30593260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of STRAP autophagy inhibition in vivo unknown\", \"Whether this connects to STRAP's other cytoplasmic functions unaddressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genome-wide eCLIP-seq in mouse embryos and snRNP assembly assays revealed that STRAP directly binds RNA, preferentially targets neurodevelopmental transcripts, regulates U2 snRNP assembly and alternative splicing, and is required for neural tube closure in Xenopus—unifying its SMN complex role with a direct RNA-binding and splicing regulatory function.\",\n      \"evidence\": \"eCLIP-seq, STRAP-knockout embryoid bodies, U2 snRNP assembly assay, Xenopus morpholino knockdown, RNA-seq splicing analysis\",\n      \"pmids\": [\"33230114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STRAP binds RNA through the OB-fold domain not determined\", \"Human neurodevelopmental disease association not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of CBP as the acetyltransferase and SIRT7 as the deacetylase for STRAP at Lys147/148/156 provided a regulatory PTM code that tunes STRAP's p53 co-activator function, complementing the earlier ATM/Chk2 phosphorylation axis.\",\n      \"evidence\": \"Mass spectrometry acetylation site mapping, mutagenesis (3KR/3KQ), co-IP for CBP and SIRT7, p53 functional assays\",\n      \"pmids\": [\"32527012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How acetylation and phosphorylation are coordinated on STRAP unclear\", \"Whether acetylation affects non-p53 functions of STRAP unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The Csde1–Strap complex was shown to couple Bach2 mRNA decay with translation to control plasma cell differentiation, and USP38 was identified as the deubiquitinase stabilizing STRAP to enhance TGF-β/SMAD-dependent atrial fibrosis, revealing tissue-specific post-translational and RNA-level regulatory circuits centered on STRAP.\",\n      \"evidence\": \"CRISPR screen, RIP, mRNA decay/polysome assays for Csde1–Strap–Bach2; deubiquitination assay and cardiomyocyte-specific mouse genetics for USP38–STRAP\",\n      \"pmids\": [\"40133358\", \"40514673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP38 regulation of STRAP is relevant outside cardiac fibrosis not tested\", \"Structural basis of Csde1–Strap complex unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"iNOS-mediated S-nitrosylation of STRAP at Cys152/270 disrupts its interaction with ASK1, activating the ASK1–MKK3–p38 apoptotic axis—demonstrating that the same cysteine residues used for multiple protein interactions are also redox-regulated switches.\",\n      \"evidence\": \"Biotin switch S-nitrosylation assay, cysteine-to-serine mutagenesis, kinase activity assays, apoptosis assays\",\n      \"pmids\": [\"41519199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether S-nitrosylation also disrupts STRAP–p53 or STRAP–MPK38 interactions not tested\", \"In vivo relevance in inflammatory or ischemic contexts not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how STRAP partitions among its many complexes (SMN, TGF-β receptor, TLR, mitochondria, chromatin) in a cell-type-specific manner; whether high-resolution structures of STRAP bound to its partners will reveal allosteric mechanisms; and whether STRAP mutations cause human developmental or immune disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of any STRAP–partner complex\", \"No Mendelian disease linked to STRAP mutations\", \"Cell-type-specific partitioning mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 17, 18]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [23, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 12, 22, 29]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [14, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 30]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 4, 10]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 8, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 18]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [23, 30, 31]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 12, 13, 29]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [14, 19]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 25]}\n    ],\n    \"complexes\": [\n      \"SMN complex\",\n      \"Csde1-Strap complex\",\n      \"TAK1-IKKα-p65 signaling complex\"\n    ],\n    \"partners\": [\n      \"SMAD7\",\n      \"GSK3B\",\n      \"TP53\",\n      \"GEMIN7\",\n      \"CSDE1\",\n      \"LARP6\",\n      \"JMY\",\n      \"TBK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}