{"gene":"SKP2","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2001,"finding":"Cks1 (CDK subunit 1) is an essential accessory protein required for SCF(Skp2)-mediated ubiquitination of phospho-Thr187-p27; Cks1 binds directly to Skp2 and greatly increases binding of T187-phosphorylated p27 to Skp2, reconstituting ubiquitin ligation of p27 in a fully purified system.","method":"Biochemical reconstitution with purified components, in vitro ubiquitination assay, binding assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — fully reconstituted in vitro ubiquitination with purified components, replicated across labs","pmids":["11231585"],"is_preprint":false},{"year":2001,"finding":"Skp2 accumulation depends on both cell adhesion to the ECM and growth factors; ectopic Skp2 in nonadherent G1 cells downregulates p27, drives S-phase entry and cell division, establishing Skp2 as a key mediator of adhesion-dependent cell cycle progression.","method":"Ectopic expression, cell cycle analysis, Western blot, loss-of-adhesion assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean gain-of-function with specific phenotypic readout (S-phase entry, division), pathway placement relative to p27 and cyclin D1","pmids":["11425869"],"is_preprint":false},{"year":2003,"finding":"Skp2 ubiquitylates Myc, regulating its stability and degradation; additionally, Skp2 acts as a transcriptional coactivator for Myc by recognizing an essential element in the Myc activation domain and activating Myc target genes.","method":"Ubiquitination assay, transcriptional reporter assays, co-immunoprecipitation","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ubiquitination assay + transcriptional reporter + co-IP) in a single lab","pmids":["12769843"],"is_preprint":false},{"year":2003,"finding":"SKP2 associates with p130 (a retinoblastoma family member) and promotes its polyubiquitylation and proteasomal degradation during the cell cycle, identifying p130 as a substrate of SCF(SKP2).","method":"Co-immunoprecipitation, ectopic expression, ubiquitination assay, protein half-life analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and ubiquitination assay, single lab","pmids":["12717421"],"is_preprint":false},{"year":2003,"finding":"GA-binding protein (GABP) binds the Skp2 promoter in a cell cycle-dependent manner and is required for cell cycle-dependent transcription of Skp2; overexpression of GABPβ increases Skp2 promoter activity and siRNA knockdown of GABP reduces it.","method":"Promoter-reporter assay, EMSA, site-directed mutagenesis, ChIP, siRNA knockdown","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (EMSA, ChIP, mutagenesis, reporter assay, siRNA) in one study","pmids":["12907639"],"is_preprint":false},{"year":2004,"finding":"Eight amino acid residues in two discrete regions of Skp2 form the functional binding interface for Cks1; mutation of any of these residues abolishes Cks1 association and negates Skp2-dependent p27 ubiquitination, including residues in the flexible C-terminal tail.","method":"Site-directed mutagenesis, binding assays, in vitro ubiquitination assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with in vitro ubiquitination assay, single lab","pmids":["15452136"],"is_preprint":false},{"year":2004,"finding":"Genetic epistasis in mice shows that loss of p27 (a single Skp2 substrate) rescues the cell size, DNA content, and proliferation defects observed in Skp2 knockout hepatocytes, establishing p27 as the principal downstream effector of SCF(Skp2) for cell cycle control.","method":"Genetic epistasis: Skp2 knockout vs. skp2-KO/p27T187A knock-in double mutant mice, histological and cell cycle analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with multiple readouts, replicated conceptually across labs","pmids":["15520280"],"is_preprint":false},{"year":2006,"finding":"The Skp2 gene contains a functional E2F response element; E2F1 directly induces endogenous Skp2 expression, and antisense-mediated E2F1 knockdown reduces Skp2 in tumor cell lines, establishing Skp2 as a transcriptional target of E2F.","method":"Promoter-reporter assay, ectopic E2F1 expression, antisense knockdown, chromatin analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (reporter assay, gain- and loss-of-function) in single lab","pmids":["16331253"],"is_preprint":false},{"year":2008,"finding":"Androgen receptor (AR) stabilizes Skp2 by blocking D-box-dependent degradation of Skp2; Skp2 is an essential downstream effector of AR-driven proliferation in androgen-dependent prostate cancer cells, independently of AR's differentiation-promoting functions.","method":"Co-immunoprecipitation, ectopic expression, loss-of-function (siRNA/dominant-negative), cell proliferation assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (co-IP, gain/loss of function), single lab","pmids":["18628304"],"is_preprint":false},{"year":2011,"finding":"pVHL (von Hippel-Lindau protein) destabilizes Skp2 through its β-domain interaction with Skp2, promoting proteasome-dependent Skp2 degradation independently of pVHL's E3 ligase activity; pVHL antagonizes Akt-mediated phosphorylation that stabilizes Skp2, and DNA damage induces pVHL-dependent Skp2 degradation.","method":"Co-immunoprecipitation, ectopic expression, protein half-life assay, mutagenesis, VHL-null renal cell carcinoma reconstitution","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (co-IP, reconstitution in VHL-null cells, mutagenesis), single lab","pmids":["21358672"],"is_preprint":false},{"year":2012,"finding":"Skp2 is acetylated by p300 at K68 and K71; this acetylation is reversed by SIRT3 deacetylase, impairs Cdh1-mediated proteolysis, increases Skp2 stability, and promotes cytoplasmic retention of Skp2 via its nuclear localization signal. Cytoplasmic Skp2 ubiquitinates and destroys E-cadherin, promoting cell migration.","method":"Mass spectrometry, acetylation-mimetic and acetylation-dead mutagenesis, co-immunoprecipitation, ubiquitination assay, cell fractionation, migration assay, in vivo tumorigenesis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mass spec identification, mutagenesis, multiple orthogonal assays, in vivo validation","pmids":["22770219"],"is_preprint":false},{"year":2015,"finding":"Skp2 SCF complex ubiquitinates and degrades macroH2A1 (mH2A1); loss of mH2A1 promotes CDK8 gene expression, and CDK8 in turn facilitates Skp2-mediated p27 ubiquitination and degradation, establishing a Skp2-mH2A1-CDK8 axis regulating G2/M transition.","method":"Co-immunoprecipitation, ubiquitination assay, western blot, mouse tumor models with genetic rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo genetic rescue experiments, multiple orthogonal assays, mouse models","pmids":["25818643"],"is_preprint":false},{"year":2016,"finding":"SKP2 ubiquitinates CARM1 (via K48-linked chains) in the nucleus under nutrient-rich conditions, promoting its proteasomal degradation; nutrient starvation activates AMPK, which phosphorylates FOXO3a to transcriptionally repress SKP2, thereby stabilizing CARM1 to drive autophagy-gene transcription through TFEB.","method":"Co-immunoprecipitation, ubiquitination assay, genetic knockdown/knockout, AMPK inhibitor/activator treatment, ChIP, genome-wide analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, ubiquitination, ChIP, genome-wide), genetic epistasis established","pmids":["27309807"],"is_preprint":false},{"year":2016,"finding":"Skp2 inactivation decreases JARID1B K63-linked ubiquitination (mediated by TRAF6) — meaning Skp2 protects JARID1B from TRAF6-dependent ubiquitination — thereby reducing JARID1B demethylase activity and increasing H3K4me3, linked to prostate cancer suppression and senescence induction.","method":"Co-immunoprecipitation, ubiquitination assay (K63-linked), mouse tumor models (Pten/Trp53 knockout), Skp2 knockdown","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo approaches, single lab","pmids":["25596733"],"is_preprint":false},{"year":2016,"finding":"SKP2 loss destabilizes EZH2 by allowing TRAF6-mediated K63-linked ubiquitination of EZH2, promoting its degradation; Skp2 protects EZH2 from TRAF6-dependent ubiquitination in prostate cancer cells and in vivo mouse prostate tumor models.","method":"Co-immunoprecipitation, K63-ubiquitination assay, in vitro ubiquitination with catalytic dead TRAF6 mutant, mouse models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro ubiquitination with mutagenesis (TRAF6-C70A), co-IP, mouse models, single lab","pmids":["27869166"],"is_preprint":false},{"year":2017,"finding":"YAP (Hippo pathway effector) induces p300-mediated acetylation of Skp2 via Akt signaling; acetylated Skp2 is exclusively cytosolic, causing p27 accumulation (mitotic arrest, polyploidy) while also degrading FoxO1/3 pro-apoptotic factors, leading to polyploid cell division and oncogenesis.","method":"Co-immunoprecipitation, acetylation assay, cell fractionation, genetic epistasis (Akt/Skp2 depletion), mouse liver tumorigenesis model","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, in vivo mouse tumor model, genetic epistasis","pmids":["28486106"],"is_preprint":false},{"year":2017,"finding":"YAP directly promotes Skp2 transcription in response to mechanical cues (matrix stiffness); YAP inactivation downregulates Skp2, causing p21/p27 accumulation and cell cycle exit (G0), whereas Skp2 reconstitution rescues proliferation.","method":"ChIP, luciferase reporter, siRNA knockdown, Skp2 reconstitution, 3D culture system","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays establish direct transcriptional regulation, single lab","pmids":["28673931"],"is_preprint":false},{"year":2017,"finding":"Skp2 promotes K63-linked polyubiquitination of MTH1 (stabilization, not degradation) via the SCF complex; this increases MTH1 protein levels in melanoma cells and protects them from oxidative stress-induced DNA damage and apoptosis.","method":"Co-immunoprecipitation, ubiquitination assay (K63-linked), Skp2 overexpression/knockdown, SCF inhibition","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay with K63-linkage specificity, single lab","pmids":["28947420"],"is_preprint":false},{"year":2018,"finding":"SCFSKP2 catalyzes K63-linked (non-proteolytic) polyubiquitination of YAP at K321 and K497, which enhances YAP interaction with TEAD and promotes YAP nuclear localization and transcriptional activity independently of Hippo signaling; the deubiquitinase OTUD1 reverses this modification.","method":"Co-immunoprecipitation, K63-ubiquitination assay, mutagenesis of ubiquitination sites, nuclear/cytoplasmic fractionation, transcriptional reporter assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-specific mutagenesis, K63-ubiquitination assay, multiple orthogonal localization and functional assays","pmids":["29891922"],"is_preprint":false},{"year":2018,"finding":"Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors in triple-negative breast cancer; Skp2 ubiquitylates AKT (K63-linked) to reactivate it via IGF-1R/PDK-1/mTORC2 signaling, independently of PI3K activity or PIP3.","method":"AKT ubiquitination assay, genetic knockdown, kinase inhibitor treatment, xenograft tumor growth assay","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay and functional rescue assays, single lab","pmids":["29535262"],"is_preprint":false},{"year":2018,"finding":"SKP2 functions as an adaptor to promote interaction between active IKKβ and the autophagic cargo receptor p62, mediating IKKβ degradation via selective autophagy and thereby suppressing NF-κB activation.","method":"Co-immunoprecipitation, genetic knockdown (siRNA/KO), Western blot, NF-κB reporter assay","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional reporter assays with genetic manipulation, single lab","pmids":["29474632"],"is_preprint":false},{"year":2019,"finding":"SKP2 executes K48-linked polyubiquitination of BECN1 (Beclin1), promoting its proteasomal degradation; SKP2 activity is regulated by phosphorylation within a heterocomplex involving FKBP51, PHLPP, AKT1, and BECN1. SKP2 inhibition enhances autophagic flux and reduces MERS-CoV replication.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linked), genetic/pharmacological SKP2 inhibition, autophagic flux assay, viral infection assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — K48-ubiquitination assay, complex characterization by co-IP, multiple functional readouts, viral infection model","pmids":["31852899"],"is_preprint":false},{"year":2019,"finding":"SKP2 promotes PDCD4 phosphorylation, ubiquitination, and proteasomal degradation; this suppresses apoptosis and enhances DNA-damage response in breast cancer cells, establishing PDCD4 as a ubiquitination substrate of SKP2.","method":"Mass spectrometry, reciprocal co-immunoprecipitation, ubiquitination assay, SKP2 overexpression/knockdown, in vivo xenograft","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and ubiquitination assay with in vivo validation, single lab","pmids":["30760284"],"is_preprint":false},{"year":2019,"finding":"Skp2 promotes K63-linked ubiquitination of Akt, enhancing Akt activation, mitochondrial localization, HK2 phosphorylation (Thr473), and HK2 mitochondrial localization, thereby promoting glycolysis and cisplatin resistance.","method":"Co-immunoprecipitation, K63-ubiquitination assay, ectopic expression/knockdown, mitochondrial fractionation, xenograft model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — K63-ubiquitination assay and fractionation with in vivo validation, single lab","pmids":["31435020"],"is_preprint":false},{"year":2019,"finding":"Notch and pre-TCR signaling cooperatively induce expression of the F-box protein Fbxl1 (SKP2/FBXL1) and Fbxl12; both SCF complexes target Cdkn1b (p27) for polyubiquitination and proteasomal degradation to drive proliferation of β-selected thymocytes, with Notch specifically inducing Fbxl1 transcription.","method":"Genetic mouse models, T-cell development assays, ubiquitination assay, transcriptional analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic models with pathway dissection, multiple orthogonal assays","pmids":["31451788"],"is_preprint":false},{"year":2019,"finding":"USP18 (a Skp2 substrate) stabilizes SKP2 protein; free ISG15 disrupts the USP18-SKP2 complex, driving SKP2 to degradation and/or ISGylation. USP18 silencing slows S-phase entry, showing USP18 and ISG15 as SKP2 regulators impacting cell cycle progression.","method":"Co-immunoprecipitation, siRNA knockdown, protein stability assay, cell cycle analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional cell cycle assay, single lab","pmids":["30858391"],"is_preprint":false},{"year":2020,"finding":"Skp2 promotes K48-linked ubiquitination and proteasomal degradation of IDH1 and IDH2 (key TCA cycle enzymes) in a cell cycle-dependent manner, coupling cell cycle phase to metabolic oscillation between glycolysis (S phase, high Skp2) and TCA cycle (G1 phase, low Skp2).","method":"Co-immunoprecipitation, ubiquitination assay, metabolic flux analysis, cell cycle synchronization, SKP2 knockout","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (ubiquitination assay, metabolic analysis, genetic KO), cell cycle coupling established","pmids":["32669607"],"is_preprint":false},{"year":2020,"finding":"PGK1 interacts with AR and inhibits AR ubiquitination levels in an E3 ligase SKP2-dependent manner, thereby increasing AR protein stability in granulosa cells; this promotes AR nuclear translocation and regulates ovulation-related gene expression.","method":"Co-immunoprecipitation, GST pulldown, ubiquitination assay, siRNA knockdown, Western blot","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, GST pulldown, ubiquitination assay, single lab","pmids":["33096483"],"is_preprint":false},{"year":2021,"finding":"NUCKS1 transcription factor is recruited to chromatin upon mitogenic stimulation to activate SKP2 expression, leading to p21/p27 degradation and S-phase entry; DNA damage induces p53-dependent NUCKS1 repression, reducing SKP2 and causing cell cycle arrest.","method":"ChIP, siRNA knockdown, reporter assay, cell cycle analysis, genetic epistasis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, reporter assay, and genetic epistasis with multiple cell line validations","pmids":["34845229"],"is_preprint":false},{"year":2021,"finding":"USP2 is a deubiquitylase that binds SKP2 via the leucine-rich repeat substrate-binding domain, deubiquitylates and stabilizes SKP2 protein; unexpectedly, USP2-stabilized SKP2 disrupts SKP2-substrate binding, leading to co-stabilization of p21 and p27.","method":"DUB screen, co-immunoprecipitation, ubiquitination assay, protein half-life assay (cycloheximide chase), siRNA knockdown, small-molecule inhibitor","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay with mechanistic follow-up, single lab","pmids":["34425107"],"is_preprint":false},{"year":2021,"finding":"Reconstitution of stable complexes shows SKP1-SKP2 interacts with CDK2-cyclin A via a direct SKP2 N-terminal motif that engages a site on cyclin A not present in cyclin B or E, providing a CKS1-independent mechanism to stabilize the complex and fine-tune p27KIP1 degradation by cyclin A specifically.","method":"Protein complex reconstitution, structural mapping, mutagenesis, biochemical binding assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution of stable complexes with structural mapping and mutagenesis, single lab","pmids":["33422522"],"is_preprint":false},{"year":2021,"finding":"SKP2 deficiency reduces β-catenin expression and its target genes; knockdown of β-catenin mimics the defect in hematopoietic stem cell (HSC) homing seen in Skp2-deficient mice, placing Skp2 upstream of β-catenin in HSC homing.","method":"Microarray, co-immunoprecipitation/Western blot, HSC transplantation assay, β-catenin knockdown epistasis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — microarray + biochemical validation + genetic epistasis in HSC model, single lab","pmids":["24561244"],"is_preprint":false},{"year":2022,"finding":"Skp2 stabilizes Mcl-1 by competing with FBW7-mediated ubiquitination of Mcl-1; Skp2 deficiency facilitates FBW7-mediated Mcl-1 ubiquitination and degradation, enhancing radiation-induced apoptosis in colorectal cancer cells.","method":"CRISPR-Cas9 knockout, co-immunoprecipitation, ubiquitination assay, xenograft model, apoptosis assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, genetic KO, in vivo model, single lab","pmids":["35301297"],"is_preprint":false},{"year":2022,"finding":"Nuclear FAK N-terminal domain interacts with Skp2 and the APC/C activator Fzr1 (Cdh1) to promote ubiquitination and degradation of both Skp2 and Fzr1, thereby controlling p27 and p21 levels in vascular smooth muscle cells and restraining neointima formation.","method":"Co-immunoprecipitation, genetic FAK inhibition/FAK kinase-dead knock-in, cell fractionation, wire injury mouse model","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with genetic epistasis in cell and animal model, single lab","pmids":["33839758"],"is_preprint":false},{"year":2022,"finding":"TRIM33 protects AR from Skp2-mediated ubiquitination and proteasomal degradation in prostate cancer cells, stabilizing AR protein; identified by proteomics and confirmed by ubiquitination assay.","method":"Proteomics (mass spectrometry), co-immunoprecipitation, ubiquitination assay, knockdown, cell cycle/apoptosis assay","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics identification followed by co-IP and ubiquitination assay validation, single lab","pmids":["35785414"],"is_preprint":false},{"year":2023,"finding":"SKP2 depletion reduces K48-linked ubiquitination of SLC3A2, impairing its membrane localization and cystine/glutamate exchange function, thereby triggering ferroptosis in pulmonary epithelial cells; sepsis activates MEK/ERK to suppress Skp2, driving this pathway.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linked), membrane fractionation, ferroptosis assay, lipid nanoparticle mRNA delivery in mouse model","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and K48-ubiquitination assay with in vivo mRNA rescue, single lab","pmids":["39079969"],"is_preprint":false},{"year":2024,"finding":"SKP2 is O-GlcNAcylated at Ser34 by OGT; this modification stabilizes SKP2 by reducing APC-CDH1-mediated ubiquitination and degradation, and also enhances SKP2 binding to SKP1, increasing the ubiquitin ligase function and promoting p27/p21 degradation and G1-S transition in hepatocellular carcinoma.","method":"Mass spectrometry, co-immunoprecipitation, mutagenesis (Ser34 site), ubiquitination assay, cell cycle analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mass spec identification, mutagenesis, ubiquitination assay, single lab","pmids":["38396292"],"is_preprint":false},{"year":2024,"finding":"SKP2 depletion in pancreatic ductal adenocarcinoma (PDAC) results in polyubiquitination of PSPC1 by TRIM21, promoting its degradation; SKP2 normally protects PSPC1 from TRIM21-mediated ubiquitination, thereby promoting PDAC metastasis.","method":"Co-immunoprecipitation, ubiquitination assay, SMIP004 inhibitor treatment, migration assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay with functional migration readout, single lab","pmids":["38360141"],"is_preprint":false},{"year":2021,"finding":"USP10 binds Skp2 in the cytoplasm and removes polyubiquitin from Skp2, stabilizing Skp2 protein; USP10 deficiency reduces Skp2 levels, causing cell cycle arrest in vascular smooth muscle cells and reducing neointima formation.","method":"Co-immunoprecipitation, protein half-life assay (cycloheximide chase), siRNA knockdown, cell cycle analysis, mouse carotid ligation model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with functional cell cycle and in vivo model, single lab","pmids":["34599966"],"is_preprint":false},{"year":2023,"finding":"SKP2 promotes K63-linked ubiquitination of Lkb1, facilitating formation of the Strad-Mo25-Lkb1 complex and enhancing Lkb1-mediated fatty acid oxidation (FAO), which drives Treg cell generation; this pathway is transcriptionally induced by AhR binding to the Skp2 promoter.","method":"Co-immunoprecipitation, K63-ubiquitination assay, luciferase reporter (AhR binding to Skp2 promoter), FAO metabolic assay, flow cytometry (Treg induction), in vivo colitis/arthritis models","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, reporter assay, functional in vivo models, single lab","pmids":["36930164"],"is_preprint":false},{"year":2009,"finding":"Skp2 binds to TIS21/BTG2 via its leucine-rich repeat (LRR) domain and promotes TIS21 polyubiquitination and proteasomal degradation; LRR-deleted Skp2 or C-terminus-deleted TIS21 fail to interact, prolonging TIS21 half-life. FoxM1 transcriptionally regulates Skp2 expression upstream of this pathway.","method":"Co-immunoprecipitation, ubiquitination assay, mutagenesis (LRR-deleted Skp2 and TIS21ΔC), protein half-life assay, reporter assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay with mutagenesis validation, single lab","pmids":["19615363"],"is_preprint":false},{"year":2016,"finding":"Skp2 promotes ubiquitin-proteasome-mediated degradation of the osteogenic transcription factor Runx2; Skp2 physically interacts with Runx2 (co-IP in heterologous and physiological systems) and Skp2-mediated Runx2 downregulation reduces osteoblast differentiation.","method":"Co-immunoprecipitation, ubiquitination assay, promoter-reporter assay, osteoblast differentiation assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay with functional differentiation readout, single lab","pmids":["26778333"],"is_preprint":false},{"year":2023,"finding":"SKP2 mediates K63-linked ubiquitination of Akt to promote Akt activity; this is inhibited by gastrodin-mediated Akt suppression, and SKP2 depletion reduces K63-Akt ubiquitination and glycolysis in cisplatin-resistant oral squamous cell carcinoma.","method":"Co-immunoprecipitation, K63-ubiquitination assay, siRNA knockdown, xenograft model","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primarily a pharmacology study with limited mechanistic resolution of SKP2's direct role","pmids":["37779163"],"is_preprint":false},{"year":2024,"finding":"SKP2 interacts with NLRP3 and mediates its K48-linked ubiquitination, promoting NLRP3 proteasomal degradation; HSPA8 suppression reduces SKP2, attenuating NLRP3 ubiquitination and thereby activating NLRP3 inflammasome-mediated pyroptosis in alveolar epithelial cells.","method":"Co-immunoprecipitation, ubiquitination assay, AAV9-SKP2 in vivo delivery, genetic knockdown","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, in vivo AAV rescue, single lab","pmids":["38698431"],"is_preprint":false},{"year":2023,"finding":"In FN-RMS, MYOD binds an intronic enhancer of SKP2 to transcriptionally upregulate it; SKP2 in turn directly targets both p27Kip1 and p57Kip2 for ubiquitination and degradation, promoting cell cycle progression and preventing myogenic differentiation.","method":"ChIP, luciferase reporter, co-immunoprecipitation, ubiquitination assay, genetic knockdown, in vivo tumor model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP identifies MYOD binding, ubiquitination assay validates p57 as substrate, multiple methods, single lab","pmids":["38102140"],"is_preprint":false},{"year":2023,"finding":"SKP2 interacts with PHLPP1 and promotes its ubiquitination and degradation, activating AKT-related pathways; cytoplasmic translocation of SKP2 is regulated reciprocally by AKT activity, establishing a feedback loop between SKP2 and AKT via PHLPP1.","method":"Co-immunoprecipitation, ubiquitination assay, cell fractionation, genetic knockdown, xenograft model","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay with in vivo model, single lab","pmids":["36694914"],"is_preprint":false}],"current_model":"SKP2 is the substrate-recognition F-box subunit of the SCF(SKP2) E3 ubiquitin ligase complex that, together with the accessory protein CKS1, binds phosphorylated substrates (most prominently p27KIP1 at Thr187) to catalyze their K48-linked polyubiquitination and proteasomal degradation, driving G1/S cell cycle progression; SKP2 also attaches K63-linked (non-proteolytic) ubiquitin chains to substrates including AKT, YAP, and Lkb1 to modulate their activity and localization; SKP2 abundance and subcellular localization are tightly regulated by acetylation (p300/SIRT3), O-GlcNAcylation (OGT), phosphorylation (Akt), and multiple deubiquitylases (USP2, USP10, USP14), while its transcription is governed by E2F, GABP, STAT3, and NUCKS1; cytoplasmic SKP2 promotes migration by degrading E-cadherin, and nuclear SKP2 couples cell cycle phase to metabolism by degrading IDH1/2."},"narrative":{"mechanistic_narrative":"SKP2 is the substrate-recognition F-box subunit of the SCF(SKP2) E3 ubiquitin ligase that drives G1/S cell cycle progression by targeting cyclin-dependent kinase inhibitors for destruction [PMID:15520280]. Its best-defined activity requires the accessory protein CKS1, which binds SKP2 directly through eight residues across two discrete regions and dramatically enhances recruitment of Thr187-phosphorylated p27KIP1, reconstituting K48-linked ubiquitination of p27 in a fully purified system [PMID:11231585, PMID:15452136]; a CKS1-independent SKP2 N-terminal motif also engages cyclin A within CDK2–cyclin A complexes to fine-tune p27 turnover [PMID:33422522]. Genetic epistasis establishes p27 as the principal downstream effector through which SCF(SKP2) controls proliferation and cell size [PMID:15520280], and SKP2 extends this control to additional cell-cycle and chromatin regulators including p130, p57Kip2, macroH2A1, and IDH1/2, the last coupling cell-cycle phase to metabolic oscillation between glycolysis and the TCA cycle [PMID:12717421, PMID:38102140, PMID:25818643, PMID:32669607]. Beyond proteolytic K48-linked ubiquitination, SKP2 catalyzes non-degradative K63-linked ubiquitination of substrates such as AKT, YAP, and Lkb1 to enhance their activity, localization, and downstream signaling [PMID:29535262, PMID:29891922, PMID:36930164], and acts as an adaptor coupling IKKβ to selective autophagy [PMID:29474632]. SKP2 abundance and subcellular distribution are heavily regulated post-translationally: p300-mediated acetylation at K68/K71 (reversed by SIRT3) impairs Cdh1-dependent proteolysis and drives cytoplasmic retention, where SKP2 degrades E-cadherin to promote migration [PMID:22770219], while OGT-mediated O-GlcNAcylation at Ser34 stabilizes SKP2 and enhances SKP1 binding [PMID:38396292]. Multiple deubiquitylases (USP2, USP10, USP18) and protein partners (pVHL, AR, FAK) tune SKP2 stability [PMID:34425107, PMID:34599966, PMID:30858391, PMID:21358672, PMID:18628304], and its transcription is governed by E2F, GABP, YAP, NUCKS1, and lineage-specific factors [PMID:16331253, PMID:12907639, PMID:28673931, PMID:34845229]. Through these activities SKP2 functions as an oncogenic node coordinating proliferation, migration, metabolism, and survival across diverse tissues.","teleology":[{"year":2001,"claim":"Established the minimal biochemical requirements for SCF(SKP2) substrate recognition by showing CKS1 is an obligate cofactor bridging SKP2 to phosphorylated p27.","evidence":"Fully reconstituted in vitro ubiquitination with purified components and binding assays","pmids":["11231585"],"confidence":"High","gaps":["Did not define which SKP2 residues form the CKS1 interface","Substrate scope beyond p27 not addressed"]},{"year":2001,"claim":"Placed SKP2 as the effector linking extracellular adhesion and growth-factor cues to cell-cycle entry by showing ectopic SKP2 overrides adhesion dependence to degrade p27 and drive S-phase.","evidence":"Ectopic expression and loss-of-adhesion assays with cell-cycle readout","pmids":["11425869"],"confidence":"High","gaps":["Mechanism connecting adhesion signaling to SKP2 abundance not defined"]},{"year":2003,"claim":"Expanded SKP2 substrate range beyond p27 to p130 and Myc and revealed a non-catalytic transcriptional coactivator role for Myc.","evidence":"Co-IP, ubiquitination assays, transcriptional reporter assays","pmids":["12769843","12717421"],"confidence":"Medium","gaps":["Physiological weighting of these substrates versus p27 unresolved","Coactivator mechanism not structurally defined"]},{"year":2003,"claim":"Identified transcriptional control of SKP2 by demonstrating cell-cycle-dependent promoter occupancy by GABP and induction by E2F1.","evidence":"EMSA, ChIP, promoter-reporter, gain/loss-of-function","pmids":["12907639","16331253"],"confidence":"Medium","gaps":["Interplay between multiple SKP2 transcription factors not integrated"]},{"year":2004,"claim":"Defined the CKS1-binding interface on SKP2 and established p27 as the principal in vivo SCF(SKP2) effector via genetic epistasis.","evidence":"Site-directed mutagenesis with in vitro ubiquitination; Skp2-KO vs Skp2-KO/p27T187A knock-in mice","pmids":["15452136","15520280"],"confidence":"High","gaps":["Tissue-specific substrate contributions outside hepatocytes not tested"]},{"year":2008,"claim":"Showed SKP2 stability is set by oncogenic upstream regulators, with AR blocking D-box-dependent SKP2 degradation to drive prostate cancer proliferation.","evidence":"Co-IP, ectopic expression, siRNA/dominant-negative, proliferation assays","pmids":["18628304"],"confidence":"Medium","gaps":["Direct E3 mediating D-box degradation not defined in this study"]},{"year":2011,"claim":"Identified pVHL as a non-canonical destabilizer of SKP2 that antagonizes Akt-mediated stabilizing phosphorylation, linking SKP2 turnover to DNA damage.","evidence":"Co-IP, half-life assay, mutagenesis, VHL-null RCC reconstitution","pmids":["21358672"],"confidence":"Medium","gaps":["Mechanism of E3-independent destabilization not resolved"]},{"year":2012,"claim":"Revealed acetylation as a switch controlling SKP2 localization and a non-canonical cytoplasmic function, with p300/SIRT3-regulated K68/K71 acetylation driving E-cadherin degradation and migration.","evidence":"Mass spec, acetyl-mimetic/dead mutants, fractionation, migration and in vivo tumorigenesis assays","pmids":["22770219"],"confidence":"High","gaps":["Cytoplasmic substrate repertoire beyond E-cadherin not catalogued"]},{"year":2015,"claim":"Connected SKP2 to chromatin and G2/M control through a Skp2–macroH2A1–CDK8 feedback axis enhancing p27 degradation.","evidence":"Co-IP, ubiquitination assay, mouse tumor models with genetic rescue","pmids":["25818643"],"confidence":"High","gaps":["Direct enzymatic step of mH2A1 ubiquitination relative to chromatin context not detailed"]},{"year":2016,"claim":"Established SKP2 as a nutrient-responsive coupler of cell cycle to autophagy by degrading CARM1 under nutrient-rich conditions, with AMPK/FOXO3a repressing SKP2 during starvation.","evidence":"Co-IP, ubiquitination assay, ChIP, genome-wide analysis, AMPK modulation","pmids":["27309807"],"confidence":"High","gaps":["Quantitative threshold of SKP2 repression needed to license autophagy not defined"]},{"year":2016,"claim":"Showed SKP2 can protect substrates by antagonizing alternative E3s, shielding JARID1B and EZH2 from TRAF6-mediated K63 ubiquitination.","evidence":"Co-IP, K63-ubiquitination assays, TRAF6 catalytic-dead mutant, mouse prostate tumor models","pmids":["25596733","27869166"],"confidence":"Medium","gaps":["Direct biochemical mechanism of SKP2 shielding (competition vs modification) unresolved"]},{"year":2017,"claim":"Defined SKP2 K63-linked ubiquitination as an activating modification for substrates, stabilizing MTH1 and driving YAP nuclear activity independently of Hippo signaling.","evidence":"Site-specific mutagenesis, K63-ubiquitination assays, fractionation, reporter assays","pmids":["28947420","29891922"],"confidence":"High","gaps":["Determinants selecting K48 versus K63 chain output on different substrates not defined"]},{"year":2017,"claim":"Established reciprocal YAP–SKP2 regulation, with YAP transcribing SKP2 under mechanical cues and inducing its Akt/p300-dependent cytosolic acetylation to drive polyploidy and oncogenesis.","evidence":"ChIP, reporter assays, fractionation, genetic epistasis, mouse liver tumor model","pmids":["28673931","28486106"],"confidence":"High","gaps":["Integration of transcriptional versus post-translational arms in a single tissue not fully dissected"]},{"year":2018,"claim":"Implicated SKP2-mediated K63 ubiquitination of AKT in PI3K-inhibitor resistance and showed SKP2 acts as an autophagy adaptor degrading IKKβ to suppress NF-κB.","evidence":"AKT ubiquitination assays, kinase-inhibitor and xenograft studies; co-IP and NF-κB reporter assays","pmids":["29535262","29474632"],"confidence":"Medium","gaps":["Direct AKT ubiquitination site mapping limited","Adaptor versus ligase contributions to IKKβ turnover not separated"]},{"year":2019,"claim":"Broadened the SKP2 proteolytic substrate set to apoptosis and metabolic regulators (BECN1, PDCD4) and showed K63-AKT ubiquitination promotes mitochondrial glycolysis and chemoresistance.","evidence":"K48/K63 ubiquitination assays, complex characterization, fractionation, xenograft and viral infection models","pmids":["31852899","30760284","31435020"],"confidence":"Medium","gaps":["Composition and regulation of the FKBP51/PHLPP/AKT1/BECN1 heterocomplex incompletely defined"]},{"year":2019,"claim":"Demonstrated lineage-specific transcriptional induction of SKP2 (by Notch/pre-TCR) drives p27 degradation in developing thymocytes, and identified ISG15/USP18 as cell-cycle-linked SKP2 stability regulators.","evidence":"Genetic mouse models, T-cell development and ubiquitination assays; co-IP and stability assays","pmids":["31451788","30858391"],"confidence":"High","gaps":["Redundancy with Fbxl12 in p27 turnover not quantitatively partitioned"]},{"year":2020,"claim":"Coupled SKP2 to metabolic oscillation by showing cell-cycle-dependent K48 degradation of IDH1/2, and connected SKP2 to AR stability and ovulation gene regulation via PGK1.","evidence":"Ubiquitination assays, metabolic flux analysis, cell-cycle synchronization, SKP2 knockout; co-IP and GST pulldown","pmids":["32669607","33096483"],"confidence":"High","gaps":["Whether IDH and AR effects share regulatory inputs not addressed"]},{"year":2021,"claim":"Resolved a CKS1-independent route for SKP2 substrate targeting via direct cyclin A engagement and defined deubiquitylase control of SKP2 by USP2 and USP10, including a paradoxical USP2-driven substrate co-stabilization.","evidence":"Complex reconstitution and structural mapping; DUB screen, co-IP, half-life assays, inhibitors, in vivo models","pmids":["33422522","34425107","34599966"],"confidence":"High","gaps":["Structural basis for USP2 disrupting SKP2–substrate binding not solved"]},{"year":2021,"claim":"Identified NUCKS1 as a mitogen- and p53-responsive transcriptional activator of SKP2, and placed SKP2 upstream of β-catenin in hematopoietic stem cell homing.","evidence":"ChIP, reporter and cell-cycle assays, genetic epistasis; microarray and HSC transplantation","pmids":["34845229","24561244"],"confidence":"Medium","gaps":["Mechanism by which SKP2 controls β-catenin levels not defined"]},{"year":2022,"claim":"Showed SKP2 can stabilize substrates by competing with rival E3s (Mcl-1 vs FBW7) and that nuclear FAK/Fzr1 directs SKP2 turnover to regulate vascular proliferation.","evidence":"CRISPR KO, co-IP, ubiquitination assays, xenograft and wire-injury models","pmids":["35301297","33839758"],"confidence":"Medium","gaps":["Direct competition versus indirect effects on FBW7 substrate access not fully separated"]},{"year":2023,"claim":"Extended SKP2 substrate protection and K63-activation paradigms to immunometabolism and ferroptosis, including AhR-driven SKP2 induction promoting Lkb1 K63 ubiquitination and Treg generation, and K48 ubiquitination of SLC3A2 suppressing ferroptosis.","evidence":"Co-IP, K48/K63 ubiquitination assays, FAO and ferroptosis assays, reporter assays, in vivo disease models","pmids":["36930164","39079969","37779163","36694914"],"confidence":"Medium","gaps":["Some claims rest on single-lab pharmacology with limited direct mechanistic resolution","Tissue specificity of opposing K48/K63 outputs unresolved"]},{"year":2024,"claim":"Defined O-GlcNAcylation as a SKP2-stabilizing modification enhancing SKP1 binding and extended the substrate-protection model to PSPC1 and NLRP3 inflammasome control.","evidence":"Mass spec, Ser34 mutagenesis, ubiquitination assays, co-IP, AAV9 in vivo delivery","pmids":["38396292","38360141","38698431"],"confidence":"Medium","gaps":["Crosstalk between O-GlcNAcylation and acetylation/phosphorylation in setting SKP2 levels not integrated"]},{"year":null,"claim":"What molecular features dictate whether SKP2 directs K48-linked degradative versus K63-linked activating ubiquitination on a given substrate, and how the converging post-translational modifications (acetylation, O-GlcNAcylation, phosphorylation) are integrated to set SKP2 localization and activity, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of chain-type selection","No quantitative hierarchy among SKP2-stabilizing modifications","Substrate competition logic with rival E3s not generalized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,6,10,12,18,26]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,5,26]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,20,30]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,12,26]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,15,38,45]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,6,26,28,30]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,6,10,26]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12,20,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[18,19,45]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[23,26,39]}],"complexes":["SCF(SKP2) E3 ubiquitin ligase"],"partners":["CKS1","SKP1","CDK2-CYCLIN A","P27KIP1","YAP","AKT","VHL","USP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13309","full_name":"S-phase kinase-associated protein 2","aliases":["Cyclin-A/CDK2-associated protein p45","F-box protein Skp2","F-box/LRR-repeat protein 1","p45skp2"],"length_aa":424,"mass_kda":47.8,"function":"Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins involved in cell cycle progression, signal transduction and transcription (PubMed:9736735, PubMed:11931757, PubMed:12435635, PubMed:12769844, PubMed:12840033, PubMed:15342634, PubMed:15668399, PubMed:15949444, PubMed:16103164, PubMed:16262255, PubMed:16581786, PubMed:16951159, PubMed:17908926, PubMed:17962192, PubMed:22464731, PubMed:22770219, PubMed:32267835). Specifically recognizes phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition (By similarity). Degradation of CDKN1B/p27kip also requires CKS1 (By similarity). Recognizes target proteins ORC1, CDT1, RBL2, KMT2A/MLL1, CDK9, RAG2, NBN, FOXO1, UBP43, YTHDF2, and probably MYC, TOB1 and TAL1 (PubMed:11931757, PubMed:12435635, PubMed:12769844, PubMed:12840033, PubMed:15342634, PubMed:15668399, PubMed:15949444, PubMed:16103164, PubMed:16581786, PubMed:16951159, PubMed:17908926, PubMed:17962192, PubMed:22464731, PubMed:32267835). Degradation of TAL1 also requires STUB1 (PubMed:17962192). Recognizes CDKN1A in association with CCNE1 or CCNE2 and CDK2 (PubMed:9736735, PubMed:16262255). Promotes ubiquitination and destruction of CDH1 in a CK1-dependent manner, thereby regulating cell migration (PubMed:22770219). Following phosphorylation in response to DNA damage, mediates 'Lys-63'-linked ubiquitination of NBN, promoting ATM recruitment to DNA damage sites and DNA repair via homologous recombination (PubMed:22464731) Through the ubiquitin-mediated proteasomal degradation of hepatitis C virus non-structural protein 5A, has an antiviral activity towards that virus","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13309/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SKP2","classification":"Common Essential","n_dependent_lines":886,"n_total_lines":1208,"dependency_fraction":0.7334437086092715},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CDK2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SKP2","total_profiled":1310},"omim":[{"mim_id":"617819","title":"RAL GUANINE NUCLEOTIDE EXCHANGE FACTOR WITH PH DOMAIN AND SH3 DOMAIN-BINDING MOTIF 2; RALGPS2","url":"https://www.omim.org/entry/617819"},{"mim_id":"614472","title":"RING FINGER PROTEIN 123; RNF123","url":"https://www.omim.org/entry/614472"},{"mim_id":"614041","title":"RB TRANSCRIPTIONAL COREPRESSOR 1; RB1","url":"https://www.omim.org/entry/614041"},{"mim_id":"609577","title":"CULLIN 7; CUL7","url":"https://www.omim.org/entry/609577"},{"mim_id":"607727","title":"CULLIN-ASSOCIATED NEDDYLATION-DISSOCIATED PROTEIN 1; CAND1","url":"https://www.omim.org/entry/607727"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"placenta","ntpm":35.6}],"url":"https://www.proteinatlas.org/search/SKP2"},"hgnc":{"alias_symbol":["FBXL1","FBL1","p45"],"prev_symbol":[]},"alphafold":{"accession":"Q13309","domains":[{"cath_id":"1.20.1280.50","chopping":"100-136","consensus_level":"medium","plddt":96.3246,"start":100,"end":136},{"cath_id":"3.80.10.10","chopping":"138-416","consensus_level":"medium","plddt":96.7308,"start":138,"end":416}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13309","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13309-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13309-F1-predicted_aligned_error_v6.png","plddt_mean":82.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SKP2","jax_strain_url":"https://www.jax.org/strain/search?query=SKP2"},"sequence":{"accession":"Q13309","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13309.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13309/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13309"}},"corpus_meta":[{"pmid":"18500245","id":"PMC_18500245","title":"Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer.","date":"2008","source":"Nature reviews. 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vitro ubiquitination assay, binding assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — fully reconstituted in vitro ubiquitination with purified components, replicated across labs\",\n      \"pmids\": [\"11231585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Skp2 accumulation depends on both cell adhesion to the ECM and growth factors; ectopic Skp2 in nonadherent G1 cells downregulates p27, drives S-phase entry and cell division, establishing Skp2 as a key mediator of adhesion-dependent cell cycle progression.\",\n      \"method\": \"Ectopic expression, cell cycle analysis, Western blot, loss-of-adhesion assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean gain-of-function with specific phenotypic readout (S-phase entry, division), pathway placement relative to p27 and cyclin D1\",\n      \"pmids\": [\"11425869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Skp2 ubiquitylates Myc, regulating its stability and degradation; additionally, Skp2 acts as a transcriptional coactivator for Myc by recognizing an essential element in the Myc activation domain and activating Myc target genes.\",\n      \"method\": \"Ubiquitination assay, transcriptional reporter assays, co-immunoprecipitation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ubiquitination assay + transcriptional reporter + co-IP) in a single lab\",\n      \"pmids\": [\"12769843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SKP2 associates with p130 (a retinoblastoma family member) and promotes its polyubiquitylation and proteasomal degradation during the cell cycle, identifying p130 as a substrate of SCF(SKP2).\",\n      \"method\": \"Co-immunoprecipitation, ectopic expression, ubiquitination assay, protein half-life analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and ubiquitination assay, single lab\",\n      \"pmids\": [\"12717421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GA-binding protein (GABP) binds the Skp2 promoter in a cell cycle-dependent manner and is required for cell cycle-dependent transcription of Skp2; overexpression of GABPβ increases Skp2 promoter activity and siRNA knockdown of GABP reduces it.\",\n      \"method\": \"Promoter-reporter assay, EMSA, site-directed mutagenesis, ChIP, siRNA knockdown\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (EMSA, ChIP, mutagenesis, reporter assay, siRNA) in one study\",\n      \"pmids\": [\"12907639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Eight amino acid residues in two discrete regions of Skp2 form the functional binding interface for Cks1; mutation of any of these residues abolishes Cks1 association and negates Skp2-dependent p27 ubiquitination, including residues in the flexible C-terminal tail.\",\n      \"method\": \"Site-directed mutagenesis, binding assays, in vitro ubiquitination assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with in vitro ubiquitination assay, single lab\",\n      \"pmids\": [\"15452136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Genetic epistasis in mice shows that loss of p27 (a single Skp2 substrate) rescues the cell size, DNA content, and proliferation defects observed in Skp2 knockout hepatocytes, establishing p27 as the principal downstream effector of SCF(Skp2) for cell cycle control.\",\n      \"method\": \"Genetic epistasis: Skp2 knockout vs. skp2-KO/p27T187A knock-in double mutant mice, histological and cell cycle analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with multiple readouts, replicated conceptually across labs\",\n      \"pmids\": [\"15520280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The Skp2 gene contains a functional E2F response element; E2F1 directly induces endogenous Skp2 expression, and antisense-mediated E2F1 knockdown reduces Skp2 in tumor cell lines, establishing Skp2 as a transcriptional target of E2F.\",\n      \"method\": \"Promoter-reporter assay, ectopic E2F1 expression, antisense knockdown, chromatin analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (reporter assay, gain- and loss-of-function) in single lab\",\n      \"pmids\": [\"16331253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Androgen receptor (AR) stabilizes Skp2 by blocking D-box-dependent degradation of Skp2; Skp2 is an essential downstream effector of AR-driven proliferation in androgen-dependent prostate cancer cells, independently of AR's differentiation-promoting functions.\",\n      \"method\": \"Co-immunoprecipitation, ectopic expression, loss-of-function (siRNA/dominant-negative), cell proliferation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (co-IP, gain/loss of function), single lab\",\n      \"pmids\": [\"18628304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"pVHL (von Hippel-Lindau protein) destabilizes Skp2 through its β-domain interaction with Skp2, promoting proteasome-dependent Skp2 degradation independently of pVHL's E3 ligase activity; pVHL antagonizes Akt-mediated phosphorylation that stabilizes Skp2, and DNA damage induces pVHL-dependent Skp2 degradation.\",\n      \"method\": \"Co-immunoprecipitation, ectopic expression, protein half-life assay, mutagenesis, VHL-null renal cell carcinoma reconstitution\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (co-IP, reconstitution in VHL-null cells, mutagenesis), single lab\",\n      \"pmids\": [\"21358672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Skp2 is acetylated by p300 at K68 and K71; this acetylation is reversed by SIRT3 deacetylase, impairs Cdh1-mediated proteolysis, increases Skp2 stability, and promotes cytoplasmic retention of Skp2 via its nuclear localization signal. Cytoplasmic Skp2 ubiquitinates and destroys E-cadherin, promoting cell migration.\",\n      \"method\": \"Mass spectrometry, acetylation-mimetic and acetylation-dead mutagenesis, co-immunoprecipitation, ubiquitination assay, cell fractionation, migration assay, in vivo tumorigenesis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mass spec identification, mutagenesis, multiple orthogonal assays, in vivo validation\",\n      \"pmids\": [\"22770219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Skp2 SCF complex ubiquitinates and degrades macroH2A1 (mH2A1); loss of mH2A1 promotes CDK8 gene expression, and CDK8 in turn facilitates Skp2-mediated p27 ubiquitination and degradation, establishing a Skp2-mH2A1-CDK8 axis regulating G2/M transition.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, western blot, mouse tumor models with genetic rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo genetic rescue experiments, multiple orthogonal assays, mouse models\",\n      \"pmids\": [\"25818643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SKP2 ubiquitinates CARM1 (via K48-linked chains) in the nucleus under nutrient-rich conditions, promoting its proteasomal degradation; nutrient starvation activates AMPK, which phosphorylates FOXO3a to transcriptionally repress SKP2, thereby stabilizing CARM1 to drive autophagy-gene transcription through TFEB.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, genetic knockdown/knockout, AMPK inhibitor/activator treatment, ChIP, genome-wide analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, ubiquitination, ChIP, genome-wide), genetic epistasis established\",\n      \"pmids\": [\"27309807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Skp2 inactivation decreases JARID1B K63-linked ubiquitination (mediated by TRAF6) — meaning Skp2 protects JARID1B from TRAF6-dependent ubiquitination — thereby reducing JARID1B demethylase activity and increasing H3K4me3, linked to prostate cancer suppression and senescence induction.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K63-linked), mouse tumor models (Pten/Trp53 knockout), Skp2 knockdown\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo approaches, single lab\",\n      \"pmids\": [\"25596733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SKP2 loss destabilizes EZH2 by allowing TRAF6-mediated K63-linked ubiquitination of EZH2, promoting its degradation; Skp2 protects EZH2 from TRAF6-dependent ubiquitination in prostate cancer cells and in vivo mouse prostate tumor models.\",\n      \"method\": \"Co-immunoprecipitation, K63-ubiquitination assay, in vitro ubiquitination with catalytic dead TRAF6 mutant, mouse models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro ubiquitination with mutagenesis (TRAF6-C70A), co-IP, mouse models, single lab\",\n      \"pmids\": [\"27869166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YAP (Hippo pathway effector) induces p300-mediated acetylation of Skp2 via Akt signaling; acetylated Skp2 is exclusively cytosolic, causing p27 accumulation (mitotic arrest, polyploidy) while also degrading FoxO1/3 pro-apoptotic factors, leading to polyploid cell division and oncogenesis.\",\n      \"method\": \"Co-immunoprecipitation, acetylation assay, cell fractionation, genetic epistasis (Akt/Skp2 depletion), mouse liver tumorigenesis model\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, in vivo mouse tumor model, genetic epistasis\",\n      \"pmids\": [\"28486106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YAP directly promotes Skp2 transcription in response to mechanical cues (matrix stiffness); YAP inactivation downregulates Skp2, causing p21/p27 accumulation and cell cycle exit (G0), whereas Skp2 reconstitution rescues proliferation.\",\n      \"method\": \"ChIP, luciferase reporter, siRNA knockdown, Skp2 reconstitution, 3D culture system\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays establish direct transcriptional regulation, single lab\",\n      \"pmids\": [\"28673931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Skp2 promotes K63-linked polyubiquitination of MTH1 (stabilization, not degradation) via the SCF complex; this increases MTH1 protein levels in melanoma cells and protects them from oxidative stress-induced DNA damage and apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K63-linked), Skp2 overexpression/knockdown, SCF inhibition\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay with K63-linkage specificity, single lab\",\n      \"pmids\": [\"28947420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SCFSKP2 catalyzes K63-linked (non-proteolytic) polyubiquitination of YAP at K321 and K497, which enhances YAP interaction with TEAD and promotes YAP nuclear localization and transcriptional activity independently of Hippo signaling; the deubiquitinase OTUD1 reverses this modification.\",\n      \"method\": \"Co-immunoprecipitation, K63-ubiquitination assay, mutagenesis of ubiquitination sites, nuclear/cytoplasmic fractionation, transcriptional reporter assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-specific mutagenesis, K63-ubiquitination assay, multiple orthogonal localization and functional assays\",\n      \"pmids\": [\"29891922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors in triple-negative breast cancer; Skp2 ubiquitylates AKT (K63-linked) to reactivate it via IGF-1R/PDK-1/mTORC2 signaling, independently of PI3K activity or PIP3.\",\n      \"method\": \"AKT ubiquitination assay, genetic knockdown, kinase inhibitor treatment, xenograft tumor growth assay\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay and functional rescue assays, single lab\",\n      \"pmids\": [\"29535262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SKP2 functions as an adaptor to promote interaction between active IKKβ and the autophagic cargo receptor p62, mediating IKKβ degradation via selective autophagy and thereby suppressing NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, genetic knockdown (siRNA/KO), Western blot, NF-κB reporter assay\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional reporter assays with genetic manipulation, single lab\",\n      \"pmids\": [\"29474632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SKP2 executes K48-linked polyubiquitination of BECN1 (Beclin1), promoting its proteasomal degradation; SKP2 activity is regulated by phosphorylation within a heterocomplex involving FKBP51, PHLPP, AKT1, and BECN1. SKP2 inhibition enhances autophagic flux and reduces MERS-CoV replication.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linked), genetic/pharmacological SKP2 inhibition, autophagic flux assay, viral infection assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — K48-ubiquitination assay, complex characterization by co-IP, multiple functional readouts, viral infection model\",\n      \"pmids\": [\"31852899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SKP2 promotes PDCD4 phosphorylation, ubiquitination, and proteasomal degradation; this suppresses apoptosis and enhances DNA-damage response in breast cancer cells, establishing PDCD4 as a ubiquitination substrate of SKP2.\",\n      \"method\": \"Mass spectrometry, reciprocal co-immunoprecipitation, ubiquitination assay, SKP2 overexpression/knockdown, in vivo xenograft\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and ubiquitination assay with in vivo validation, single lab\",\n      \"pmids\": [\"30760284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Skp2 promotes K63-linked ubiquitination of Akt, enhancing Akt activation, mitochondrial localization, HK2 phosphorylation (Thr473), and HK2 mitochondrial localization, thereby promoting glycolysis and cisplatin resistance.\",\n      \"method\": \"Co-immunoprecipitation, K63-ubiquitination assay, ectopic expression/knockdown, mitochondrial fractionation, xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — K63-ubiquitination assay and fractionation with in vivo validation, single lab\",\n      \"pmids\": [\"31435020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Notch and pre-TCR signaling cooperatively induce expression of the F-box protein Fbxl1 (SKP2/FBXL1) and Fbxl12; both SCF complexes target Cdkn1b (p27) for polyubiquitination and proteasomal degradation to drive proliferation of β-selected thymocytes, with Notch specifically inducing Fbxl1 transcription.\",\n      \"method\": \"Genetic mouse models, T-cell development assays, ubiquitination assay, transcriptional analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic models with pathway dissection, multiple orthogonal assays\",\n      \"pmids\": [\"31451788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP18 (a Skp2 substrate) stabilizes SKP2 protein; free ISG15 disrupts the USP18-SKP2 complex, driving SKP2 to degradation and/or ISGylation. USP18 silencing slows S-phase entry, showing USP18 and ISG15 as SKP2 regulators impacting cell cycle progression.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, protein stability assay, cell cycle analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional cell cycle assay, single lab\",\n      \"pmids\": [\"30858391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Skp2 promotes K48-linked ubiquitination and proteasomal degradation of IDH1 and IDH2 (key TCA cycle enzymes) in a cell cycle-dependent manner, coupling cell cycle phase to metabolic oscillation between glycolysis (S phase, high Skp2) and TCA cycle (G1 phase, low Skp2).\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, metabolic flux analysis, cell cycle synchronization, SKP2 knockout\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (ubiquitination assay, metabolic analysis, genetic KO), cell cycle coupling established\",\n      \"pmids\": [\"32669607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PGK1 interacts with AR and inhibits AR ubiquitination levels in an E3 ligase SKP2-dependent manner, thereby increasing AR protein stability in granulosa cells; this promotes AR nuclear translocation and regulates ovulation-related gene expression.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, ubiquitination assay, siRNA knockdown, Western blot\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, GST pulldown, ubiquitination assay, single lab\",\n      \"pmids\": [\"33096483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NUCKS1 transcription factor is recruited to chromatin upon mitogenic stimulation to activate SKP2 expression, leading to p21/p27 degradation and S-phase entry; DNA damage induces p53-dependent NUCKS1 repression, reducing SKP2 and causing cell cycle arrest.\",\n      \"method\": \"ChIP, siRNA knockdown, reporter assay, cell cycle analysis, genetic epistasis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, reporter assay, and genetic epistasis with multiple cell line validations\",\n      \"pmids\": [\"34845229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP2 is a deubiquitylase that binds SKP2 via the leucine-rich repeat substrate-binding domain, deubiquitylates and stabilizes SKP2 protein; unexpectedly, USP2-stabilized SKP2 disrupts SKP2-substrate binding, leading to co-stabilization of p21 and p27.\",\n      \"method\": \"DUB screen, co-immunoprecipitation, ubiquitination assay, protein half-life assay (cycloheximide chase), siRNA knockdown, small-molecule inhibitor\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay with mechanistic follow-up, single lab\",\n      \"pmids\": [\"34425107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Reconstitution of stable complexes shows SKP1-SKP2 interacts with CDK2-cyclin A via a direct SKP2 N-terminal motif that engages a site on cyclin A not present in cyclin B or E, providing a CKS1-independent mechanism to stabilize the complex and fine-tune p27KIP1 degradation by cyclin A specifically.\",\n      \"method\": \"Protein complex reconstitution, structural mapping, mutagenesis, biochemical binding assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution of stable complexes with structural mapping and mutagenesis, single lab\",\n      \"pmids\": [\"33422522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SKP2 deficiency reduces β-catenin expression and its target genes; knockdown of β-catenin mimics the defect in hematopoietic stem cell (HSC) homing seen in Skp2-deficient mice, placing Skp2 upstream of β-catenin in HSC homing.\",\n      \"method\": \"Microarray, co-immunoprecipitation/Western blot, HSC transplantation assay, β-catenin knockdown epistasis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — microarray + biochemical validation + genetic epistasis in HSC model, single lab\",\n      \"pmids\": [\"24561244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Skp2 stabilizes Mcl-1 by competing with FBW7-mediated ubiquitination of Mcl-1; Skp2 deficiency facilitates FBW7-mediated Mcl-1 ubiquitination and degradation, enhancing radiation-induced apoptosis in colorectal cancer cells.\",\n      \"method\": \"CRISPR-Cas9 knockout, co-immunoprecipitation, ubiquitination assay, xenograft model, apoptosis assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, genetic KO, in vivo model, single lab\",\n      \"pmids\": [\"35301297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nuclear FAK N-terminal domain interacts with Skp2 and the APC/C activator Fzr1 (Cdh1) to promote ubiquitination and degradation of both Skp2 and Fzr1, thereby controlling p27 and p21 levels in vascular smooth muscle cells and restraining neointima formation.\",\n      \"method\": \"Co-immunoprecipitation, genetic FAK inhibition/FAK kinase-dead knock-in, cell fractionation, wire injury mouse model\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with genetic epistasis in cell and animal model, single lab\",\n      \"pmids\": [\"33839758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM33 protects AR from Skp2-mediated ubiquitination and proteasomal degradation in prostate cancer cells, stabilizing AR protein; identified by proteomics and confirmed by ubiquitination assay.\",\n      \"method\": \"Proteomics (mass spectrometry), co-immunoprecipitation, ubiquitination assay, knockdown, cell cycle/apoptosis assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics identification followed by co-IP and ubiquitination assay validation, single lab\",\n      \"pmids\": [\"35785414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SKP2 depletion reduces K48-linked ubiquitination of SLC3A2, impairing its membrane localization and cystine/glutamate exchange function, thereby triggering ferroptosis in pulmonary epithelial cells; sepsis activates MEK/ERK to suppress Skp2, driving this pathway.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linked), membrane fractionation, ferroptosis assay, lipid nanoparticle mRNA delivery in mouse model\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and K48-ubiquitination assay with in vivo mRNA rescue, single lab\",\n      \"pmids\": [\"39079969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SKP2 is O-GlcNAcylated at Ser34 by OGT; this modification stabilizes SKP2 by reducing APC-CDH1-mediated ubiquitination and degradation, and also enhances SKP2 binding to SKP1, increasing the ubiquitin ligase function and promoting p27/p21 degradation and G1-S transition in hepatocellular carcinoma.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, mutagenesis (Ser34 site), ubiquitination assay, cell cycle analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mass spec identification, mutagenesis, ubiquitination assay, single lab\",\n      \"pmids\": [\"38396292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SKP2 depletion in pancreatic ductal adenocarcinoma (PDAC) results in polyubiquitination of PSPC1 by TRIM21, promoting its degradation; SKP2 normally protects PSPC1 from TRIM21-mediated ubiquitination, thereby promoting PDAC metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, SMIP004 inhibitor treatment, migration assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay with functional migration readout, single lab\",\n      \"pmids\": [\"38360141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP10 binds Skp2 in the cytoplasm and removes polyubiquitin from Skp2, stabilizing Skp2 protein; USP10 deficiency reduces Skp2 levels, causing cell cycle arrest in vascular smooth muscle cells and reducing neointima formation.\",\n      \"method\": \"Co-immunoprecipitation, protein half-life assay (cycloheximide chase), siRNA knockdown, cell cycle analysis, mouse carotid ligation model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with functional cell cycle and in vivo model, single lab\",\n      \"pmids\": [\"34599966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SKP2 promotes K63-linked ubiquitination of Lkb1, facilitating formation of the Strad-Mo25-Lkb1 complex and enhancing Lkb1-mediated fatty acid oxidation (FAO), which drives Treg cell generation; this pathway is transcriptionally induced by AhR binding to the Skp2 promoter.\",\n      \"method\": \"Co-immunoprecipitation, K63-ubiquitination assay, luciferase reporter (AhR binding to Skp2 promoter), FAO metabolic assay, flow cytometry (Treg induction), in vivo colitis/arthritis models\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, reporter assay, functional in vivo models, single lab\",\n      \"pmids\": [\"36930164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Skp2 binds to TIS21/BTG2 via its leucine-rich repeat (LRR) domain and promotes TIS21 polyubiquitination and proteasomal degradation; LRR-deleted Skp2 or C-terminus-deleted TIS21 fail to interact, prolonging TIS21 half-life. FoxM1 transcriptionally regulates Skp2 expression upstream of this pathway.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, mutagenesis (LRR-deleted Skp2 and TIS21ΔC), protein half-life assay, reporter assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay with mutagenesis validation, single lab\",\n      \"pmids\": [\"19615363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Skp2 promotes ubiquitin-proteasome-mediated degradation of the osteogenic transcription factor Runx2; Skp2 physically interacts with Runx2 (co-IP in heterologous and physiological systems) and Skp2-mediated Runx2 downregulation reduces osteoblast differentiation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, promoter-reporter assay, osteoblast differentiation assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay with functional differentiation readout, single lab\",\n      \"pmids\": [\"26778333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SKP2 mediates K63-linked ubiquitination of Akt to promote Akt activity; this is inhibited by gastrodin-mediated Akt suppression, and SKP2 depletion reduces K63-Akt ubiquitination and glycolysis in cisplatin-resistant oral squamous cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, K63-ubiquitination assay, siRNA knockdown, xenograft model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primarily a pharmacology study with limited mechanistic resolution of SKP2's direct role\",\n      \"pmids\": [\"37779163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SKP2 interacts with NLRP3 and mediates its K48-linked ubiquitination, promoting NLRP3 proteasomal degradation; HSPA8 suppression reduces SKP2, attenuating NLRP3 ubiquitination and thereby activating NLRP3 inflammasome-mediated pyroptosis in alveolar epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, AAV9-SKP2 in vivo delivery, genetic knockdown\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, in vivo AAV rescue, single lab\",\n      \"pmids\": [\"38698431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In FN-RMS, MYOD binds an intronic enhancer of SKP2 to transcriptionally upregulate it; SKP2 in turn directly targets both p27Kip1 and p57Kip2 for ubiquitination and degradation, promoting cell cycle progression and preventing myogenic differentiation.\",\n      \"method\": \"ChIP, luciferase reporter, co-immunoprecipitation, ubiquitination assay, genetic knockdown, in vivo tumor model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP identifies MYOD binding, ubiquitination assay validates p57 as substrate, multiple methods, single lab\",\n      \"pmids\": [\"38102140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SKP2 interacts with PHLPP1 and promotes its ubiquitination and degradation, activating AKT-related pathways; cytoplasmic translocation of SKP2 is regulated reciprocally by AKT activity, establishing a feedback loop between SKP2 and AKT via PHLPP1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, cell fractionation, genetic knockdown, xenograft model\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay with in vivo model, single lab\",\n      \"pmids\": [\"36694914\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SKP2 is the substrate-recognition F-box subunit of the SCF(SKP2) E3 ubiquitin ligase complex that, together with the accessory protein CKS1, binds phosphorylated substrates (most prominently p27KIP1 at Thr187) to catalyze their K48-linked polyubiquitination and proteasomal degradation, driving G1/S cell cycle progression; SKP2 also attaches K63-linked (non-proteolytic) ubiquitin chains to substrates including AKT, YAP, and Lkb1 to modulate their activity and localization; SKP2 abundance and subcellular localization are tightly regulated by acetylation (p300/SIRT3), O-GlcNAcylation (OGT), phosphorylation (Akt), and multiple deubiquitylases (USP2, USP10, USP14), while its transcription is governed by E2F, GABP, STAT3, and NUCKS1; cytoplasmic SKP2 promotes migration by degrading E-cadherin, and nuclear SKP2 couples cell cycle phase to metabolism by degrading IDH1/2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SKP2 is the substrate-recognition F-box subunit of the SCF(SKP2) E3 ubiquitin ligase that drives G1/S cell cycle progression by targeting cyclin-dependent kinase inhibitors for destruction [#6]. Its best-defined activity requires the accessory protein CKS1, which binds SKP2 directly through eight residues across two discrete regions and dramatically enhances recruitment of Thr187-phosphorylated p27KIP1, reconstituting K48-linked ubiquitination of p27 in a fully purified system [#0, #5]; a CKS1-independent SKP2 N-terminal motif also engages cyclin A within CDK2–cyclin A complexes to fine-tune p27 turnover [#30]. Genetic epistasis establishes p27 as the principal downstream effector through which SCF(SKP2) controls proliferation and cell size [#6], and SKP2 extends this control to additional cell-cycle and chromatin regulators including p130, p57Kip2, macroH2A1, and IDH1/2, the last coupling cell-cycle phase to metabolic oscillation between glycolysis and the TCA cycle [#3, #44, #11, #26]. Beyond proteolytic K48-linked ubiquitination, SKP2 catalyzes non-degradative K63-linked ubiquitination of substrates such as AKT, YAP, and Lkb1 to enhance their activity, localization, and downstream signaling [#19, #18, #39], and acts as an adaptor coupling IKKβ to selective autophagy [#20]. SKP2 abundance and subcellular distribution are heavily regulated post-translationally: p300-mediated acetylation at K68/K71 (reversed by SIRT3) impairs Cdh1-dependent proteolysis and drives cytoplasmic retention, where SKP2 degrades E-cadherin to promote migration [#10], while OGT-mediated O-GlcNAcylation at Ser34 stabilizes SKP2 and enhances SKP1 binding [#36]. Multiple deubiquitylases (USP2, USP10, USP18) and protein partners (pVHL, AR, FAK) tune SKP2 stability [#29, #38, #25, #9, #8], and its transcription is governed by E2F, GABP, YAP, NUCKS1, and lineage-specific factors [#7, #4, #16, #28]. Through these activities SKP2 functions as an oncogenic node coordinating proliferation, migration, metabolism, and survival across diverse tissues.\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the minimal biochemical requirements for SCF(SKP2) substrate recognition by showing CKS1 is an obligate cofactor bridging SKP2 to phosphorylated p27.\",\n      \"evidence\": \"Fully reconstituted in vitro ubiquitination with purified components and binding assays\",\n      \"pmids\": [\"11231585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which SKP2 residues form the CKS1 interface\", \"Substrate scope beyond p27 not addressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Placed SKP2 as the effector linking extracellular adhesion and growth-factor cues to cell-cycle entry by showing ectopic SKP2 overrides adhesion dependence to degrade p27 and drive S-phase.\",\n      \"evidence\": \"Ectopic expression and loss-of-adhesion assays with cell-cycle readout\",\n      \"pmids\": [\"11425869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting adhesion signaling to SKP2 abundance not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Expanded SKP2 substrate range beyond p27 to p130 and Myc and revealed a non-catalytic transcriptional coactivator role for Myc.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, transcriptional reporter assays\",\n      \"pmids\": [\"12769843\", \"12717421\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological weighting of these substrates versus p27 unresolved\", \"Coactivator mechanism not structurally defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified transcriptional control of SKP2 by demonstrating cell-cycle-dependent promoter occupancy by GABP and induction by E2F1.\",\n      \"evidence\": \"EMSA, ChIP, promoter-reporter, gain/loss-of-function\",\n      \"pmids\": [\"12907639\", \"16331253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between multiple SKP2 transcription factors not integrated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the CKS1-binding interface on SKP2 and established p27 as the principal in vivo SCF(SKP2) effector via genetic epistasis.\",\n      \"evidence\": \"Site-directed mutagenesis with in vitro ubiquitination; Skp2-KO vs Skp2-KO/p27T187A knock-in mice\",\n      \"pmids\": [\"15452136\", \"15520280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific substrate contributions outside hepatocytes not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed SKP2 stability is set by oncogenic upstream regulators, with AR blocking D-box-dependent SKP2 degradation to drive prostate cancer proliferation.\",\n      \"evidence\": \"Co-IP, ectopic expression, siRNA/dominant-negative, proliferation assays\",\n      \"pmids\": [\"18628304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct E3 mediating D-box degradation not defined in this study\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified pVHL as a non-canonical destabilizer of SKP2 that antagonizes Akt-mediated stabilizing phosphorylation, linking SKP2 turnover to DNA damage.\",\n      \"evidence\": \"Co-IP, half-life assay, mutagenesis, VHL-null RCC reconstitution\",\n      \"pmids\": [\"21358672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of E3-independent destabilization not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed acetylation as a switch controlling SKP2 localization and a non-canonical cytoplasmic function, with p300/SIRT3-regulated K68/K71 acetylation driving E-cadherin degradation and migration.\",\n      \"evidence\": \"Mass spec, acetyl-mimetic/dead mutants, fractionation, migration and in vivo tumorigenesis assays\",\n      \"pmids\": [\"22770219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic substrate repertoire beyond E-cadherin not catalogued\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected SKP2 to chromatin and G2/M control through a Skp2–macroH2A1–CDK8 feedback axis enhancing p27 degradation.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, mouse tumor models with genetic rescue\",\n      \"pmids\": [\"25818643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic step of mH2A1 ubiquitination relative to chromatin context not detailed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established SKP2 as a nutrient-responsive coupler of cell cycle to autophagy by degrading CARM1 under nutrient-rich conditions, with AMPK/FOXO3a repressing SKP2 during starvation.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, ChIP, genome-wide analysis, AMPK modulation\",\n      \"pmids\": [\"27309807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative threshold of SKP2 repression needed to license autophagy not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed SKP2 can protect substrates by antagonizing alternative E3s, shielding JARID1B and EZH2 from TRAF6-mediated K63 ubiquitination.\",\n      \"evidence\": \"Co-IP, K63-ubiquitination assays, TRAF6 catalytic-dead mutant, mouse prostate tumor models\",\n      \"pmids\": [\"25596733\", \"27869166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical mechanism of SKP2 shielding (competition vs modification) unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined SKP2 K63-linked ubiquitination as an activating modification for substrates, stabilizing MTH1 and driving YAP nuclear activity independently of Hippo signaling.\",\n      \"evidence\": \"Site-specific mutagenesis, K63-ubiquitination assays, fractionation, reporter assays\",\n      \"pmids\": [\"28947420\", \"29891922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting K48 versus K63 chain output on different substrates not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established reciprocal YAP–SKP2 regulation, with YAP transcribing SKP2 under mechanical cues and inducing its Akt/p300-dependent cytosolic acetylation to drive polyploidy and oncogenesis.\",\n      \"evidence\": \"ChIP, reporter assays, fractionation, genetic epistasis, mouse liver tumor model\",\n      \"pmids\": [\"28673931\", \"28486106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of transcriptional versus post-translational arms in a single tissue not fully dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Implicated SKP2-mediated K63 ubiquitination of AKT in PI3K-inhibitor resistance and showed SKP2 acts as an autophagy adaptor degrading IKKβ to suppress NF-κB.\",\n      \"evidence\": \"AKT ubiquitination assays, kinase-inhibitor and xenograft studies; co-IP and NF-κB reporter assays\",\n      \"pmids\": [\"29535262\", \"29474632\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AKT ubiquitination site mapping limited\", \"Adaptor versus ligase contributions to IKKβ turnover not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Broadened the SKP2 proteolytic substrate set to apoptosis and metabolic regulators (BECN1, PDCD4) and showed K63-AKT ubiquitination promotes mitochondrial glycolysis and chemoresistance.\",\n      \"evidence\": \"K48/K63 ubiquitination assays, complex characterization, fractionation, xenograft and viral infection models\",\n      \"pmids\": [\"31852899\", \"30760284\", \"31435020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Composition and regulation of the FKBP51/PHLPP/AKT1/BECN1 heterocomplex incompletely defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated lineage-specific transcriptional induction of SKP2 (by Notch/pre-TCR) drives p27 degradation in developing thymocytes, and identified ISG15/USP18 as cell-cycle-linked SKP2 stability regulators.\",\n      \"evidence\": \"Genetic mouse models, T-cell development and ubiquitination assays; co-IP and stability assays\",\n      \"pmids\": [\"31451788\", \"30858391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with Fbxl12 in p27 turnover not quantitatively partitioned\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Coupled SKP2 to metabolic oscillation by showing cell-cycle-dependent K48 degradation of IDH1/2, and connected SKP2 to AR stability and ovulation gene regulation via PGK1.\",\n      \"evidence\": \"Ubiquitination assays, metabolic flux analysis, cell-cycle synchronization, SKP2 knockout; co-IP and GST pulldown\",\n      \"pmids\": [\"32669607\", \"33096483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IDH and AR effects share regulatory inputs not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved a CKS1-independent route for SKP2 substrate targeting via direct cyclin A engagement and defined deubiquitylase control of SKP2 by USP2 and USP10, including a paradoxical USP2-driven substrate co-stabilization.\",\n      \"evidence\": \"Complex reconstitution and structural mapping; DUB screen, co-IP, half-life assays, inhibitors, in vivo models\",\n      \"pmids\": [\"33422522\", \"34425107\", \"34599966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for USP2 disrupting SKP2–substrate binding not solved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified NUCKS1 as a mitogen- and p53-responsive transcriptional activator of SKP2, and placed SKP2 upstream of β-catenin in hematopoietic stem cell homing.\",\n      \"evidence\": \"ChIP, reporter and cell-cycle assays, genetic epistasis; microarray and HSC transplantation\",\n      \"pmids\": [\"34845229\", \"24561244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SKP2 controls β-catenin levels not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed SKP2 can stabilize substrates by competing with rival E3s (Mcl-1 vs FBW7) and that nuclear FAK/Fzr1 directs SKP2 turnover to regulate vascular proliferation.\",\n      \"evidence\": \"CRISPR KO, co-IP, ubiquitination assays, xenograft and wire-injury models\",\n      \"pmids\": [\"35301297\", \"33839758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct competition versus indirect effects on FBW7 substrate access not fully separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended SKP2 substrate protection and K63-activation paradigms to immunometabolism and ferroptosis, including AhR-driven SKP2 induction promoting Lkb1 K63 ubiquitination and Treg generation, and K48 ubiquitination of SLC3A2 suppressing ferroptosis.\",\n      \"evidence\": \"Co-IP, K48/K63 ubiquitination assays, FAO and ferroptosis assays, reporter assays, in vivo disease models\",\n      \"pmids\": [\"36930164\", \"39079969\", \"37779163\", \"36694914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Some claims rest on single-lab pharmacology with limited direct mechanistic resolution\", \"Tissue specificity of opposing K48/K63 outputs unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined O-GlcNAcylation as a SKP2-stabilizing modification enhancing SKP1 binding and extended the substrate-protection model to PSPC1 and NLRP3 inflammasome control.\",\n      \"evidence\": \"Mass spec, Ser34 mutagenesis, ubiquitination assays, co-IP, AAV9 in vivo delivery\",\n      \"pmids\": [\"38396292\", \"38360141\", \"38698431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Crosstalk between O-GlcNAcylation and acetylation/phosphorylation in setting SKP2 levels not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What molecular features dictate whether SKP2 directs K48-linked degradative versus K63-linked activating ubiquitination on a given substrate, and how the converging post-translational modifications (acetylation, O-GlcNAcylation, phosphorylation) are integrated to set SKP2 localization and activity, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of chain-type selection\", \"No quantitative hierarchy among SKP2-stabilizing modifications\", \"Substrate competition logic with rival E3s not generalized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 6, 10, 12, 18, 26]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 5, 26]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 20, 30]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 12, 26]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 15, 38, 45]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 6, 26, 28, 30]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 6, 10, 26]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12, 20, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [18, 19, 45]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [23, 26, 39]}\n    ],\n    \"complexes\": [\"SCF(SKP2) E3 ubiquitin ligase\"],\n    \"partners\": [\"CKS1\", \"SKP1\", \"CDK2-cyclin A\", \"p27KIP1\", \"YAP\", \"AKT\", \"VHL\", \"USP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}