{"gene":"STIL","run_date":"2026-06-10T07:46:42","timeline":{"discoveries":[{"year":2011,"finding":"STIL localizes asymmetrically to the daughter centriole and is required for procentriole formation. STIL directly interacts with CPAP/CENPJ and forms a complex with hSAS6. STIL depletion inhibited centriole duplication, Plk4-induced centriole amplification, and CPAP-induced centriole elongation, and caused failure to localize hSAS6 and CPAP to the nascent procentriole. hSAS6 depletion also hindered STIL targeting, indicating mutual dependence for centriolar localization.","method":"Co-immunoprecipitation, siRNA depletion, overexpression, immunofluorescence microscopy","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, loss-of-function with defined phenotypic readouts, replicated across multiple orthogonal approaches in one study","pmids":["22020124"],"is_preprint":false},{"year":2011,"finding":"STIL is essential for centriole formation and proper spindle positioning in human cells. Conditions mimicking CPAP MCPH mutations compromise centriole formation and correlate with randomized spindle position, and STIL depletion phenocopies this defect.","method":"siRNA depletion, adhesive micropatterns for spindle positioning assay, immunofluorescence","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype (spindle misorientation), single lab, two orthogonal readouts","pmids":["22100914"],"is_preprint":false},{"year":2012,"finding":"STIL is required for centriole duplication in human cells; its overexpression triggers formation of multiple daughter centrioles. STIL is recruited to nascent daughter centrioles at onset of duplication and degraded in an APC/C(Cdc20-Cdh1)-dependent manner upon passage through mitosis.","method":"RNA interference, fluorescence time-lapse imaging, immunoelectron microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KD and OE with defined phenotypes, APC/C-dependent degradation established by pathway inhibition, replicated across two independent studies (PMID 22349698 and 22349705)","pmids":["22349698"],"is_preprint":false},{"year":2012,"finding":"STIL is required for SAS6 recruitment to centrioles and interacts with CPAP. Stil-/- mouse embryonic fibroblasts lack primary cilia, a phenotype rescued by restoration of STIL expression, linking STIL-dependent centriole formation to ciliogenesis.","method":"siRNA depletion, overexpression, Stil knockout MEFs, immunofluorescence, rescue experiments","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined phenotype (loss of cilia), rescue experiment, replicated in two independent 2012 papers","pmids":["22349705"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of the CPAP TCP domain in complex with a short conserved STIL motif reveal a 1:1 complex. The TCP domain is a novel proline-recognition domain. A microcephaly mutation in CPAP (E1235V) compromises this complex. Point mutations in the STIL binding motif abolish centriole duplication in vivo.","method":"X-ray crystallography, isothermal titration calorimetry, point mutagenesis, centriole duplication assay in U2OS cells","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure + mutagenesis + in vivo functional validation in one study, disease-relevant mutations tested","pmids":["24052813"],"is_preprint":false},{"year":2014,"finding":"Plk4 and STIL form a protein complex that provides a scaffold for recruiting HsSAS-6 at the onset of procentriole formation. Plk4 phosphorylates STIL to facilitate the STIL/HsSAS-6 interaction and centriolar loading of HsSAS-6. Centriolar STIL exerts negative feedback on Plk4's bimodal centriolar distribution, restricting procentriole formation to one site per parental centriole.","method":"Co-immunoprecipitation, in vitro kinase assay, phosphorylation site mapping, overexpression and depletion in human cells, live imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay, reciprocal Co-IP, multiple orthogonal methods establishing phospho-dependent interaction and negative feedback","pmids":["25342035"],"is_preprint":false},{"year":2014,"finding":"STIL is degraded via the APC/C-proteasome pathway in a two-step process: CDK1 triggers STIL translocation from centrosomes to cytoplasm at nuclear envelope breakdown, followed by APC/C(Cdc20/Cdh1)-dependent proteasomal degradation. A C-terminal KEN box in STIL is critical for its degradation. MCPH mutations that delete this KEN box render STIL resistant to degradation and cause centriole amplification.","method":"Fluorescence time-lapse imaging, APC/C inhibition, proteasome inhibition, mutant STIL constructs, flow cytometry","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection with multiple pathway components, disease-relevant mutants tested, live imaging plus biochemical validation","pmids":["24485834"],"is_preprint":false},{"year":2015,"finding":"Direct binding of STIL to PLK4 activates PLK4 by promoting self-phosphorylation of the kinase activation loop. PLK4 activity is required for STIL recruitment to the centriole. PLK4 then phosphorylates STIL to promote direct binding of STIL to the C terminus of SAS6, initiating cartwheel assembly.","method":"Chemical genetic system (ATP analogue-sensitive Plk4 allele in gene-edited human cells), in vitro kinase assays, Co-IP, FACS cell cycle analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — chemical genetics plus in vitro reconstitution of activation, multiple orthogonal methods, rigorous controls","pmids":["26101219"],"is_preprint":false},{"year":2015,"finding":"STIL interacts with Plk4 in vivo; the STIL fragment containing the coiled-coil domain and STAN motif shows the strongest binding affinity to Plk4. Plk4 phosphorylates STIL at specific C-terminal sites and this phosphorylation is required to trigger centriole duplication.","method":"Co-immunoprecipitation, in vitro kinase assay, phosphorylation site identification by mass spectrometry, dominant-negative phospho-mutant overexpression","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus Co-IP, phospho-mutant functional test; single lab","pmids":["25701666"],"is_preprint":false},{"year":2015,"finding":"STIL interacts via its coiled-coil region (STIL-CC) with PLK4 Polo-box 3 (PB3) — the first identified PB3 interaction partner — and also uses a secondary interaction site in PLK4 L1. NMR and crystal structures reveal a novel coiled-coil mimicry mode of Polo-box–peptide interaction. Structure-guided STIL mutants disrupt PLK4 binding and impair centriole duplication in vivo. STIL oligomerization interplays with PLK4 binding.","method":"NMR spectroscopy, X-ray crystallography, structure-guided mutagenesis, Co-IP, centriole duplication assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure + NMR + structure-guided mutagenesis + in vivo functional validation in one study","pmids":["26188084"],"is_preprint":false},{"year":2016,"finding":"CDK1-CyclinB binds STIL in mitosis and prevents formation of the PLK4-STIL complex, thereby blocking STIL phosphorylation by PLK4 and preventing untimely onset of centriole biogenesis. After CDK1 inactivation upon mitotic exit, PLK4 can bind and phosphorylate STIL to allow procentriole assembly in S phase.","method":"Co-immunoprecipitation, in vitro kinase assay, overexpression/depletion experiments, cell cycle synchronization","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay, reciprocal Co-IP, epistasis via cell-cycle synchronization; multiple orthogonal methods","pmids":["27112295"],"is_preprint":false},{"year":2016,"finding":"The central coiled-coil domain (CCD) of STIL mediates oligomerization via eight specific hydrophobic residues. Mutations in these residues destabilize the coiled-coil and impair centrosomal localization of STIL. STIL oligomerization is required for both canonical centriole duplication and de novo centriole biogenesis in STIL-null mouse embryonic fibroblasts.","method":"Circular dichroism spectroscopy, size exclusion chromatography, mutagenesis, reconstitution in Stil-/- MEFs","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biophysical characterization of domain plus rescue experiment in null cells; single lab but multiple orthogonal methods","pmids":["27075531"],"is_preprint":false},{"year":2017,"finding":"RTTN directly interacts with STIL and acts downstream of STIL-mediated centriole assembly. RTTN is recruited to the proximal end of the procentriole at early S phase. The microcephaly mutant RTTN(A578P) shows reduced affinity for STIL binding and blocks centriole assembly.","method":"Co-immunoprecipitation, super-resolution and electron microscopy, CRISPR/Cas9 knockout, pulldown with mutant proteins","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction by Co-IP plus CRISPR KO, mutant binding assay, super-resolution localization; multiple orthogonal methods","pmids":["28811500"],"is_preprint":false},{"year":2018,"finding":"STIL binds PLK4 in a bimodal manner: the conserved short coiled-coil region stabilizes PLK4 at the procentriole site (positive regulation), while the C-terminal TIM domain promotes autophosphorylation and degradation of adjacent PLK4 (negative regulation). This bimodal interaction restricts procentriole formation to one site per parental centriole.","method":"Co-immunoprecipitation, in vitro kinase assay, domain-mapping pulldown, overexpression of truncation mutants, live imaging","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay, domain mapping, Co-IP; multiple orthogonal methods in one study","pmids":["29898389"],"is_preprint":false},{"year":2018,"finding":"CEP85 directly interacts with STIL through a conserved interface involving a previously uncharacterized STIL domain. This interaction is essential for efficient centriolar targeting of STIL, PLK4 activation, and daughter centriole assembly. Structure-guided mutational analyses confirmed that the CEP85-STIL interaction interface is functionally critical in vivo.","method":"Protein proximity mapping (BioID), X-ray crystallography, structure-guided mutagenesis, Co-IP, centriole duplication assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — crystal structure + mutagenesis + in vivo functional validation; multiple orthogonal methods","pmids":["29712910"],"is_preprint":false},{"year":2018,"finding":"SCF-βTrCP E3 ubiquitin ligase binds STIL via a DSG motif (phosphorylated at serine 395 in vivo) and mediates STIL degradation throughout interphase. CDK2 activity protects STIL against SCF-βTrCP-mediated degradation. Mutations in the DSG motif cause massive centrosome amplification.","method":"Proteomics, co-immunoprecipitation, in vivo phosphorylation analysis, CDK2 inhibition, DSG motif mutagenesis, centrosome counting","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — substrate-ligase interaction by Co-IP, phospho-site identification, mutant functional test; multiple methods in one study","pmids":["29445034"],"is_preprint":false},{"year":2019,"finding":"PLK4 phosphorylates STIL on a conserved site S428 to promote STIL binding to CPAP. This phospho-dependent interaction is conserved in Drosophila and facilitates stable incorporation of both STIL and CPAP into the centriole. PLK4 thus phosphorylates STIL in two regions: STAN motif phosphorylation enables STIL-SAS6 binding for cartwheel assembly, while S428 phosphorylation enables STIL-CPAP binding to link the cartwheel to the centriole wall.","method":"In vitro kinase assay, phospho-specific mutant analysis, Co-IP, structure-guided mutagenesis, Drosophila conservation assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with defined phosphosite, Co-IP, cross-species validation; multiple orthogonal methods","pmids":["31115335"],"is_preprint":false},{"year":2019,"finding":"SFI1 interacts with USP9X and localizes it to the centrosome during S phase. USP9X deubiquitylates STIL, protecting it from degradation. Cells from USP9X loss-of-function patients have reduced STIL levels, confirming the physiological relevance of this stabilization pathway.","method":"Co-immunoprecipitation, deubiquitylation assay, patient-derived cells, centrosome analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — enzymatic deubiquitylation assay, Co-IP, patient cell validation; multiple orthogonal methods","pmids":["31197030"],"is_preprint":false},{"year":2019,"finding":"STIL forms a ternary complex with ARHGEF7 (β-PIX) and PAK1 and accumulates with these proteins at lamellipodia protrusions of motile cells. STIL knockdown reduces ARHGEF7-PAK1 complex accumulation in membrane ruffles, attenuates PAK1 substrate phosphorylation, impairs cortical actin remodeling, and reduces Rac1 activity at the migrating front, thereby impairing cancer cell migration.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, migration assay, Rac1 FRET biosensor","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP of ternary complex, KD with defined biochemical and cell biological phenotypes; single lab","pmids":["31754215"],"is_preprint":false},{"year":2011,"finding":"Stil suppresses Chfr protein stability by increasing Chfr auto-ubiquitination, thereby reducing Chfr's substrate Plk1 levels. Mouse fibroblasts lacking Stil exhibit high Chfr, low Plk1, slow growth, low mitotic index, and absent centrosomes. Knockdown of Chfr or overexpression of Plk1 rescues the abnormal mitotic phenotypes of Stil-null fibroblasts.","method":"Knockout and siRNA depletion, rescue overexpression, ubiquitination assay, western blot, immunofluorescence","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by rescue experiment, ubiquitination assay; single lab, multiple methods","pmids":["21245198"],"is_preprint":false},{"year":2014,"finding":"Stil-/- mouse embryos lack centrioles and primary cilia (shown by focused ion beam scanning electron microscopy). Absence of primary cilia explains the loss of Hedgehog signaling in Stil-/- cells. Re-expression of STIL or MCPH-compatible STIL mutants induces non-templated de novo generation of centrioles in Stil-/- cells.","method":"Focused ion beam scanning electron microscopy, Hedgehog pathway reporter assay, genetic rescue with exogenous STIL expression","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ultrastructural evidence of centriole absence, pathway epistasis (cilia→Hh), de novo rescue experiment; multiple orthogonal methods","pmids":["25486474"],"is_preprint":false},{"year":2013,"finding":"The central domain of STIL is intrinsically disordered and mediates its protein-protein interactions. This intrinsic disorder provides conformational flexibility required for STIL's multiple binding activities.","method":"Biophysical methods (NMR, circular dichroism, size exclusion chromatography), limited proteolysis","journal":"Chemical communications (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biophysical structural characterization; single lab, single study","pmids":["24022511"],"is_preprint":false},{"year":2016,"finding":"Zn2+ ions bind to both the structured N-terminal domain (NTD) and the intrinsically disordered region (IDR) of STIL. Zn2+ binding induces structural rearrangement of the NTD and promotes oligomerization of the IDR, suggesting zinc-dependent conformational changes regulate STIL activity and oligomerization.","method":"Circular dichroism spectroscopy, size exclusion chromatography, isothermal titration calorimetry, fluorescence spectroscopy","journal":"Chemical science","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — rigorous biophysical characterization; single lab, no in vivo functional follow-up reported in abstract","pmids":["30155058"],"is_preprint":false},{"year":2019,"finding":"Live-cell imaging of endogenously tagged proteins showed that centriolar Plk4 peaks and decreases in late G1, coinciding with STIL accumulation at centrioles; HsSAS6 then increases steeply at the procentriole site. Both STIL and HsSAS6 are necessary for attenuating Plk4 levels. Mathematical modeling supported a negative feedback effect of the STIL-HsSAS6 cartwheel complex on centriolar Plk4.","method":"Live-cell imaging of endogenously tagged proteins (CRISPR knock-in), quantitative tracking, mathematical modeling, siRNA depletion","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenously tagged proteins imaged through cell cycle, supported by depletion experiments and modeling; single lab","pmids":["31533936"],"is_preprint":false},{"year":2020,"finding":"Plk4 autophosphorylation is sufficient to initiate its ring-to-dot localization conversion around the centriole; STIL is not required for this initial step but greatly enhances Plk4's ability to generate a spherical condensate and recruit Sas6 once co-expressed. STIL-dependent reinforcement of the PLK4 condensate is essential for procentriole assembly.","method":"Photoconvertible mEOS-fused Plk4 live imaging, catalytically inactive Plk4 mutant, siRNA depletion, in vivo condensate assay in human cells and E. coli","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with photoconversion, catalytic mutant, depletion experiments; single lab, multiple methods","pmids":["33323015"],"is_preprint":false},{"year":2022,"finding":"Cdk/Cyclin-dependent phosphorylation of Ana2/STIL (Drosophila ortholog) reduces its cytoplasmic diffusion rate toward the end of S-phase, limiting daughter centriole growth. A non-phosphorylatable Ana2 mutant allows daughters to grow for an extended period, demonstrating that Cdk/Cyclin activity on Ana2/STIL stops centriole elongation at the correct time.","method":"Fluorescence correlation spectroscopy in Drosophila embryos, phospho-mutant Ana2 expression, live imaging","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-mutant functional test in vivo, biophysical diffusion measurement; single study in Drosophila ortholog","pmids":["35861803"],"is_preprint":false},{"year":2023,"finding":"The STIL CCD peptide undergoes concentration-dependent oligomerization forming dimers (KD = 8 µM) and tetramers (KD = 68 µM). Crystal structures of CCD mutants reveal dimeric and tetrameric antiparallel coiled-coil structures. Disrupting STIL oligomerization via the CCD inhibits its activity in vivo.","method":"Analytical ultracentrifugation, fluorescence spectroscopy, circular dichroism, X-ray crystallography","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — crystal structures plus biophysical characterization; single lab, limited in vivo follow-up referenced","pmids":["37834064"],"is_preprint":false},{"year":2025,"finding":"FBXW7 SCF E3 ubiquitin ligase mediates degradation of the STIL-SAS6 cartwheel complex. Plk4 kinase activity is required for FBXW7-dependent STIL degradation. Phosphorylation of Plk4-targeting sites in STIL that drive centriole assembly (facilitating STIL-SAS6 interaction) also stabilizes FBXW7 binding to STIL, creating a negative feedback that limits centriole overduplication. FBXW7 depletion causes premature centriole duplication via STIL-SAS6 stabilization.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, Plk4 kinase inhibition, FBXW7 depletion, centriole counting","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro ubiquitination assay plus Co-IP and KD; single lab, multiple methods","pmids":["41453690"],"is_preprint":false},{"year":2020,"finding":"CEP85 and STIL are required for PLK4-driven directional cancer cell migration. PLK4 drives recruitment of CEP85 and STIL to the leading edge of cells to promote protrusive activity. Downregulation of CEP85 and STIL reduces ARP2 phosphorylation and impairs actin cytoskeleton reorganization and directional migration.","method":"Mutational and functional analyses, Co-IP, siRNA knockdown, migration assay, immunofluorescence at leading edge, phosphorylation assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, KD with defined phenotypic readout (migration, ARP2 phosphorylation), interaction interface mutagenesis; single lab","pmids":["32107292"],"is_preprint":false},{"year":2025,"finding":"STIL associates with ARHGEF7 in dendritic spines. Knockdown of Stil reduces dendritic spines in neurons in vitro and in vivo. This function depends on STIL's coiled-coil domain that mediates ARHGEF7 binding. STIL knockdown impairs Rac1 activation in spines, and overexpression of Rac1/Cdc42 compensates for STIL loss. Chemical LTP promotes STIL accumulation in spines.","method":"Co-immunoprecipitation, in vitro and in vivo shRNA knockdown, FRET-based Rac1 activity assay, rescue with Rac1/Cdc42, domain mutagenesis","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, FRET biosensor, in vivo KD with morphological phenotype, rescue experiment; single lab","pmids":["39851490"],"is_preprint":false},{"year":2022,"finding":"A subset of STIL translocates to the nucleus and associates with FOXM1 to promote tumor metastasis and stemness via FOXM1-mediated target genes. HIF1α directly binds the STIL promoter and upregulates STIL expression under hypoxia. Excess STIL activates the EMT pathway and enhances cancer cell migration and invasion.","method":"ChIP-qPCR (HIF1α binding to STIL promoter), Co-IP (STIL-FOXM1 interaction), RNA-seq, reporter assays, xenograft metastasis assay, siRNA depletion","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ChIP-qPCR plus Co-IP plus in vivo metastasis; single lab, multiple methods","pmids":["35365182"],"is_preprint":false},{"year":2024,"finding":"STIL interacts with BRCA1 and regulates its stability; a cancer-associated heterozygous missense mutation (S76L) in STIL disrupts this interaction and redistributes BRCA1 from the nucleus to centrosomes. STIL-S76L overexpression elevates centrosomal Aurora-A and PLK1 kinases, causing centrosome amplification and DNA damage. Mutant cells maintain pseudo-bipolar spindles via HSET-dependent centrosome clustering.","method":"Co-immunoprecipitation, overexpression of S76L mutant, immunofluorescence, DNA damage assay, rescue with WT BRCA1","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and rescue experiment in single paper, single lab, no in vitro reconstitution; details limited in abstract","pmids":["41749477"],"is_preprint":false},{"year":2018,"finding":"Inactivation of PLK4 or STIL in human pluripotent stem cells leads to centrosome loss followed by p53-dependent upregulation, chromosome instability, reduction of pluripotency markers, and induction of differentiation. Loss of STIL function causes prolonged cell divisions and alterations in mitotic timing and protein turnover.","method":"PLK4 chemical inhibition, STIL siRNA knockdown in hESCs and hiPSCs, flow cytometry, immunofluorescence, western blot","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotypes (centrosome loss, differentiation, p53 induction); single lab","pmids":["30197118"],"is_preprint":false},{"year":2014,"finding":"STIL functions through the Sonic hedgehog (Shh) signaling pathway: co-immunoprecipitation revealed that STIL interacts with Shh downstream components SUFU and GLI1. Overexpression of STIL increased Shh signaling and PC12 cell proliferation; knockdown inhibited Shh signaling and proliferation.","method":"Co-immunoprecipitation, overexpression and shRNA knockdown in PC12 cells, qPCR of Shh target genes","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, single lab, no mutagenesis or structural validation","pmids":["24853807"],"is_preprint":false},{"year":2025,"finding":"STIL interacts with FOXM1 and co-occupies the SF3A3 promoter (by ChIP-qPCR) to regulate SF3A3 transcription in hepatocellular carcinoma cells. STIL loss inhibits HCC malignant behavior partly by promoting p53 expression. Knockdown of FOXM1 enhances the anti-tumor effects of STIL loss.","method":"Co-IP, ChIP-qPCR, siRNA knockdown, xenograft tumor model","journal":"Cell division","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP plus ChIP; single lab, mechanistic details limited","pmids":["39825314"],"is_preprint":false}],"current_model":"STIL is a core centriole duplication factor that is recruited to the nascent procentriole in S phase, where it acts as a scaffold and allosteric activator: direct binding of STIL to PLK4 activates PLK4 by promoting its activation-loop autophosphorylation, and PLK4 in turn phosphorylates STIL at multiple sites—including the STAN motif (to drive STIL–SAS6 interaction and cartwheel assembly) and S428 (to promote STIL–CPAP binding linking cartwheel to centriole wall)—while Plk4-phosphorylated STIL simultaneously exerts negative feedback on adjacent PLK4 to restrict procentriole formation to a single site; STIL levels are tightly cell-cycle-regulated through sequential degradation by CDK1-mediated dissociation from centrosomes in mitosis, APC/C(Cdc20/Cdh1)-dependent proteasomal degradation via a KEN box, SCF-βTrCP-mediated degradation via a CDK2-regulated DSG motif, and FBXW7-mediated degradation of the STIL-SAS6 complex, with USP9X/SFI1 antagonizing degradation during S phase; beyond centriole biogenesis, STIL also regulates directional cell migration by scaffolding the ARHGEF7–PAK1 complex at lamellipodia, supports dendritic spine formation via ARHGEF7-dependent Rac1 activation, and promotes Hedgehog signaling through interaction with SUFU and GLI1."},"narrative":{"mechanistic_narrative":"STIL is a core centriole duplication factor that is recruited asymmetrically to the nascent procentriole in S phase, where it acts as both a scaffold and an allosteric activator of the master centriolar kinase PLK4 [PMID:22020124, PMID:25342035, PMID:26101219]. Direct binding of STIL to PLK4 activates the kinase by promoting autophosphorylation of its activation loop, and PLK4 in turn phosphorylates STIL at multiple sites: STAN-motif phosphorylation drives the STIL–SAS6 interaction that initiates cartwheel assembly, while phosphorylation at S428 promotes STIL–CPAP binding to link the cartwheel to the centriole wall [PMID:25342035, PMID:26101219, PMID:31115335]. STIL engages PLK4 bimodally—its coiled-coil region stabilizes PLK4 at the procentriole through Polo-box 3 while a C-terminal element drives autophosphorylation and degradation of adjacent PLK4—thereby restricting procentriole formation to a single site per parent centriole [PMID:26188084, PMID:29898389, PMID:31533936]. STIL function requires its central coiled-coil-mediated oligomerization for centrosomal localization and centriole assembly [PMID:27075531, PMID:37834064], and it nucleates a wider assembly network through direct interactions with CPAP/CENPJ, hSAS6, CEP85, and RTTN [PMID:22020124, PMID:24052813, PMID:28811500, PMID:29712910]. Because unrestrained STIL drives centriole amplification, its levels are tightly cell-cycle controlled: CDK1–CyclinB sequesters STIL in mitosis to block premature PLK4 complex formation, and STIL is degraded by APC/C(Cdc20/Cdh1) via a KEN box, by SCF-βTrCP via a CDK2-regulated DSG motif, and by FBXW7 acting on the STIL–SAS6 complex, while USP9X (localized by SFI1) deubiquitylates and stabilizes STIL in S phase [PMID:24485834, PMID:27112295, PMID:29445034, PMID:31197030, PMID:41453690]. STIL-dependent centriole formation is required for primary cilium assembly and downstream Hedgehog signaling, and for genome stability in stem cells, where its loss triggers p53-dependent differentiation [PMID:22349705, PMID:25486474, PMID:30197118]. Beyond centriole biogenesis, STIL scaffolds an ARHGEF7(β-PIX)–PAK1 complex at lamellipodia to promote Rac1 activation, actin remodeling, and directional cell migration, and supports dendritic spine formation through ARHGEF7-dependent Rac1 activity [PMID:31754215, PMID:32107292, PMID:39851490].","teleology":[{"year":2011,"claim":"Established STIL as a procentriole assembly factor by placing it within the SAS6–CPAP module and showing it is required for their centriolar loading.","evidence":"Reciprocal Co-IP, siRNA depletion, overexpression, and immunofluorescence in human cells","pmids":["22020124"],"confidence":"High","gaps":["Molecular basis of asymmetric daughter-centriole targeting unresolved","Order of recruitment relative to PLK4 not defined"]},{"year":2011,"claim":"Linked STIL-dependent centriole formation to spindle positioning, connecting it to the microcephaly (MCPH) phenotype of CPAP loss.","evidence":"siRNA depletion with micropattern spindle-orientation assay","pmids":["22100914"],"confidence":"Medium","gaps":["Direct molecular role of STIL in spindle orientation versus indirect centriole effect not separated"]},{"year":2011,"claim":"Identified an early, non-centriolar STIL function regulating mitotic progression via Chfr/Plk1 stability.","evidence":"Knockout/siDNA, rescue, and ubiquitination assays in mouse fibroblasts","pmids":["21245198"],"confidence":"Medium","gaps":["Mechanism by which STIL controls Chfr auto-ubiquitination unknown","Relationship to STIL's centriolar role unclear"]},{"year":2012,"claim":"Defined the cell-cycle behavior of STIL—recruitment at duplication onset and APC/C-dependent removal through mitosis—and showed overexpression drives centriole amplification.","evidence":"RNAi, time-lapse imaging, immuno-EM, and APC/C pathway manipulation across two independent studies","pmids":["22349698","22349705"],"confidence":"High","gaps":["Degron sequences not yet mapped","Coupling of degradation timing to procentriole completion undefined"]},{"year":2013,"claim":"Provided the structural basis for STIL–CPAP recognition and showed a disease mutation disrupts it, establishing the interaction as functionally essential.","evidence":"X-ray crystallography of the CPAP TCP domain–STIL motif, ITC, and centriole duplication assays in U2OS cells","pmids":["24052813"],"confidence":"High","gaps":["Phospho-regulation of this interface not yet known at this stage"]},{"year":2013,"claim":"Characterized the STIL central domain as intrinsically disordered, rationalizing its capacity for multiple binding partners.","evidence":"NMR, circular dichroism, SEC, and limited proteolysis","pmids":["24022511"],"confidence":"Medium","gaps":["Functional consequences of disorder in cells not directly tested"]},{"year":2014,"claim":"Established the reciprocal PLK4–STIL relationship: STIL scaffolds SAS6 recruitment, PLK4 phosphorylation enables this, and centriolar STIL feeds back to restrict PLK4 to a single site.","evidence":"Co-IP, in vitro kinase assays, phospho-site mapping, and live imaging","pmids":["25342035"],"confidence":"High","gaps":["Identity of the negative-feedback effector element not yet resolved","Direct phospho-sites driving SAS6 binding not fully mapped"]},{"year":2014,"claim":"Dissected STIL degradation into CDK1-driven centrosome dissociation followed by APC/C/KEN-box proteasomal turnover, and tied KEN-box loss to MCPH-associated amplification.","evidence":"Time-lapse imaging, APC/C and proteasome inhibition, KEN-box mutants, flow cytometry","pmids":["24485834"],"confidence":"High","gaps":["How CDK1 triggers translocation mechanistically unclear"]},{"year":2014,"claim":"Connected STIL-dependent centriole formation to ciliogenesis and Hedgehog signaling and demonstrated de novo centriole generation upon STIL re-expression in null cells.","evidence":"FIB-SEM ultrastructure, Hedgehog reporter assays, and genetic rescue in Stil-/- cells/embryos","pmids":["22349705","25486474"],"confidence":"High","gaps":["Whether STIL acts directly in Hh signaling beyond enabling cilia not separated here"]},{"year":2014,"claim":"Reported a direct, but weakly validated, STIL link to Hedgehog components SUFU and GLI1.","evidence":"Single Co-IP with overexpression/knockdown and target-gene qPCR in PC12 cells","pmids":["24853807"],"confidence":"Low","gaps":["Single Co-IP without mutagenesis or reciprocal validation","Cilium-independent Hh role not established"]},{"year":2015,"claim":"Resolved the activation logic: STIL binding directly activates PLK4 via activation-loop autophosphorylation, and activated PLK4 then phosphorylates STIL to drive SAS6 binding and cartwheel initiation.","evidence":"Analog-sensitive PLK4 chemical genetics, in vitro kinase assays, Co-IP in gene-edited human cells","pmids":["26101219","25701666"],"confidence":"High","gaps":["Stoichiometry of the active complex not defined","Spatial trigger for initial STIL recruitment unresolved"]},{"year":2015,"claim":"Defined the structural mode of STIL–PLK4 binding, identifying STIL as the first PLK4 Polo-box 3 partner via coiled-coil mimicry.","evidence":"NMR, X-ray crystallography, structure-guided mutagenesis, and centriole duplication assays","pmids":["26188084"],"confidence":"High","gaps":["Interplay between STIL oligomerization and PLK4 binding only partially defined"]},{"year":2016,"claim":"Showed CDK1–CyclinB gates duplication timing by binding STIL in mitosis to prevent premature PLK4–STIL complex formation.","evidence":"Co-IP, in vitro kinase assays, and cell-cycle synchronization epistasis","pmids":["27112295"],"confidence":"High","gaps":["CDK1 phospho-sites on STIL not fully mapped"]},{"year":2016,"claim":"Defined the coiled-coil oligomerization determinants of STIL required for centrosomal localization and both canonical and de novo centriole assembly.","evidence":"CD spectroscopy, SEC, mutagenesis, and reconstitution in Stil-/- MEFs","pmids":["27075531"],"confidence":"High","gaps":["Oligomeric state in the assembling procentriole in vivo not resolved"]},{"year":2016,"claim":"Identified zinc-dependent conformational regulation of STIL's N-terminal domain and disordered region promoting oligomerization.","evidence":"CD, SEC, ITC, and fluorescence spectroscopy","pmids":["30155058"],"confidence":"Medium","gaps":["No in vivo functional follow-up of zinc binding","Physiological relevance of zinc regulation untested"]},{"year":2017,"claim":"Placed RTTN downstream of STIL in the assembly hierarchy via a direct interaction disrupted by a microcephaly mutation.","evidence":"Co-IP, CRISPR KO, super-resolution/EM, and mutant pulldown","pmids":["28811500"],"confidence":"High","gaps":["Structural basis of STIL–RTTN interface undefined"]},{"year":2018,"claim":"Identified CEP85 as a direct STIL partner required for STIL centriolar targeting and PLK4 activation, extending the upstream recruitment network.","evidence":"BioID, crystallography, structure-guided mutagenesis, Co-IP, and duplication assay","pmids":["29712910"],"confidence":"High","gaps":["How CEP85 cooperates with CDK1/PLK4 timing not integrated"]},{"year":2018,"claim":"Resolved the bimodal STIL–PLK4 interaction—coiled-coil stabilization versus C-terminal TIM-domain-driven PLK4 degradation—as the basis for single-site procentriole restriction.","evidence":"Co-IP, in vitro kinase assays, domain mapping, truncation mutants, and live imaging","pmids":["29898389"],"confidence":"High","gaps":["Quantitative threshold distinguishing positive from negative regulation undefined"]},{"year":2018,"claim":"Added SCF-βTrCP as an interphase-wide STIL degradation pathway acting through a phosphorylated DSG motif and counteracted by CDK2.","evidence":"Proteomics, Co-IP, in vivo phospho-analysis, CDK2 inhibition, and DSG mutagenesis","pmids":["29445034"],"confidence":"High","gaps":["Kinase phosphorylating the DSG degron not identified"]},{"year":2018,"claim":"Demonstrated STIL is essential for genome stability and pluripotency maintenance, with loss triggering p53-dependent differentiation.","evidence":"STIL siRNA and PLK4 inhibition in hESCs/hiPSCs with flow cytometry and protein analysis","pmids":["30197118"],"confidence":"Medium","gaps":["Mechanistic link between centrosome loss and p53 activation not dissected"]},{"year":2019,"claim":"Defined a second PLK4 phospho-site on STIL (S428) that drives STIL–CPAP binding, linking cartwheel to centriole wall, conserved to Drosophila.","evidence":"In vitro kinase assays, phospho-mutants, Co-IP, structure-guided mutagenesis, and Drosophila conservation","pmids":["31115335"],"confidence":"High","gaps":["Temporal coordination of STAN-motif versus S428 phosphorylation unresolved"]},{"year":2019,"claim":"Identified a STIL stabilization arm: SFI1-localized USP9X deubiquitylates STIL in S phase, validated in patient cells.","evidence":"Co-IP, deubiquitylation assay, and USP9X loss-of-function patient cells","pmids":["31197030"],"confidence":"High","gaps":["Balance between USP9X and the multiple E3 ligases not quantified"]},{"year":2019,"claim":"Provided endogenous-protein kinetics confirming that the STIL–HsSAS6 cartwheel exerts negative feedback attenuating centriolar PLK4.","evidence":"Live imaging of CRISPR knock-in proteins, quantitative tracking, depletion, and mathematical modeling","pmids":["31533936"],"confidence":"Medium","gaps":["Molecular mechanism of feedback distinct from TIM-domain effect not reconciled"]},{"year":2019,"claim":"Revealed a centriole-independent STIL function: scaffolding the ARHGEF7–PAK1 complex at lamellipodia to drive Rac1-dependent cancer cell migration.","evidence":"Co-IP of ternary complex, siRNA knockdown, migration assays, and Rac1 FRET biosensor","pmids":["31754215"],"confidence":"Medium","gaps":["Single lab; whether centriolar and migratory pools of STIL are distinct unresolved"]},{"year":2020,"claim":"Clarified that PLK4 autophosphorylation initiates its ring-to-dot condensation while STIL reinforces the condensate to enable SAS6 recruitment.","evidence":"Photoconvertible PLK4 live imaging, catalytic mutant, depletion, and condensate assays","pmids":["33323015"],"confidence":"Medium","gaps":["Biophysical nature of the condensate in physiological cells not fully defined"]},{"year":2020,"claim":"Extended the migratory role by showing PLK4 recruits CEP85 and STIL to the leading edge to promote ARP2 phosphorylation and directional migration.","evidence":"Co-IP, interface mutagenesis, knockdown, migration and phosphorylation assays","pmids":["32107292"],"confidence":"Medium","gaps":["Direct kinase–substrate relationship to ARP2 not established"]},{"year":2022,"claim":"Used the Drosophila ortholog to show Cdk/Cyclin phosphorylation of Ana2/STIL slows its diffusion to terminate daughter centriole growth at the correct time.","evidence":"FCS in Drosophila embryos, phospho-mutant expression, live imaging","pmids":["35861803"],"confidence":"Medium","gaps":["Conservation of this diffusion-based timing mechanism in human STIL untested"]},{"year":2022,"claim":"Proposed an oncogenic nuclear STIL function partnering FOXM1 to drive metastasis, with HIF1α transcriptionally inducing STIL under hypoxia.","evidence":"ChIP-qPCR, Co-IP, RNA-seq, reporter assays, and xenograft metastasis","pmids":["35365182"],"confidence":"Medium","gaps":["Mechanism of nuclear STIL translocation unclear","Separation from centriolar role not established"]},{"year":2023,"claim":"Quantified STIL coiled-coil self-association equilibria and resolved dimeric and tetrameric antiparallel structures essential for activity.","evidence":"Analytical ultracentrifugation, fluorescence, CD, and X-ray crystallography","pmids":["37834064"],"confidence":"Medium","gaps":["Oligomeric state at the procentriole in vivo not directly observed"]},{"year":2025,"claim":"Added FBXW7-mediated degradation of the STIL–SAS6 complex as a PLK4-coupled negative feedback limiting overduplication.","evidence":"Co-IP, in vitro ubiquitination, PLK4 inhibition, FBXW7 depletion, centriole counting","pmids":["41453690"],"confidence":"Medium","gaps":["Degron site and phospho-dependence on STIL not fully mapped","Single lab"]},{"year":2025,"claim":"Identified a neuronal STIL function supporting dendritic spine formation through coiled-coil-mediated ARHGEF7 binding and Rac1 activation.","evidence":"Co-IP, in vivo/in vitro shRNA knockdown, FRET Rac1 assay, Rac1/Cdc42 rescue, domain mutagenesis","pmids":["39851490"],"confidence":"Medium","gaps":["Relationship to centriolar function in post-mitotic neurons unclear"]},{"year":2024,"claim":"Proposed a STIL–BRCA1 interaction whose disruption by a cancer mutation redistributes BRCA1 and causes centrosome amplification and DNA damage.","evidence":"Co-IP, S76L overexpression, immunofluorescence, DNA damage and rescue assays","pmids":["41749477"],"confidence":"Low","gaps":["Co-IP and rescue in single paper without in vitro reconstitution","Direct versus indirect BRCA1 effect not separated"]},{"year":2025,"claim":"Reported a hepatocellular carcinoma role in which STIL–FOXM1 co-occupy the SF3A3 promoter and modulate p53.","evidence":"Co-IP, ChIP-qPCR, knockdown, and xenograft model","pmids":["39825314"],"confidence":"Low","gaps":["Mechanistic details limited; direct transcriptional role of STIL not established"]},{"year":null,"claim":"How the multiple STIL degradation pathways, deubiquitylation, oligomerization, and PLK4 feedback loops are quantitatively integrated to ensure exactly one procentriole per parent remains unresolved, as does whether the migratory, neuronal, and nuclear oncogenic functions use the same molecular pool and binding surfaces as the centriolar role.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model coupling activation, feedback, and degradation","Centriolar versus non-centriolar STIL pools not physically distinguished","Structural basis of full STIL–PLK4 active assembly incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,14,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7,13]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[18,28,29]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,2,11]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[3,20]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[18,28]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[30,31]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,2,4,7]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,10,32]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,15,17,27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[20,18,29]}],"complexes":["STIL-SAS6 cartwheel complex","STIL-PLK4 complex","ARHGEF7(β-PIX)-PAK1-STIL complex"],"partners":["PLK4","SAS6","CPAP","CEP85","RTTN","ARHGEF7","PAK1","USP9X"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15468","full_name":"SCL-interrupting locus protein","aliases":["TAL-1-interrupting locus protein"],"length_aa":1287,"mass_kda":143.0,"function":"Immediate-early gene. Plays an important role in embryonic development as well as in cellular growth and proliferation; its long-term silencing affects cell survival and cell cycle distribution as well as decreases CDK1 activity correlated with reduced phosphorylation of CDK1. Plays a role as a positive regulator of the sonic hedgehog pathway, acting downstream of PTCH1 (PubMed:16024801, PubMed:9372240). Plays an important role in the regulation of centriole duplication. Required for the onset of procentriole formation and proper mitotic progression. During procentriole formation, is essential for the correct loading of SASS6 and CPAP to the base of the procentriole to initiate procentriole assembly (PubMed:22020124). In complex with STIL acts as a modulator of PLK4-driven cytoskeletal rearrangements and directional cell motility (PubMed:29712910, PubMed:32107292)","subcellular_location":"Cytoplasm, cytosol; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasm, cell cortex","url":"https://www.uniprot.org/uniprotkb/Q15468/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/STIL","classification":"Common Essential","n_dependent_lines":774,"n_total_lines":1208,"dependency_fraction":0.640728476821192},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/STIL","total_profiled":1310},"omim":[{"mim_id":"618898","title":"CENTROSOMAL PROTEIN, 85-KD; CEP85","url":"https://www.omim.org/entry/618898"},{"mim_id":"616364","title":"WHITE-SUTTON SYNDROME; WHSUS","url":"https://www.omim.org/entry/616364"},{"mim_id":"614787","title":"POGO TRANSPOSABLE ELEMENT-DERIVED PROTEIN WITH ZNF DOMAIN; POGZ","url":"https://www.omim.org/entry/614787"},{"mim_id":"612703","title":"MICROCEPHALY 7, PRIMARY, AUTOSOMAL RECESSIVE; MCPH7","url":"https://www.omim.org/entry/612703"},{"mim_id":"606726","title":"SOLUTE CARRIER FAMILY 12 (POTASSIUM/CHLORIDE TRANSPORTER), MEMBER 5; SLC12A5","url":"https://www.omim.org/entry/606726"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Centrosome","reliability":"Supported"},{"location":"Basal body","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":8.4},{"tissue":"lymphoid tissue","ntpm":8.2}],"url":"https://www.proteinatlas.org/search/STIL"},"hgnc":{"alias_symbol":["MCPH7"],"prev_symbol":["SIL"]},"alphafold":{"accession":"Q15468","domains":[{"cath_id":"-","chopping":"26-49_199-326","consensus_level":"medium","plddt":91.8473,"start":26,"end":326},{"cath_id":"3.40.140,3.40.140","chopping":"53-197_327-357","consensus_level":"medium","plddt":88.2714,"start":53,"end":357}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15468","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15468-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15468-F1-predicted_aligned_error_v6.png","plddt_mean":53.78},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STIL","jax_strain_url":"https://www.jax.org/strain/search?query=STIL"},"sequence":{"accession":"Q15468","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15468.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15468/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15468"}},"corpus_meta":[{"pmid":"22020124","id":"PMC_22020124","title":"The 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daughter centriole and is required for procentriole formation. STIL directly interacts with CPAP/CENPJ and forms a complex with hSAS6. STIL depletion inhibited centriole duplication, Plk4-induced centriole amplification, and CPAP-induced centriole elongation, and caused failure to localize hSAS6 and CPAP to the nascent procentriole. hSAS6 depletion also hindered STIL targeting, indicating mutual dependence for centriolar localization.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, overexpression, immunofluorescence microscopy\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, loss-of-function with defined phenotypic readouts, replicated across multiple orthogonal approaches in one study\",\n      \"pmids\": [\"22020124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STIL is essential for centriole formation and proper spindle positioning in human cells. Conditions mimicking CPAP MCPH mutations compromise centriole formation and correlate with randomized spindle position, and STIL depletion phenocopies this defect.\",\n      \"method\": \"siRNA depletion, adhesive micropatterns for spindle positioning assay, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype (spindle misorientation), single lab, two orthogonal readouts\",\n      \"pmids\": [\"22100914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STIL is required for centriole duplication in human cells; its overexpression triggers formation of multiple daughter centrioles. STIL is recruited to nascent daughter centrioles at onset of duplication and degraded in an APC/C(Cdc20-Cdh1)-dependent manner upon passage through mitosis.\",\n      \"method\": \"RNA interference, fluorescence time-lapse imaging, immunoelectron microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KD and OE with defined phenotypes, APC/C-dependent degradation established by pathway inhibition, replicated across two independent studies (PMID 22349698 and 22349705)\",\n      \"pmids\": [\"22349698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STIL is required for SAS6 recruitment to centrioles and interacts with CPAP. Stil-/- mouse embryonic fibroblasts lack primary cilia, a phenotype rescued by restoration of STIL expression, linking STIL-dependent centriole formation to ciliogenesis.\",\n      \"method\": \"siRNA depletion, overexpression, Stil knockout MEFs, immunofluorescence, rescue experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined phenotype (loss of cilia), rescue experiment, replicated in two independent 2012 papers\",\n      \"pmids\": [\"22349705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of the CPAP TCP domain in complex with a short conserved STIL motif reveal a 1:1 complex. The TCP domain is a novel proline-recognition domain. A microcephaly mutation in CPAP (E1235V) compromises this complex. Point mutations in the STIL binding motif abolish centriole duplication in vivo.\",\n      \"method\": \"X-ray crystallography, isothermal titration calorimetry, point mutagenesis, centriole duplication assay in U2OS cells\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure + mutagenesis + in vivo functional validation in one study, disease-relevant mutations tested\",\n      \"pmids\": [\"24052813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Plk4 and STIL form a protein complex that provides a scaffold for recruiting HsSAS-6 at the onset of procentriole formation. Plk4 phosphorylates STIL to facilitate the STIL/HsSAS-6 interaction and centriolar loading of HsSAS-6. Centriolar STIL exerts negative feedback on Plk4's bimodal centriolar distribution, restricting procentriole formation to one site per parental centriole.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phosphorylation site mapping, overexpression and depletion in human cells, live imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay, reciprocal Co-IP, multiple orthogonal methods establishing phospho-dependent interaction and negative feedback\",\n      \"pmids\": [\"25342035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STIL is degraded via the APC/C-proteasome pathway in a two-step process: CDK1 triggers STIL translocation from centrosomes to cytoplasm at nuclear envelope breakdown, followed by APC/C(Cdc20/Cdh1)-dependent proteasomal degradation. A C-terminal KEN box in STIL is critical for its degradation. MCPH mutations that delete this KEN box render STIL resistant to degradation and cause centriole amplification.\",\n      \"method\": \"Fluorescence time-lapse imaging, APC/C inhibition, proteasome inhibition, mutant STIL constructs, flow cytometry\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection with multiple pathway components, disease-relevant mutants tested, live imaging plus biochemical validation\",\n      \"pmids\": [\"24485834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Direct binding of STIL to PLK4 activates PLK4 by promoting self-phosphorylation of the kinase activation loop. PLK4 activity is required for STIL recruitment to the centriole. PLK4 then phosphorylates STIL to promote direct binding of STIL to the C terminus of SAS6, initiating cartwheel assembly.\",\n      \"method\": \"Chemical genetic system (ATP analogue-sensitive Plk4 allele in gene-edited human cells), in vitro kinase assays, Co-IP, FACS cell cycle analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — chemical genetics plus in vitro reconstitution of activation, multiple orthogonal methods, rigorous controls\",\n      \"pmids\": [\"26101219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STIL interacts with Plk4 in vivo; the STIL fragment containing the coiled-coil domain and STAN motif shows the strongest binding affinity to Plk4. Plk4 phosphorylates STIL at specific C-terminal sites and this phosphorylation is required to trigger centriole duplication.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phosphorylation site identification by mass spectrometry, dominant-negative phospho-mutant overexpression\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus Co-IP, phospho-mutant functional test; single lab\",\n      \"pmids\": [\"25701666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STIL interacts via its coiled-coil region (STIL-CC) with PLK4 Polo-box 3 (PB3) — the first identified PB3 interaction partner — and also uses a secondary interaction site in PLK4 L1. NMR and crystal structures reveal a novel coiled-coil mimicry mode of Polo-box–peptide interaction. Structure-guided STIL mutants disrupt PLK4 binding and impair centriole duplication in vivo. STIL oligomerization interplays with PLK4 binding.\",\n      \"method\": \"NMR spectroscopy, X-ray crystallography, structure-guided mutagenesis, Co-IP, centriole duplication assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure + NMR + structure-guided mutagenesis + in vivo functional validation in one study\",\n      \"pmids\": [\"26188084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CDK1-CyclinB binds STIL in mitosis and prevents formation of the PLK4-STIL complex, thereby blocking STIL phosphorylation by PLK4 and preventing untimely onset of centriole biogenesis. After CDK1 inactivation upon mitotic exit, PLK4 can bind and phosphorylate STIL to allow procentriole assembly in S phase.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, overexpression/depletion experiments, cell cycle synchronization\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay, reciprocal Co-IP, epistasis via cell-cycle synchronization; multiple orthogonal methods\",\n      \"pmids\": [\"27112295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The central coiled-coil domain (CCD) of STIL mediates oligomerization via eight specific hydrophobic residues. Mutations in these residues destabilize the coiled-coil and impair centrosomal localization of STIL. STIL oligomerization is required for both canonical centriole duplication and de novo centriole biogenesis in STIL-null mouse embryonic fibroblasts.\",\n      \"method\": \"Circular dichroism spectroscopy, size exclusion chromatography, mutagenesis, reconstitution in Stil-/- MEFs\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biophysical characterization of domain plus rescue experiment in null cells; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"27075531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RTTN directly interacts with STIL and acts downstream of STIL-mediated centriole assembly. RTTN is recruited to the proximal end of the procentriole at early S phase. The microcephaly mutant RTTN(A578P) shows reduced affinity for STIL binding and blocks centriole assembly.\",\n      \"method\": \"Co-immunoprecipitation, super-resolution and electron microscopy, CRISPR/Cas9 knockout, pulldown with mutant proteins\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction by Co-IP plus CRISPR KO, mutant binding assay, super-resolution localization; multiple orthogonal methods\",\n      \"pmids\": [\"28811500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"STIL binds PLK4 in a bimodal manner: the conserved short coiled-coil region stabilizes PLK4 at the procentriole site (positive regulation), while the C-terminal TIM domain promotes autophosphorylation and degradation of adjacent PLK4 (negative regulation). This bimodal interaction restricts procentriole formation to one site per parental centriole.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, domain-mapping pulldown, overexpression of truncation mutants, live imaging\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay, domain mapping, Co-IP; multiple orthogonal methods in one study\",\n      \"pmids\": [\"29898389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CEP85 directly interacts with STIL through a conserved interface involving a previously uncharacterized STIL domain. This interaction is essential for efficient centriolar targeting of STIL, PLK4 activation, and daughter centriole assembly. Structure-guided mutational analyses confirmed that the CEP85-STIL interaction interface is functionally critical in vivo.\",\n      \"method\": \"Protein proximity mapping (BioID), X-ray crystallography, structure-guided mutagenesis, Co-IP, centriole duplication assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — crystal structure + mutagenesis + in vivo functional validation; multiple orthogonal methods\",\n      \"pmids\": [\"29712910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SCF-βTrCP E3 ubiquitin ligase binds STIL via a DSG motif (phosphorylated at serine 395 in vivo) and mediates STIL degradation throughout interphase. CDK2 activity protects STIL against SCF-βTrCP-mediated degradation. Mutations in the DSG motif cause massive centrosome amplification.\",\n      \"method\": \"Proteomics, co-immunoprecipitation, in vivo phosphorylation analysis, CDK2 inhibition, DSG motif mutagenesis, centrosome counting\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — substrate-ligase interaction by Co-IP, phospho-site identification, mutant functional test; multiple methods in one study\",\n      \"pmids\": [\"29445034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PLK4 phosphorylates STIL on a conserved site S428 to promote STIL binding to CPAP. This phospho-dependent interaction is conserved in Drosophila and facilitates stable incorporation of both STIL and CPAP into the centriole. PLK4 thus phosphorylates STIL in two regions: STAN motif phosphorylation enables STIL-SAS6 binding for cartwheel assembly, while S428 phosphorylation enables STIL-CPAP binding to link the cartwheel to the centriole wall.\",\n      \"method\": \"In vitro kinase assay, phospho-specific mutant analysis, Co-IP, structure-guided mutagenesis, Drosophila conservation assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with defined phosphosite, Co-IP, cross-species validation; multiple orthogonal methods\",\n      \"pmids\": [\"31115335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SFI1 interacts with USP9X and localizes it to the centrosome during S phase. USP9X deubiquitylates STIL, protecting it from degradation. Cells from USP9X loss-of-function patients have reduced STIL levels, confirming the physiological relevance of this stabilization pathway.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitylation assay, patient-derived cells, centrosome analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — enzymatic deubiquitylation assay, Co-IP, patient cell validation; multiple orthogonal methods\",\n      \"pmids\": [\"31197030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STIL forms a ternary complex with ARHGEF7 (β-PIX) and PAK1 and accumulates with these proteins at lamellipodia protrusions of motile cells. STIL knockdown reduces ARHGEF7-PAK1 complex accumulation in membrane ruffles, attenuates PAK1 substrate phosphorylation, impairs cortical actin remodeling, and reduces Rac1 activity at the migrating front, thereby impairing cancer cell migration.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, migration assay, Rac1 FRET biosensor\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP of ternary complex, KD with defined biochemical and cell biological phenotypes; single lab\",\n      \"pmids\": [\"31754215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Stil suppresses Chfr protein stability by increasing Chfr auto-ubiquitination, thereby reducing Chfr's substrate Plk1 levels. Mouse fibroblasts lacking Stil exhibit high Chfr, low Plk1, slow growth, low mitotic index, and absent centrosomes. Knockdown of Chfr or overexpression of Plk1 rescues the abnormal mitotic phenotypes of Stil-null fibroblasts.\",\n      \"method\": \"Knockout and siRNA depletion, rescue overexpression, ubiquitination assay, western blot, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by rescue experiment, ubiquitination assay; single lab, multiple methods\",\n      \"pmids\": [\"21245198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Stil-/- mouse embryos lack centrioles and primary cilia (shown by focused ion beam scanning electron microscopy). Absence of primary cilia explains the loss of Hedgehog signaling in Stil-/- cells. Re-expression of STIL or MCPH-compatible STIL mutants induces non-templated de novo generation of centrioles in Stil-/- cells.\",\n      \"method\": \"Focused ion beam scanning electron microscopy, Hedgehog pathway reporter assay, genetic rescue with exogenous STIL expression\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ultrastructural evidence of centriole absence, pathway epistasis (cilia→Hh), de novo rescue experiment; multiple orthogonal methods\",\n      \"pmids\": [\"25486474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The central domain of STIL is intrinsically disordered and mediates its protein-protein interactions. This intrinsic disorder provides conformational flexibility required for STIL's multiple binding activities.\",\n      \"method\": \"Biophysical methods (NMR, circular dichroism, size exclusion chromatography), limited proteolysis\",\n      \"journal\": \"Chemical communications (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biophysical structural characterization; single lab, single study\",\n      \"pmids\": [\"24022511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Zn2+ ions bind to both the structured N-terminal domain (NTD) and the intrinsically disordered region (IDR) of STIL. Zn2+ binding induces structural rearrangement of the NTD and promotes oligomerization of the IDR, suggesting zinc-dependent conformational changes regulate STIL activity and oligomerization.\",\n      \"method\": \"Circular dichroism spectroscopy, size exclusion chromatography, isothermal titration calorimetry, fluorescence spectroscopy\",\n      \"journal\": \"Chemical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous biophysical characterization; single lab, no in vivo functional follow-up reported in abstract\",\n      \"pmids\": [\"30155058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Live-cell imaging of endogenously tagged proteins showed that centriolar Plk4 peaks and decreases in late G1, coinciding with STIL accumulation at centrioles; HsSAS6 then increases steeply at the procentriole site. Both STIL and HsSAS6 are necessary for attenuating Plk4 levels. Mathematical modeling supported a negative feedback effect of the STIL-HsSAS6 cartwheel complex on centriolar Plk4.\",\n      \"method\": \"Live-cell imaging of endogenously tagged proteins (CRISPR knock-in), quantitative tracking, mathematical modeling, siRNA depletion\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenously tagged proteins imaged through cell cycle, supported by depletion experiments and modeling; single lab\",\n      \"pmids\": [\"31533936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Plk4 autophosphorylation is sufficient to initiate its ring-to-dot localization conversion around the centriole; STIL is not required for this initial step but greatly enhances Plk4's ability to generate a spherical condensate and recruit Sas6 once co-expressed. STIL-dependent reinforcement of the PLK4 condensate is essential for procentriole assembly.\",\n      \"method\": \"Photoconvertible mEOS-fused Plk4 live imaging, catalytically inactive Plk4 mutant, siRNA depletion, in vivo condensate assay in human cells and E. coli\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with photoconversion, catalytic mutant, depletion experiments; single lab, multiple methods\",\n      \"pmids\": [\"33323015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cdk/Cyclin-dependent phosphorylation of Ana2/STIL (Drosophila ortholog) reduces its cytoplasmic diffusion rate toward the end of S-phase, limiting daughter centriole growth. A non-phosphorylatable Ana2 mutant allows daughters to grow for an extended period, demonstrating that Cdk/Cyclin activity on Ana2/STIL stops centriole elongation at the correct time.\",\n      \"method\": \"Fluorescence correlation spectroscopy in Drosophila embryos, phospho-mutant Ana2 expression, live imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-mutant functional test in vivo, biophysical diffusion measurement; single study in Drosophila ortholog\",\n      \"pmids\": [\"35861803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The STIL CCD peptide undergoes concentration-dependent oligomerization forming dimers (KD = 8 µM) and tetramers (KD = 68 µM). Crystal structures of CCD mutants reveal dimeric and tetrameric antiparallel coiled-coil structures. Disrupting STIL oligomerization via the CCD inhibits its activity in vivo.\",\n      \"method\": \"Analytical ultracentrifugation, fluorescence spectroscopy, circular dichroism, X-ray crystallography\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures plus biophysical characterization; single lab, limited in vivo follow-up referenced\",\n      \"pmids\": [\"37834064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXW7 SCF E3 ubiquitin ligase mediates degradation of the STIL-SAS6 cartwheel complex. Plk4 kinase activity is required for FBXW7-dependent STIL degradation. Phosphorylation of Plk4-targeting sites in STIL that drive centriole assembly (facilitating STIL-SAS6 interaction) also stabilizes FBXW7 binding to STIL, creating a negative feedback that limits centriole overduplication. FBXW7 depletion causes premature centriole duplication via STIL-SAS6 stabilization.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, Plk4 kinase inhibition, FBXW7 depletion, centriole counting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro ubiquitination assay plus Co-IP and KD; single lab, multiple methods\",\n      \"pmids\": [\"41453690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CEP85 and STIL are required for PLK4-driven directional cancer cell migration. PLK4 drives recruitment of CEP85 and STIL to the leading edge of cells to promote protrusive activity. Downregulation of CEP85 and STIL reduces ARP2 phosphorylation and impairs actin cytoskeleton reorganization and directional migration.\",\n      \"method\": \"Mutational and functional analyses, Co-IP, siRNA knockdown, migration assay, immunofluorescence at leading edge, phosphorylation assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, KD with defined phenotypic readout (migration, ARP2 phosphorylation), interaction interface mutagenesis; single lab\",\n      \"pmids\": [\"32107292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STIL associates with ARHGEF7 in dendritic spines. Knockdown of Stil reduces dendritic spines in neurons in vitro and in vivo. This function depends on STIL's coiled-coil domain that mediates ARHGEF7 binding. STIL knockdown impairs Rac1 activation in spines, and overexpression of Rac1/Cdc42 compensates for STIL loss. Chemical LTP promotes STIL accumulation in spines.\",\n      \"method\": \"Co-immunoprecipitation, in vitro and in vivo shRNA knockdown, FRET-based Rac1 activity assay, rescue with Rac1/Cdc42, domain mutagenesis\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, FRET biosensor, in vivo KD with morphological phenotype, rescue experiment; single lab\",\n      \"pmids\": [\"39851490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A subset of STIL translocates to the nucleus and associates with FOXM1 to promote tumor metastasis and stemness via FOXM1-mediated target genes. HIF1α directly binds the STIL promoter and upregulates STIL expression under hypoxia. Excess STIL activates the EMT pathway and enhances cancer cell migration and invasion.\",\n      \"method\": \"ChIP-qPCR (HIF1α binding to STIL promoter), Co-IP (STIL-FOXM1 interaction), RNA-seq, reporter assays, xenograft metastasis assay, siRNA depletion\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ChIP-qPCR plus Co-IP plus in vivo metastasis; single lab, multiple methods\",\n      \"pmids\": [\"35365182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STIL interacts with BRCA1 and regulates its stability; a cancer-associated heterozygous missense mutation (S76L) in STIL disrupts this interaction and redistributes BRCA1 from the nucleus to centrosomes. STIL-S76L overexpression elevates centrosomal Aurora-A and PLK1 kinases, causing centrosome amplification and DNA damage. Mutant cells maintain pseudo-bipolar spindles via HSET-dependent centrosome clustering.\",\n      \"method\": \"Co-immunoprecipitation, overexpression of S76L mutant, immunofluorescence, DNA damage assay, rescue with WT BRCA1\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and rescue experiment in single paper, single lab, no in vitro reconstitution; details limited in abstract\",\n      \"pmids\": [\"41749477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Inactivation of PLK4 or STIL in human pluripotent stem cells leads to centrosome loss followed by p53-dependent upregulation, chromosome instability, reduction of pluripotency markers, and induction of differentiation. Loss of STIL function causes prolonged cell divisions and alterations in mitotic timing and protein turnover.\",\n      \"method\": \"PLK4 chemical inhibition, STIL siRNA knockdown in hESCs and hiPSCs, flow cytometry, immunofluorescence, western blot\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotypes (centrosome loss, differentiation, p53 induction); single lab\",\n      \"pmids\": [\"30197118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STIL functions through the Sonic hedgehog (Shh) signaling pathway: co-immunoprecipitation revealed that STIL interacts with Shh downstream components SUFU and GLI1. Overexpression of STIL increased Shh signaling and PC12 cell proliferation; knockdown inhibited Shh signaling and proliferation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and shRNA knockdown in PC12 cells, qPCR of Shh target genes\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, single lab, no mutagenesis or structural validation\",\n      \"pmids\": [\"24853807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STIL interacts with FOXM1 and co-occupies the SF3A3 promoter (by ChIP-qPCR) to regulate SF3A3 transcription in hepatocellular carcinoma cells. STIL loss inhibits HCC malignant behavior partly by promoting p53 expression. Knockdown of FOXM1 enhances the anti-tumor effects of STIL loss.\",\n      \"method\": \"Co-IP, ChIP-qPCR, siRNA knockdown, xenograft tumor model\",\n      \"journal\": \"Cell division\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP plus ChIP; single lab, mechanistic details limited\",\n      \"pmids\": [\"39825314\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STIL is a core centriole duplication factor that is recruited to the nascent procentriole in S phase, where it acts as a scaffold and allosteric activator: direct binding of STIL to PLK4 activates PLK4 by promoting its activation-loop autophosphorylation, and PLK4 in turn phosphorylates STIL at multiple sites—including the STAN motif (to drive STIL–SAS6 interaction and cartwheel assembly) and S428 (to promote STIL–CPAP binding linking cartwheel to centriole wall)—while Plk4-phosphorylated STIL simultaneously exerts negative feedback on adjacent PLK4 to restrict procentriole formation to a single site; STIL levels are tightly cell-cycle-regulated through sequential degradation by CDK1-mediated dissociation from centrosomes in mitosis, APC/C(Cdc20/Cdh1)-dependent proteasomal degradation via a KEN box, SCF-βTrCP-mediated degradation via a CDK2-regulated DSG motif, and FBXW7-mediated degradation of the STIL-SAS6 complex, with USP9X/SFI1 antagonizing degradation during S phase; beyond centriole biogenesis, STIL also regulates directional cell migration by scaffolding the ARHGEF7–PAK1 complex at lamellipodia, supports dendritic spine formation via ARHGEF7-dependent Rac1 activation, and promotes Hedgehog signaling through interaction with SUFU and GLI1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STIL is a core centriole duplication factor that is recruited asymmetrically to the nascent procentriole in S phase, where it acts as both a scaffold and an allosteric activator of the master centriolar kinase PLK4 [#0, #5, #7]. Direct binding of STIL to PLK4 activates the kinase by promoting autophosphorylation of its activation loop, and PLK4 in turn phosphorylates STIL at multiple sites: STAN-motif phosphorylation drives the STIL\\u2013SAS6 interaction that initiates cartwheel assembly, while phosphorylation at S428 promotes STIL\\u2013CPAP binding to link the cartwheel to the centriole wall [#5, #7, #16]. STIL engages PLK4 bimodally\\u2014its coiled-coil region stabilizes PLK4 at the procentriole through Polo-box 3 while a C-terminal element drives autophosphorylation and degradation of adjacent PLK4\\u2014thereby restricting procentriole formation to a single site per parent centriole [#9, #13, #23]. STIL function requires its central coiled-coil-mediated oligomerization for centrosomal localization and centriole assembly [#11, #26], and it nucleates a wider assembly network through direct interactions with CPAP/CENPJ, hSAS6, CEP85, and RTTN [#0, #4, #12, #14]. Because unrestrained STIL drives centriole amplification, its levels are tightly cell-cycle controlled: CDK1\\u2013CyclinB sequesters STIL in mitosis to block premature PLK4 complex formation, and STIL is degraded by APC/C(Cdc20/Cdh1) via a KEN box, by SCF-\\u03b2TrCP via a CDK2-regulated DSG motif, and by FBXW7 acting on the STIL\\u2013SAS6 complex, while USP9X (localized by SFI1) deubiquitylates and stabilizes STIL in S phase [#6, #10, #15, #17, #27]. STIL-dependent centriole formation is required for primary cilium assembly and downstream Hedgehog signaling, and for genome stability in stem cells, where its loss triggers p53-dependent differentiation [#3, #20, #32]. Beyond centriole biogenesis, STIL scaffolds an ARHGEF7(\\u03b2-PIX)\\u2013PAK1 complex at lamellipodia to promote Rac1 activation, actin remodeling, and directional cell migration, and supports dendritic spine formation through ARHGEF7-dependent Rac1 activity [#18, #28, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established STIL as a procentriole assembly factor by placing it within the SAS6\\u2013CPAP module and showing it is required for their centriolar loading.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA depletion, overexpression, and immunofluorescence in human cells\",\n      \"pmids\": [\"22020124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of asymmetric daughter-centriole targeting unresolved\", \"Order of recruitment relative to PLK4 not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked STIL-dependent centriole formation to spindle positioning, connecting it to the microcephaly (MCPH) phenotype of CPAP loss.\",\n      \"evidence\": \"siRNA depletion with micropattern spindle-orientation assay\",\n      \"pmids\": [\"22100914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular role of STIL in spindle orientation versus indirect centriole effect not separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified an early, non-centriolar STIL function regulating mitotic progression via Chfr/Plk1 stability.\",\n      \"evidence\": \"Knockout/siDNA, rescue, and ubiquitination assays in mouse fibroblasts\",\n      \"pmids\": [\"21245198\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which STIL controls Chfr auto-ubiquitination unknown\", \"Relationship to STIL's centriolar role unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the cell-cycle behavior of STIL\\u2014recruitment at duplication onset and APC/C-dependent removal through mitosis\\u2014and showed overexpression drives centriole amplification.\",\n      \"evidence\": \"RNAi, time-lapse imaging, immuno-EM, and APC/C pathway manipulation across two independent studies\",\n      \"pmids\": [\"22349698\", \"22349705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degron sequences not yet mapped\", \"Coupling of degradation timing to procentriole completion undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural basis for STIL\\u2013CPAP recognition and showed a disease mutation disrupts it, establishing the interaction as functionally essential.\",\n      \"evidence\": \"X-ray crystallography of the CPAP TCP domain\\u2013STIL motif, ITC, and centriole duplication assays in U2OS cells\",\n      \"pmids\": [\"24052813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phospho-regulation of this interface not yet known at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Characterized the STIL central domain as intrinsically disordered, rationalizing its capacity for multiple binding partners.\",\n      \"evidence\": \"NMR, circular dichroism, SEC, and limited proteolysis\",\n      \"pmids\": [\"24022511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of disorder in cells not directly tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the reciprocal PLK4\\u2013STIL relationship: STIL scaffolds SAS6 recruitment, PLK4 phosphorylation enables this, and centriolar STIL feeds back to restrict PLK4 to a single site.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays, phospho-site mapping, and live imaging\",\n      \"pmids\": [\"25342035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the negative-feedback effector element not yet resolved\", \"Direct phospho-sites driving SAS6 binding not fully mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Dissected STIL degradation into CDK1-driven centrosome dissociation followed by APC/C/KEN-box proteasomal turnover, and tied KEN-box loss to MCPH-associated amplification.\",\n      \"evidence\": \"Time-lapse imaging, APC/C and proteasome inhibition, KEN-box mutants, flow cytometry\",\n      \"pmids\": [\"24485834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDK1 triggers translocation mechanistically unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected STIL-dependent centriole formation to ciliogenesis and Hedgehog signaling and demonstrated de novo centriole generation upon STIL re-expression in null cells.\",\n      \"evidence\": \"FIB-SEM ultrastructure, Hedgehog reporter assays, and genetic rescue in Stil-/- cells/embryos\",\n      \"pmids\": [\"22349705\", \"25486474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STIL acts directly in Hh signaling beyond enabling cilia not separated here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Reported a direct, but weakly validated, STIL link to Hedgehog components SUFU and GLI1.\",\n      \"evidence\": \"Single Co-IP with overexpression/knockdown and target-gene qPCR in PC12 cells\",\n      \"pmids\": [\"24853807\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without mutagenesis or reciprocal validation\", \"Cilium-independent Hh role not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the activation logic: STIL binding directly activates PLK4 via activation-loop autophosphorylation, and activated PLK4 then phosphorylates STIL to drive SAS6 binding and cartwheel initiation.\",\n      \"evidence\": \"Analog-sensitive PLK4 chemical genetics, in vitro kinase assays, Co-IP in gene-edited human cells\",\n      \"pmids\": [\"26101219\", \"25701666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the active complex not defined\", \"Spatial trigger for initial STIL recruitment unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the structural mode of STIL\\u2013PLK4 binding, identifying STIL as the first PLK4 Polo-box 3 partner via coiled-coil mimicry.\",\n      \"evidence\": \"NMR, X-ray crystallography, structure-guided mutagenesis, and centriole duplication assays\",\n      \"pmids\": [\"26188084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between STIL oligomerization and PLK4 binding only partially defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed CDK1\\u2013CyclinB gates duplication timing by binding STIL in mitosis to prevent premature PLK4\\u2013STIL complex formation.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays, and cell-cycle synchronization epistasis\",\n      \"pmids\": [\"27112295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CDK1 phospho-sites on STIL not fully mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the coiled-coil oligomerization determinants of STIL required for centrosomal localization and both canonical and de novo centriole assembly.\",\n      \"evidence\": \"CD spectroscopy, SEC, mutagenesis, and reconstitution in Stil-/- MEFs\",\n      \"pmids\": [\"27075531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Oligomeric state in the assembling procentriole in vivo not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified zinc-dependent conformational regulation of STIL's N-terminal domain and disordered region promoting oligomerization.\",\n      \"evidence\": \"CD, SEC, ITC, and fluorescence spectroscopy\",\n      \"pmids\": [\"30155058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo functional follow-up of zinc binding\", \"Physiological relevance of zinc regulation untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed RTTN downstream of STIL in the assembly hierarchy via a direct interaction disrupted by a microcephaly mutation.\",\n      \"evidence\": \"Co-IP, CRISPR KO, super-resolution/EM, and mutant pulldown\",\n      \"pmids\": [\"28811500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of STIL\\u2013RTTN interface undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified CEP85 as a direct STIL partner required for STIL centriolar targeting and PLK4 activation, extending the upstream recruitment network.\",\n      \"evidence\": \"BioID, crystallography, structure-guided mutagenesis, Co-IP, and duplication assay\",\n      \"pmids\": [\"29712910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CEP85 cooperates with CDK1/PLK4 timing not integrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the bimodal STIL\\u2013PLK4 interaction\\u2014coiled-coil stabilization versus C-terminal TIM-domain-driven PLK4 degradation\\u2014as the basis for single-site procentriole restriction.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays, domain mapping, truncation mutants, and live imaging\",\n      \"pmids\": [\"29898389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative threshold distinguishing positive from negative regulation undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Added SCF-\\u03b2TrCP as an interphase-wide STIL degradation pathway acting through a phosphorylated DSG motif and counteracted by CDK2.\",\n      \"evidence\": \"Proteomics, Co-IP, in vivo phospho-analysis, CDK2 inhibition, and DSG mutagenesis\",\n      \"pmids\": [\"29445034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase phosphorylating the DSG degron not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated STIL is essential for genome stability and pluripotency maintenance, with loss triggering p53-dependent differentiation.\",\n      \"evidence\": \"STIL siRNA and PLK4 inhibition in hESCs/hiPSCs with flow cytometry and protein analysis\",\n      \"pmids\": [\"30197118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between centrosome loss and p53 activation not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a second PLK4 phospho-site on STIL (S428) that drives STIL\\u2013CPAP binding, linking cartwheel to centriole wall, conserved to Drosophila.\",\n      \"evidence\": \"In vitro kinase assays, phospho-mutants, Co-IP, structure-guided mutagenesis, and Drosophila conservation\",\n      \"pmids\": [\"31115335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Temporal coordination of STAN-motif versus S428 phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a STIL stabilization arm: SFI1-localized USP9X deubiquitylates STIL in S phase, validated in patient cells.\",\n      \"evidence\": \"Co-IP, deubiquitylation assay, and USP9X loss-of-function patient cells\",\n      \"pmids\": [\"31197030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Balance between USP9X and the multiple E3 ligases not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided endogenous-protein kinetics confirming that the STIL\\u2013HsSAS6 cartwheel exerts negative feedback attenuating centriolar PLK4.\",\n      \"evidence\": \"Live imaging of CRISPR knock-in proteins, quantitative tracking, depletion, and mathematical modeling\",\n      \"pmids\": [\"31533936\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of feedback distinct from TIM-domain effect not reconciled\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a centriole-independent STIL function: scaffolding the ARHGEF7\\u2013PAK1 complex at lamellipodia to drive Rac1-dependent cancer cell migration.\",\n      \"evidence\": \"Co-IP of ternary complex, siRNA knockdown, migration assays, and Rac1 FRET biosensor\",\n      \"pmids\": [\"31754215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; whether centriolar and migratory pools of STIL are distinct unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Clarified that PLK4 autophosphorylation initiates its ring-to-dot condensation while STIL reinforces the condensate to enable SAS6 recruitment.\",\n      \"evidence\": \"Photoconvertible PLK4 live imaging, catalytic mutant, depletion, and condensate assays\",\n      \"pmids\": [\"33323015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biophysical nature of the condensate in physiological cells not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the migratory role by showing PLK4 recruits CEP85 and STIL to the leading edge to promote ARP2 phosphorylation and directional migration.\",\n      \"evidence\": \"Co-IP, interface mutagenesis, knockdown, migration and phosphorylation assays\",\n      \"pmids\": [\"32107292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase\\u2013substrate relationship to ARP2 not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Used the Drosophila ortholog to show Cdk/Cyclin phosphorylation of Ana2/STIL slows its diffusion to terminate daughter centriole growth at the correct time.\",\n      \"evidence\": \"FCS in Drosophila embryos, phospho-mutant expression, live imaging\",\n      \"pmids\": [\"35861803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of this diffusion-based timing mechanism in human STIL untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Proposed an oncogenic nuclear STIL function partnering FOXM1 to drive metastasis, with HIF1\\u03b1 transcriptionally inducing STIL under hypoxia.\",\n      \"evidence\": \"ChIP-qPCR, Co-IP, RNA-seq, reporter assays, and xenograft metastasis\",\n      \"pmids\": [\"35365182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of nuclear STIL translocation unclear\", \"Separation from centriolar role not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Quantified STIL coiled-coil self-association equilibria and resolved dimeric and tetrameric antiparallel structures essential for activity.\",\n      \"evidence\": \"Analytical ultracentrifugation, fluorescence, CD, and X-ray crystallography\",\n      \"pmids\": [\"37834064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Oligomeric state at the procentriole in vivo not directly observed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added FBXW7-mediated degradation of the STIL\\u2013SAS6 complex as a PLK4-coupled negative feedback limiting overduplication.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination, PLK4 inhibition, FBXW7 depletion, centriole counting\",\n      \"pmids\": [\"41453690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron site and phospho-dependence on STIL not fully mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a neuronal STIL function supporting dendritic spine formation through coiled-coil-mediated ARHGEF7 binding and Rac1 activation.\",\n      \"evidence\": \"Co-IP, in vivo/in vitro shRNA knockdown, FRET Rac1 assay, Rac1/Cdc42 rescue, domain mutagenesis\",\n      \"pmids\": [\"39851490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship to centriolar function in post-mitotic neurons unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed a STIL\\u2013BRCA1 interaction whose disruption by a cancer mutation redistributes BRCA1 and causes centrosome amplification and DNA damage.\",\n      \"evidence\": \"Co-IP, S76L overexpression, immunofluorescence, DNA damage and rescue assays\",\n      \"pmids\": [\"41749477\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Co-IP and rescue in single paper without in vitro reconstitution\", \"Direct versus indirect BRCA1 effect not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reported a hepatocellular carcinoma role in which STIL\\u2013FOXM1 co-occupy the SF3A3 promoter and modulate p53.\",\n      \"evidence\": \"Co-IP, ChIP-qPCR, knockdown, and xenograft model\",\n      \"pmids\": [\"39825314\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanistic details limited; direct transcriptional role of STIL not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple STIL degradation pathways, deubiquitylation, oligomerization, and PLK4 feedback loops are quantitatively integrated to ensure exactly one procentriole per parent remains unresolved, as does whether the migratory, neuronal, and nuclear oncogenic functions use the same molecular pool and binding surfaces as the centriolar role.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model coupling activation, feedback, and degradation\", \"Centriolar versus non-centriolar STIL pools not physically distinguished\", \"Structural basis of full STIL\\u2013PLK4 active assembly incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 14, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7, 13]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [18, 28, 29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 2, 11]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [3, 20]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [18, 28]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [30, 31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 2, 4, 7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 10, 32]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 15, 17, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [20, 18, 29]}\n    ],\n    \"complexes\": [\n      \"STIL-SAS6 cartwheel complex\",\n      \"STIL-PLK4 complex\",\n      \"ARHGEF7(\\u03b2-PIX)-PAK1-STIL complex\"\n    ],\n    \"partners\": [\n      \"PLK4\",\n      \"SAS6\",\n      \"CPAP\",\n      \"CEP85\",\n      \"RTTN\",\n      \"ARHGEF7\",\n      \"PAK1\",\n      \"USP9X\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}