{"gene":"PLK4","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2005,"finding":"Plk4 is a key regulator of centriole duplication; both gain- and loss-of-function experiments demonstrate it is required—in cooperation with Cdk2, CP110, and Hs-SAS6—for precise centrosome reproduction during the cell cycle.","method":"Gain- and loss-of-function (siRNA/overexpression) in human cells; immunofluorescence","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function with defined centrosome phenotype, replicated across multiple subsequent studies","pmids":["16244668"],"is_preprint":false},{"year":2005,"finding":"SAK/PLK4 is necessary for centriole duplication in both Drosophila and human cells; downregulation by mutation or RNAi leads to loss of centrioles, broad disorganized mitotic spindle poles, and failure to form flagella (due to absence of basal bodies).","method":"Drosophila mutation, RNAi in Drosophila and human cells, mathematical modeling of spermatogenesis divisions","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function in two organisms with defined cellular phenotypes, independently corroborating PMID 16244668","pmids":["16326102"],"is_preprint":false},{"year":2007,"finding":"Plk4 overexpression induces simultaneous generation of multiple procentrioles adjacent to each parental centriole; Plk4, hSas-6, CPAP, Cep135, gamma-tubulin, and CP110 were ordered into a centriole assembly pathway by siRNA, with CP110 associating with growing distal tips indicating centrioles elongate by tubulin insertion underneath a CP110 cap.","method":"Plk4 overexpression, siRNA knockdown, immunoelectron microscopy in human cells","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA epistasis + immunoelectron microscopy), defined assembly pathway","pmids":["17681131"],"is_preprint":false},{"year":2001,"finding":"Sak (PLK4) polo-box domain localizes the enzyme to the nucleolus during G2, to centrosomes in G2/M, and to the cleavage furrow during cytokinesis; Sak-null mouse embryos arrest at E7.5 with cells in late anaphase/telophase retaining cyclin B1 and phospho-histone H3, indicating a role in APC-dependent cyclin B1 destruction and mitotic exit.","method":"Sak null mouse knockout, live/fixed imaging, cyclin B1/pH3 immunostaining","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout in mouse with defined biochemical (cyclin B1 retention) and cellular (anaphase arrest) phenotypes","pmids":["11301255"],"is_preprint":false},{"year":2002,"finding":"The Sak polo-box domain forms homodimers both in vitro and in vivo and is sufficient for subcellular localization to centrosomes and the cleavage furrow during cytokinesis; crystal structure at 2.0 Å reveals a dimeric fold with a deep interfacial cleft suggestive of a ligand-binding site.","method":"X-ray crystallography (2.0 Å), in vitro and in vivo dimerization assays, subcellular localization by immunofluorescence","journal":"Nature structural biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation of dimerization and localization, single lab","pmids":["12352953"],"is_preprint":false},{"year":2008,"finding":"SCF/Slimb (βTrCP) ubiquitin ligase physically interacts with SAK/PLK4 via a conserved Slimb-binding motif in PLK4, targeting it for proteolytic degradation; loss of Slimb causes PLK4 accumulation and centriole amplification, and mutations in the Slimb-binding motif also cause centrosome amplification.","method":"Co-immunoprecipitation, RNAi, site-directed mutagenesis of Slimb-binding motif in Drosophila","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction, mutagenesis of binding motif, and genetic loss-of-function with defined phenotype; independently replicated (PMID 19171756)","pmids":["19084407"],"is_preprint":false},{"year":2009,"finding":"SCF(Slimb) E3 ubiquitin ligase mediates proteolytic degradation of Drosophila Plk4 to prevent centriole reduplication; Plk4 binds Slimb, Plk4 levels are highest at mitosis and absent during S phase, and Slimb regulates Plk4 localization to centrioles during interphase.","method":"RNAi screen, co-immunoprecipitation, Slimb-binding mutant expression, immunofluorescence in Drosophila cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, and RNAi with defined phenotype; corroborates PMID 19084407","pmids":["19171756"],"is_preprint":false},{"year":2010,"finding":"Plk4 undergoes βTrCP-dependent proteasomal degradation in human cells; kinase-dead Plk4 disrupts Plk4 trans-autophosphorylation within homodimers, shielding endogenous Plk4 from βTrCP recognition, leading to centriole overduplication. Active Plk4 promotes its own degradation by catalyzing βTrCP binding through trans-autophosphorylation.","method":"Stable overexpression of kinase-dead Plk4, proteasome inhibitor assays, co-immunoprecipitation in human cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — trans-autophosphorylation mechanism established by kinase-dead dominant negative and Co-IP, two complementary approaches, single lab","pmids":["20516151"],"is_preprint":false},{"year":2010,"finding":"Cep152 interacts with the cryptic Polo-box of Plk4 via its N-terminal domain; Cep152 is required for Plk4 recruitment to the centrosome and for Plk4-induced centriole overduplication; depletion of Cep152 also prevents CPAP recruitment and leads to monopolar mitotic spindles.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence in human cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and depletion phenotypes replicated in two independent simultaneous publications (PMIDs 21059844 and 21059850)","pmids":["21059844","21059850"],"is_preprint":false},{"year":2010,"finding":"Cep152 (orthologue of Drosophila Asterless) interacts with Plk4 through residues 1-217 of Cep152 and the crypto Polo-box of Plk4; Cep152 depletion prevents Sas6 localization to the centriole (an early duplication step); Cep152 can be phosphorylated by Plk4 in vitro.","method":"Co-immunoprecipitation in human and Xenopus cells, siRNA, in vitro kinase assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vitro kinase assay, siRNA epistasis, confirmed in two organisms","pmids":["21059850"],"is_preprint":false},{"year":2011,"finding":"PLK4 phosphorylates FBXW5 at Ser151 to suppress FBXW5-mediated ubiquitylation of HsSAS-6, thereby antagonizing SCF-FBXW5-dependent degradation of the centriolar protein HsSAS-6 and promoting centrosome duplication.","method":"In vitro kinase assay, Co-IP, ubiquitylation assay, siRNA/overexpression in human cells","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay identifying phosphorylation site (Ser151), ubiquitylation assay, and Co-IP; multiple orthogonal methods","pmids":["21725316"],"is_preprint":false},{"year":2011,"finding":"PP2A(Twins) counteracts Plk4 autophosphorylation, stabilizing Plk4 and promoting centriole duplication; the PP2A regulatory subunit Twins peaks during mitosis and is required for centriole duplication, and SV40 small T antigen mimics Twins function to stabilize Plk4.","method":"Genetic and biochemical experiments in Drosophila; Twins RNAi, immunoprecipitation, immunofluorescence","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PP2A-Twins stabilization of Plk4 shown by RNAi and Co-IP, single lab","pmids":["21987638"],"is_preprint":false},{"year":2012,"finding":"GCP6 (a gamma-tubulin ring complex component) interacts with Plk4, is phosphorylated by Plk4 in vitro, and is required for Plk4-induced centriole overduplication; depletion of GCP6 prevents centriole duplication.","method":"Co-immunoprecipitation, in vitro kinase assay, siRNA in human cells, immunofluorescence","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and in vitro kinase assay with siRNA phenotype, single lab","pmids":["22302995"],"is_preprint":false},{"year":2013,"finding":"Cep192 and Cep152 cooperate to recruit Plk4 to centrioles; Cep192 binds Plk4 through an N-terminal extension, and double depletion of both completely abolishes Plk4 binding and centriole duplication; Cep192 and Cep152 binding regions are rich in negatively charged residues, suggesting electrostatic interaction with the positively charged polo-box domain.","method":"Co-immunoprecipitation, siRNA double depletion, immunofluorescence in human cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-depletion epistasis, reciprocal Co-IP, corroborated by PMID 24277814","pmids":["23641073","24277814"],"is_preprint":false},{"year":2013,"finding":"PLK4 is directly phosphorylated and activated by stress-activated protein kinase kinase kinases (SAPKKKs); stress-induced PLK4 activation promotes centrosome duplication whereas SAPK activation opposes it; p53 downregulates PLK4 expression in the late stress response to prevent centrosome amplification.","method":"In vitro kinase assay (SAPKKKs phosphorylating PLK4), immunofluorescence, genetic inactivation of MKK4 and p53 in cancer cells","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus genetic epistasis, single lab","pmids":["23653187"],"is_preprint":false},{"year":2013,"finding":"PLK4 is a suicide kinase that trans-autophosphorylates within homodimers on Ser293 and Thr297 within the SCF-Slimb/βTrCP-binding degron and on a phospho-cluster outside the degron (which regulates Thr297 phosphorylation); this multisite mechanism ensures that PLK4 concentration threshold is reached before autodestruction.","method":"In vitro kinase assays with phospho-mutants, mass spectrometry, genetic assays in Drosophila soma and germline","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with phospho-site mutagenesis and MS identification, validated in vivo","pmids":["24184099"],"is_preprint":false},{"year":2014,"finding":"Drosophila Plk4 phosphorylates four conserved serines in the STAN motif of Ana2 (STIL orthologue); this phosphorylation enables Ana2 to bind and recruit Sas6 for procentriole formation; non-phosphorylatable Ana2 still localizes to the centriole but fails to recruit Sas6.","method":"In vitro kinase assay (Plk4 phosphorylating Ana2 STAN motif), mass spectrometry, non-phosphorylatable mutant rescue experiments in Drosophila","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay, phospho-site MS, phospho-mutant in vivo validation, identifies key substrate and mechanism","pmids":["25264260"],"is_preprint":false},{"year":2014,"finding":"Plk4 and STIL form a protein complex that recruits HsSAS-6; Plk4 phosphorylates STIL to facilitate the STIL/HsSAS-6 interaction and centriolar loading of HsSAS-6; centriolar STIL provides negative feedback regulating bimodal PLK4 distribution, restricting procentriole formation to one site per parental centriole.","method":"Co-immunoprecipitation, in vitro kinase assay (PLK4 phosphorylating STIL), STIL-depletion/rescue, immunofluorescence in human cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vitro kinase assay, rescue experiments, multiple orthogonal methods","pmids":["25342035"],"is_preprint":false},{"year":2014,"finding":"Plk4 relocalizes from the inner Cep192 ring to the outer Cep152 ring as Cep152 assembles around the daughter centriole; crystal structures show Cep192- and Cep152-derived peptides bind the cryptic polo box (CPB) of Plk4 in opposite orientations and mutually exclusively; the Cep152 peptide binds CPB markedly better and can snatch it from a preformed CPB-Cep192 complex.","method":"X-ray crystallography of PLK4-CPB with Cep192/Cep152 peptides, super-resolution microscopy, in vitro competition assay, cancer-mutation functional analysis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures at atomic resolution with in vitro competition assay and in vivo functional validation of cancer-associated mutant","pmids":["24997597"],"is_preprint":false},{"year":2015,"finding":"Direct binding of STIL to Plk4 activates Plk4 by promoting self-phosphorylation of the activation loop; Plk4 activity is required for STIL localization to the centriole; Plk4 then phosphorylates STIL to promote STIL's direct binding to the C-terminus of SAS6, driving centriole assembly.","method":"Chemical genetic system (analog-sensitive PLK4 in human cells), in vitro kinase assay, Co-IP, phospho-mutant rescue","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — chemical genetic inhibition of endogenous PLK4, in vitro kinase assay, phospho-mutant analysis; multiple orthogonal methods","pmids":["26101219"],"is_preprint":false},{"year":2015,"finding":"STIL interacts with PLK4 via its coiled-coil region (STIL-CC) binding to Polo-box 3 (PB3) of PLK4 (first identified PB3 interaction partner) and a secondary site in PLK4 L1 region; NMR and crystal structures reveal a novel coiled-coil-mimicking Polo-box–peptide interaction mode; STIL-CC/PLK4 interaction mediates PLK4 activation and stabilization of centriolar PLK4.","method":"NMR spectroscopy, X-ray crystallography of PLK4-PB3/STIL-CC complex, in vivo Co-IP, structure-guided mutagenesis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure and NMR with in vivo mutagenesis validation; structural mechanism fully established","pmids":["26188084"],"is_preprint":false},{"year":2015,"finding":"STIL is phosphorylated by Plk4 at specific sites within its C-terminal domain; a STIL fragment containing the coiled-coil and STAN motif shows strongest binding to Plk4; STIL phosphorylation by Plk4 is required to trigger centriole duplication.","method":"In vitro kinase assay, Co-IP, phospho-site identification, phospho-mutant rescue in human cells","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay and Co-IP with phospho-mutant phenotype, single lab; corroborates PMIDs 25342035, 26101219","pmids":["25701666"],"is_preprint":false},{"year":2015,"finding":"KAT2A/KAT2B (GCN5/PCAF) acetyltransferases acetylate PLK4 kinase domain on K45 and K46; molecular dynamics modeling suggests K45/K46 acetylation shifts kinase to inactive conformation; PLK4 kinase activity is reduced upon in vitro acetylation; PLK4 K45R/K46R mutant overexpression does not cause centrosome overamplification; impairing KAT2A/2B activity results in diminished PLK4 phosphorylation and excess centrosome numbers.","method":"Mass spectrometry acetylome, in vitro acetylation/kinase assay, molecular dynamics modeling, K45R/K46R mutant overexpression in cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay + mutagenesis + MD modeling + cellular phenotype; multiple orthogonal methods in one study","pmids":["27796307"],"is_preprint":false},{"year":2015,"finding":"The E3 ubiquitin ligase Mind bomb 1 (Mib1) interacts with Plk4 and ubiquitylates Plk4 on multiple sites (generating K11-, K29-, and K48-linked chains), controlling Plk4 abundance and its ability to interact with centrosomal proteins, thereby counteracting centriole amplification.","method":"Co-immunoprecipitation, ubiquitylation assay with linkage-specific analysis (mass spectrometry), immunofluorescence in human cells","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and in-cell ubiquitylation assay with MS-defined linkages, single lab","pmids":["25795303"],"is_preprint":false},{"year":2015,"finding":"PLK4 trans-autoactivation (local concentration-dependent) is a critical event in spatial control of centriole biogenesis; centrioles promote PLK4 activation through local recruitment and accumulation; concentrating PLK4 artificially (e.g. at peroxisomes) is sufficient to rescue centriole amplification in centriole-less cells.","method":"PLK4 depletion/rescue, peroxisome tethering assay, Drosophila centriole-removal genetics","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — spatial tethering reconstitution with genetic centriole-removal, single lab","pmids":["26481051"],"is_preprint":false},{"year":2016,"finding":"CDK1-CyclinB binds STIL in mitosis and prevents formation of the PLK4-STIL complex and STIL phosphorylation by PLK4, thus inhibiting untimely onset of centriole biogenesis; after CDK1 inactivation at mitotic exit, PLK4 can bind and phosphorylate STIL in G1 to allow pro-centriole assembly in the next S phase.","method":"Co-immunoprecipitation, in vitro kinase assay, cell-cycle-staged analysis in human cells and Drosophila","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP of CDK1-STIL complex, in vitro kinase assay showing CDK1 prevents Plk4 phosphorylation of STIL, two organisms","pmids":["27112295"],"is_preprint":false},{"year":2016,"finding":"Plk4 interacts with members of the Arp2/3 complex (specifically Arp2) via its Polo-box 1/2 domain; Plk4 phosphorylates Arp2 at T237/T238 (activation site), and this phosphorylation is required for Plk4-driven cell movement and cancer invasion.","method":"BioID proximity labeling screen, Co-immunoprecipitation, in vitro kinase assay, phospho-mutant rescue, cell invasion assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID + Co-IP + in vitro kinase assay + phospho-mutant rescue; single lab, multiple methods","pmids":["27872092"],"is_preprint":false},{"year":2016,"finding":"Plk4 depletion leads to dispersion of centriolar satellites; Plk4 interacts with the satellite component PCM1 and phosphorylates conserved S372 of PCM1; non-phosphorylatable PCM1 S372A disperses centriolar satellites and perturbs ciliogenesis; phosphomimetic S372E partially rescues satellite organization and ciliogenesis; S372 phosphorylation occurs during G1 and promotes PCM1 dimerization and interaction with other satellite components.","method":"Co-immunoprecipitation, in vitro kinase assay, phospho-mutant rescue, ciliogenesis assay in human cells","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay + phospho-mutant rescue + Co-IP; single lab, multiple methods","pmids":["26755742"],"is_preprint":false},{"year":2010,"finding":"Plk4 haploinsufficiency disrupts RhoGTPase function during cytokinesis: Plk4+/- MEFs show high primary cytokinesis failure with aberrant actomyosin ring formation, reduced RhoA activation, and failure to localize the RhoA GEF Ect2 to the spindle midbody; Plk4 normally localizes to the midbody and binds to and phosphorylates Ect2 in vitro.","method":"Plk4+/- MEF analysis, in vitro kinase assay (Plk4 phosphorylating Ect2), RhoA activation assay, immunofluorescence","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay + functional RhoA assay + midbody localization, single lab","pmids":["20348415"],"is_preprint":false},{"year":2006,"finding":"Purified Sak/PLK4 kinase domain has robust kinase activity in vitro; the consensus phosphorylation motif for Sak is [charged]-[Ile/Leu/Val]-Ser/Thr-[large hydrophobic]-[large hydrophobic]-X-[charged/Pro], which differs from the Plk1 consensus motif.","method":"In vitro kinase assay on peptide spots arrays with purified Sak kinase domain","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro kinase assay with peptide array determination of consensus motif","pmids":["17174311"],"is_preprint":false},{"year":2001,"finding":"Sak serine-threonine kinase acts as an effector of Tec tyrosine kinase: Sak is tyrosine-phosphorylated by Tec and Sak kinase activity is detectable only in the presence of Tec; Tec activity also protects Sak from PEST sequence-dependent proteolysis.","method":"Co-immunoprecipitation (yeast two-hybrid identification), in vitro/in vivo kinase assay in HEK293 cells, PEST-deletion mutant analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, kinase activity assay, and protein stability analysis in single study","pmids":["11489907"],"is_preprint":false},{"year":2018,"finding":"PLK4 phosphorylates Ana2/STIL in an ordered sequence: first the extreme N-terminus of Ana2, which is critical for subsequent STAN domain modification; central-region phosphorylation then breaks the Plk4-Ana2 interaction; STAN domain phosphorylation recruits Sas6. Disrupting this ordered phosphorylation sequence inhibits centriole duplication and integrity.","method":"In vitro kinase assay, phospho-mutant replacement of endogenous Ana2 in Drosophila, mass spectrometry","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of ordered phosphorylation, endogenous gene replacement with phospho-mutants, MS phospho-site identification","pmids":["29496738"],"is_preprint":false},{"year":2018,"finding":"STIL bimodally interacts with Plk4: the short coiled-coil region of STIL protects Plk4 from degradation (positive regulation) while the C-terminal TIM domain of STIL promotes autophosphorylation and degradation of adjacent Plk4 (negative regulation); this bimodal binding limits procentriole formation to a single site per parental centriole.","method":"Co-immunoprecipitation, in vitro kinase/degradation assays, domain-mapping mutants in human cells","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping, Co-IP, and in vitro kinase assay; single lab, multiple methods","pmids":["29898389"],"is_preprint":false},{"year":2018,"finding":"PLK4 self-assembles into condensates in vitro and in Xenopus egg extracts that recruit α/β-tubulin, STIL, and γ-tubulin to form acentriolar MTOCs de novo; this assembly is independent of dynein and suggests PLK4 acts as a self-organizing catalytic scaffold for MTOC formation.","method":"Xenopus egg extract reconstitution, in vitro condensate assay, immunofluorescence and live microscopy","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution in Xenopus extracts; novel mechanism, single lab","pmids":["30237222"],"is_preprint":false},{"year":2018,"finding":"CEP85 directly interacts with STIL through a conserved interface and is required for efficient centriolar targeting of STIL, PLK4 activation, and faithful daughter centriole assembly; structure-guided mutational analyses in vivo confirm the interaction is essential.","method":"Protein proximity mapping (BioID), high-resolution structural analysis, Co-immunoprecipitation, structure-guided mutagenesis in human cells","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID + Co-IP + structure-guided mutagenesis + in vivo phenotype; single lab, multiple orthogonal methods","pmids":["29712910"],"is_preprint":false},{"year":2019,"finding":"TRIM37 levels determine cellular sensitivity to PLK4 inhibition: elevated TRIM37 inhibits acentrosomal spindle assembly by degrading CEP192, causing mitotic failure upon PLK4 inhibition; low TRIM37 allows PLK4 self-assembly into centrosome-independent condensates serving as ectopic MTOCs; high TRIM37 (amplified in 17q neuroblastoma and breast cancer) renders these cancers highly sensitive to PLK4 inhibition.","method":"TRIM37 knockdown/overexpression, PLK4 inhibitor (centrinone) treatment, live-cell imaging, condensate assay, CEP192 degradation assay in human cells and cancer models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell lines, mechanistic dissection of two distinct TRIM37 actions, cancer model validation; high-quality study","pmids":["32908304"],"is_preprint":false},{"year":2019,"finding":"PLK4 deubiquitination by the Spata2-CYLD deubiquitinase complex at the centrosome facilitates PLK4 binding to and phosphorylation of NEK7 at Ser204; this NEK7 phosphorylation attenuates the NEK7-NLRP3 interaction required for NLRP3 inflammasome activation, suppressing innate immune signaling.","method":"Co-immunoprecipitation, in vitro kinase assay (PLK4 phosphorylating NEK7 Ser204), Spata2-KO macrophages, mouse peritonitis model","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay + Co-IP + KO model; single lab, multiple methods, novel non-centrosomal function","pmids":["31762063"],"is_preprint":false},{"year":2017,"finding":"Plk4 functions upstream of mitotic spindle orientation control in Drosophila neural stem cells by orchestrating centriole symmetry breaking; mechanistically, Plk4 phosphorylates Spd2 (CEP192 orthologue), which induces centriole release from the apical cortex to set centrosome positioning.","method":"Drosophila genetics (plk4 mutants), live imaging of asymmetric neural stem cell divisions, phospho-mutant Spd2 rescue","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with phospho-mutant rescue in vivo, single lab","pmids":["31130353"],"is_preprint":false},{"year":2013,"finding":"Plk4 is essential for spindle assembly in the absence of centrioles in the early mouse embryo; depletion of maternal Plk4 prevents microtubule nucleation and growth, resulting in monopolar spindles, cytokinesis failure, and developmental arrest; this function depends on Plk4 kinase activity and requires its partner Cep152.","method":"Maternal Plk4 depletion in mouse embryos, live imaging, kinase-dead rescue, Cep152-membrane tethering","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo depletion with kinase-dead and Cep152-tethering rescue experiments; single study","pmids":["24268700"],"is_preprint":false},{"year":2017,"finding":"PLK4 phosphorylates CP110 at Ser98; phospho-resistant CP110 S98A inhibits centriole assembly, while the phosphomimetic CP110 S98D promotes assembly even under PLK4-limited conditions and augments centrosomal SAS6 levels.","method":"In vitro kinase assay (PLK4 phosphorylating CP110), phospho-mutant overexpression in human cells, immunofluorescence","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay + phospho-mutant phenotype; single lab","pmids":["28562169"],"is_preprint":false},{"year":2017,"finding":"Cdc6 negatively regulates centrosome duplication by binding and inhibiting Sas-6 from forming a stable complex with STIL; PLK4 colocalizes and interacts with Cdc6 at centrosomes during S phase, phosphorylates Cdc6, and disrupts the Sas-6/Cdc6 interaction, thus antagonizing Cdc6-mediated inhibition of centrosome duplication.","method":"Co-immunoprecipitation, in vitro kinase assay, phospho-mutant rescue, immunofluorescence in human cells","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro kinase assay, phospho-mutant rescue; single lab, multiple methods","pmids":["28447620"],"is_preprint":false},{"year":2020,"finding":"FAM46C/TENT5C physically interacts with Plk4, localizes to centrioles, directly inhibits Plk4 kinase activity, and suppresses Plk4-induced centriole duplication independently of FAM46C's nucleotidyl transferase activity.","method":"Co-immunoprecipitation, in vitro kinase assay (FAM46C inhibiting PLK4), siRNA/overexpression, xenograft model","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + in vitro kinase inhibition assay + domain mutant (nucleotidyl-transferase-dead) ruling out alternative mechanism; single lab","pmids":["32807875"],"is_preprint":false},{"year":2021,"finding":"TEC tyrosine kinase directly phosphorylates PLK4 at tyrosine 86, stabilizing the PLK4 protein and enhancing PLK4-mediated HCC cell invasion; transcriptome sequencing indicates PLK4 promotes focal adhesion kinase phosphorylation to regulate the focal adhesion pathway in cell migration.","method":"Co-immunoprecipitation, in vitro kinase assay (TEC phosphorylating PLK4 Y86), phospho-mutant rescue, transcriptome sequencing in HCC cells","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay identifying Y86 site + Co-IP + phospho-mutant; single lab","pmids":["34637843"],"is_preprint":false},{"year":2023,"finding":"PLK4 phosphorylates PRMT5 (a histone methyltransferase) in a PLK4/PRMT5/EZH2/H3K27me3 axis in AML cells; PLK4-induced PRMT5 phosphorylation leads to histone modification; in TP53-mutated AML, combined histone modification and PLK4-inhibition-induced polyploidy activates the cGAS-STING pathway, inducing cytokines/chemokines and immune cell activation.","method":"In vitro kinase assay (PLK4 phosphorylating PRMT5), Western blot for H3K27me3, cGAS-STING pathway analysis, macrophage/T cell co-culture, in vivo AML model","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay + pathway analysis + in vivo model; single lab, multiple methods","pmids":["37738460"],"is_preprint":false},{"year":2022,"finding":"PLK4 protein and kinase activity are both required for centriole amplification in multiciliated cells (MCCs); tracheal epithelial cells failing centriole amplification accumulate large centriole protein assemblies and do not undergo apical surface area expansion, linking centriole amplification to surface expansion.","method":"Genetically engineered mouse models (PLK4 conditional knockout and kinase-dead knock-in), immunofluorescence, tracheal epithelium analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse models with KO and kinase-dead mutations providing clean genetic evidence","pmids":["35969030"],"is_preprint":false},{"year":1994,"finding":"Sak (PLK4) encodes two isoforms (Sak-a and Sak-b) of a putative serine/threonine kinase related to polo-family kinases; Sak expression is associated with mitotic and meiotic cell division in mouse tissues; antisense Sak-a expression suppresses cell growth in CHO cells.","method":"cDNA cloning, Northern blot, in situ hybridization in mouse tissues, antisense growth suppression in CHO cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 3 / Weak — initial expression-based identification with antisense growth phenotype; no direct biochemical mechanism established","pmids":["8022793"],"is_preprint":false},{"year":1996,"finding":"Sak-a transcripts are absent in growth-arrested cells and increase late in G1 through mitosis; Sak-a protein is multiubiquitinated with a half-life of ~2-3 h; overexpression of Sak-a (but not Sak-b or kinase-dead Sak-a D154N) inhibits colony-forming efficiency and increases multinucleated cells, requiring both the kinase domain and the Sak-a-specific C-terminal region.","method":"Cell cycle synchronization/Northern blot, HA-tagged protein half-life assay, colony formation assay, multinucleation scoring in CHO cells","journal":"Molecular and cellular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — kinase domain requirement shown by D154N mutation; ubiquitination shown by immunoprecipitation; but mechanism of multinucleation not established","pmids":["8756623"],"is_preprint":false}],"current_model":"PLK4 is a serine/threonine kinase that serves as the master regulator of centriole duplication: it is recruited to centrioles hierarchically by Cep192 and then Cep152 (via its cryptic polo box), where it trans-autophosphorylates within homodimers to trigger βTrCP-dependent self-degradation, and is activated by direct binding of STIL (which promotes PLK4 activation-loop self-phosphorylation), whereupon active PLK4 phosphorylates STIL to drive SAS-6 recruitment and cartwheel assembly; its activity is restrained by PP2A-mediated dephosphorylation, by CDK1-CyclinB–mediated prevention of the PLK4-STIL complex in mitosis, by KAT2A/B-mediated acetylation of K45/K46, by SCF-Slimb/βTrCP ubiquitin-mediated degradation, and by the Mib1 E3 ligase; beyond centriole biogenesis, PLK4 phosphorylates Arp2 (T237/T238) to regulate actin cytoskeletal dynamics and cancer invasion, phosphorylates Ect2 to support RhoA activation at the cytokinetic midbody, phosphorylates NEK7 (Ser204) to suppress NLRP3 inflammasome activation, and phosphorylates PRMT5 to remodel histone methylation and activate cGAS-STING signaling in AML."},"narrative":{"mechanistic_narrative":"PLK4 is a serine/threonine kinase of the polo family that functions as the master regulator of centriole duplication, where it acts both as the trigger for procentriole assembly and as the rate-limiting determinant of centriole number [PMID:16244668, PMID:16326102, PMID:17681131]. PLK4 is recruited to the centriole hierarchically: Cep192 and Cep152 bind the cryptic polo box, with PLK4 relocalizing from an inner Cep192 ring to an outer Cep152 ring as the daughter centriole matures, a switch enforced by mutually exclusive, oppositely oriented peptide binding in which Cep152 outcompetes Cep192 [PMID:21059844, PMID:21059850, PMID:23641073, PMID:24277814, PMID:24997597]. Once positioned, PLK4 is activated through direct binding of STIL, which engages PLK4 polo-box 3 and promotes activation-loop self-phosphorylation; active PLK4 then phosphorylates STIL in an ordered, multisite sequence to drive SAS-6 recruitment and cartwheel assembly [PMID:25264260, PMID:26101219, PMID:26188084, PMID:29496738]. PLK4 abundance is tightly self-limiting: it trans-autophosphorylates within homodimers on a degron recognized by SCF-Slimb/βTrCP, coupling kinase activity to its own ubiquitin-mediated destruction so that a concentration threshold gates centriole formation [PMID:19084407, PMID:20516151, PMID:24184099]. This output is further restrained by PP2A-mediated dephosphorylation, KAT2A/B acetylation of K45/K46, CDK1-CyclinB sequestration of STIL in mitosis, and the Mib1 E3 ligase [PMID:21987638, PMID:27796307, PMID:25795303, PMID:27112295]. Beyond centriole biogenesis, PLK4 supports cytokinesis by phosphorylating Ect2 to promote RhoA activation at the midbody [PMID:20348415], organizes centriolar satellites through PCM1 phosphorylation to enable ciliogenesis [PMID:26755742], drives actin-dependent cell invasion by phosphorylating Arp2 [PMID:27872092], and is required for centriole amplification during multiciliated cell differentiation [PMID:35969030]. Differential TRIM37 levels dictate cancer sensitivity to PLK4 inhibition, since PLK4 can self-assemble into centrosome-independent condensates that serve as ectopic microtubule-organizing centers [PMID:30237222, PMID:32908304].","teleology":[{"year":1994,"claim":"Established PLK4 (Sak) as a polo-family serine/threonine kinase tied to cell division, opening the question of its specific mitotic function.","evidence":"cDNA cloning, expression profiling, and antisense growth suppression in mouse tissues and CHO cells","pmids":["8022793","8756623"],"confidence":"Low","gaps":["No direct biochemical substrate or pathway defined","Mechanism of growth/multinucleation phenotype unresolved"]},{"year":2001,"claim":"Linked PLK4 localization (polo-box domain) and an in vivo requirement to mitotic progression and cyclin B1 destruction, before its centriole role was known.","evidence":"Sak-null mouse knockout with cyclin B1/pH3 immunostaining and a polo-box dimerization crystal structure","pmids":["11301255","12352953"],"confidence":"High","gaps":["Did not yet connect localization to centriole duplication","Ligand of the interfacial cleft not identified"]},{"year":2005,"claim":"Identified PLK4 as the rate-limiting regulator of centriole duplication, defining its central biological role.","evidence":"Reciprocal gain/loss-of-function in human cells and Drosophila mutants with centriole/spindle phenotypes","pmids":["16244668","16326102","17681131"],"confidence":"High","gaps":["Activating and inhibitory partners not yet mapped","Direct substrates unknown"]},{"year":2008,"claim":"Resolved how PLK4 levels are capped, showing kinase activity feeds back onto its own ubiquitin-mediated destruction to prevent centriole amplification.","evidence":"Co-IP, Slimb-binding-motif mutagenesis, RNAi, and kinase-dead/proteasome assays in Drosophila and human cells","pmids":["19084407","19171756","20516151","24184099"],"confidence":"High","gaps":["Precise degron phospho-site stoichiometry in vivo","Coordination with positive recruitment cues not fully integrated"]},{"year":2010,"claim":"Defined the centriolar recruitment hierarchy and identified Cep192/Cep152 as the docking platforms binding the PLK4 cryptic polo box.","evidence":"Reciprocal Co-IP, siRNA double depletion, and in vitro kinase assays in human and Xenopus cells","pmids":["21059844","21059850","23641073"],"confidence":"High","gaps":["Order of Cep192-to-Cep152 handoff not yet structurally explained"]},{"year":2014,"claim":"Explained the spatial Cep192-to-Cep152 switch structurally, showing the two adaptors bind the cryptic polo box in opposite orientations and mutually exclusively.","evidence":"X-ray crystallography of PLK4-CPB with adaptor peptides, super-resolution microscopy, and in vitro competition assay","pmids":["24997597"],"confidence":"High","gaps":["Timing signals triggering Cep152 engagement during the cycle not defined"]},{"year":2015,"claim":"Established the STIL-PLK4 activation circuit: STIL binding activates PLK4, and PLK4 phosphorylates STIL to load SAS-6, with STIL bimodal binding restricting duplication to one site.","evidence":"Chemical-genetic PLK4 inhibition, in vitro kinase assays, NMR/crystallography of PB3-STIL, and phospho-mutant rescue","pmids":["25342035","26101219","26188084","25701666","29496738","29898389"],"confidence":"High","gaps":["Quantitative model of single-site selection not fully resolved","In vivo phospho-site occupancy incompletely mapped"]},{"year":2015,"claim":"Expanded the layers of PLK4 restraint beyond degradation to include dephosphorylation, acetylation, alternative ubiquitin ligases, and cell-cycle sequestration.","evidence":"RNAi, Co-IP, in vitro acetylation/kinase assays, MD modeling, and cell-cycle-staged analysis in Drosophila and human cells","pmids":["21987638","27796307","25795303","27112295"],"confidence":"Medium","gaps":["Relative contribution of each restraint in vivo unquantified","Crosstalk between regulatory modifications unresolved"]},{"year":2016,"claim":"Extended PLK4 substrate range beyond centriole biogenesis to cytokinesis, satellite/ciliogenesis control, and actin-driven invasion.","evidence":"BioID, Co-IP, in vitro kinase assays, phospho-mutant rescue, and functional assays in MEFs and human cells","pmids":["20348415","26755742","27872092"],"confidence":"Medium","gaps":["Some functions rest on single-lab evidence","In vivo significance of non-centriolar substrates not fully tested"]},{"year":2019,"claim":"Connected PLK4 to therapeutic vulnerability and innate immunity, showing TRIM37-dependent condensate behavior and NEK7 phosphorylation suppressing inflammasome signaling.","evidence":"TRIM37 modulation with PLK4 inhibitor, condensate/CEP192 degradation assays, and in vitro kinase assays with KO models","pmids":["32908304","31762063"],"confidence":"High","gaps":["NEK7/inflammasome arm rests on single-lab evidence","Physiological balance between condensate and centriolar PLK4 unclear"]},{"year":2023,"claim":"Linked PLK4 to chromatin and antitumor immunity via PRMT5 phosphorylation and cGAS-STING activation in AML.","evidence":"In vitro kinase assay, H3K27me3 analysis, cGAS-STING readouts, co-culture, and in vivo AML model","pmids":["37738460"],"confidence":"Medium","gaps":["Single-lab evidence","Direct PRMT5 phospho-site and structural basis not defined"]},{"year":null,"claim":"How PLK4's many non-centriolar substrates are spatially and temporally segregated from its centriole-duplication function within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coordinating centriolar vs. cytoplasmic PLK4 pools","Substrate selection determinants beyond localization unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[16,17,19,26,28,29,36,39,43]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[10,12,15,29,31]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,3,8,18]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[26]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,3,25]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,17,27,44]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[36,43]}],"complexes":["PLK4 homodimer"],"partners":["CEP152","CEP192","STIL","SAS6","BTRC","CEP85","ECT2","PCM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00444","full_name":"Serine/threonine-protein kinase PLK4","aliases":["Polo-like kinase 4","PLK-4","Serine/threonine-protein kinase 18","Serine/threonine-protein kinase Sak"],"length_aa":970,"mass_kda":109.0,"function":"Serine/threonine-protein kinase that plays a central role in centriole duplication. Able to trigger procentriole formation on the surface of the parental centriole cylinder, leading to the recruitment of centriole biogenesis proteins such as SASS6, CPAP, CCP110, CEP135 and gamma-tubulin. When overexpressed, it is able to induce centrosome amplification through the simultaneous generation of multiple procentrioles adjoining each parental centriole during S phase. Phosphorylates 'Ser-151' of FBXW5 during the G1/S transition, leading to inhibit FBXW5 ability to ubiquitinate SASS6. Its central role in centriole replication suggests a possible role in tumorigenesis, centrosome aberrations being frequently observed in tumors. Also involved in deuterosome-mediated centriole amplification in multiciliated that can generate more than 100 centrioles. Also involved in trophoblast differentiation by phosphorylating HAND1, leading to disrupt the interaction between HAND1 and MDFIC and activate HAND1. Phosphorylates CDC25C and CHEK2. Required for the recruitment of STIL to the centriole and for STIL-mediated centriole amplification (PubMed:22020124). Phosphorylates CEP131 at 'Ser-78' and PCM1 at 'Ser-372' which is essential for proper organization and integrity of centriolar satellites (PubMed:30804208)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Nucleus, nucleolus; Cleavage furrow; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/O00444/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PLK4","classification":"Common Essential","n_dependent_lines":1150,"n_total_lines":1208,"dependency_fraction":0.9519867549668874},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLK4","total_profiled":1310},"omim":[{"mim_id":"620791","title":"CENTROSOMAL PROTEIN, 76-KD; CEP76","url":"https://www.omim.org/entry/620791"},{"mim_id":"618898","title":"CENTROSOMAL PROTEIN, 85-KD; CEP85","url":"https://www.omim.org/entry/618898"},{"mim_id":"617728","title":"CENTROSOMAL PROTEIN, 295-KD; CEP295","url":"https://www.omim.org/entry/617728"},{"mim_id":"617110","title":"CENTROSOMAL PROTEIN, 78-KD; CEP78","url":"https://www.omim.org/entry/617110"},{"mim_id":"616426","title":"CENTROSOMAL PROTEIN, 192-KD; CEP192","url":"https://www.omim.org/entry/616426"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":21.3},{"tissue":"lymphoid tissue","ntpm":13.4},{"tissue":"testis","ntpm":21.2}],"url":"https://www.proteinatlas.org/search/PLK4"},"hgnc":{"alias_symbol":["Sak"],"prev_symbol":["STK18"]},"alphafold":{"accession":"O00444","domains":[{"cath_id":"3.30.200.20","chopping":"11-92","consensus_level":"medium","plddt":92.005,"start":11,"end":92},{"cath_id":"1.10.510.10","chopping":"103-266","consensus_level":"medium","plddt":90.1521,"start":103,"end":266},{"cath_id":"3.30.1120.120","chopping":"601-690","consensus_level":"high","plddt":90.3839,"start":601,"end":690},{"cath_id":"3.30.1120.130","chopping":"700-804","consensus_level":"high","plddt":89.2318,"start":700,"end":804},{"cath_id":"3.30.1120.30","chopping":"888-964","consensus_level":"high","plddt":84.6547,"start":888,"end":964}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00444","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00444-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00444-F1-predicted_aligned_error_v6.png","plddt_mean":65.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLK4","jax_strain_url":"https://www.jax.org/strain/search?query=PLK4"},"sequence":{"accession":"O00444","fasta_url":"https://rest.uniprot.org/uniprotkb/O00444.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00444/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00444"}},"corpus_meta":[{"pmid":"16244668","id":"PMC_16244668","title":"The 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cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function with defined centrosome phenotype, replicated across multiple subsequent studies\",\n      \"pmids\": [\"16244668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SAK/PLK4 is necessary for centriole duplication in both Drosophila and human cells; downregulation by mutation or RNAi leads to loss of centrioles, broad disorganized mitotic spindle poles, and failure to form flagella (due to absence of basal bodies).\",\n      \"method\": \"Drosophila mutation, RNAi in Drosophila and human cells, mathematical modeling of spermatogenesis divisions\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function in two organisms with defined cellular phenotypes, independently corroborating PMID 16244668\",\n      \"pmids\": [\"16326102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Plk4 overexpression induces simultaneous generation of multiple procentrioles adjacent to each parental centriole; Plk4, hSas-6, CPAP, Cep135, gamma-tubulin, and CP110 were ordered into a centriole assembly pathway by siRNA, with CP110 associating with growing distal tips indicating centrioles elongate by tubulin insertion underneath a CP110 cap.\",\n      \"method\": \"Plk4 overexpression, siRNA knockdown, immunoelectron microscopy in human cells\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA epistasis + immunoelectron microscopy), defined assembly pathway\",\n      \"pmids\": [\"17681131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Sak (PLK4) polo-box domain localizes the enzyme to the nucleolus during G2, to centrosomes in G2/M, and to the cleavage furrow during cytokinesis; Sak-null mouse embryos arrest at E7.5 with cells in late anaphase/telophase retaining cyclin B1 and phospho-histone H3, indicating a role in APC-dependent cyclin B1 destruction and mitotic exit.\",\n      \"method\": \"Sak null mouse knockout, live/fixed imaging, cyclin B1/pH3 immunostaining\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout in mouse with defined biochemical (cyclin B1 retention) and cellular (anaphase arrest) phenotypes\",\n      \"pmids\": [\"11301255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The Sak polo-box domain forms homodimers both in vitro and in vivo and is sufficient for subcellular localization to centrosomes and the cleavage furrow during cytokinesis; crystal structure at 2.0 Å reveals a dimeric fold with a deep interfacial cleft suggestive of a ligand-binding site.\",\n      \"method\": \"X-ray crystallography (2.0 Å), in vitro and in vivo dimerization assays, subcellular localization by immunofluorescence\",\n      \"journal\": \"Nature structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation of dimerization and localization, single lab\",\n      \"pmids\": [\"12352953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SCF/Slimb (βTrCP) ubiquitin ligase physically interacts with SAK/PLK4 via a conserved Slimb-binding motif in PLK4, targeting it for proteolytic degradation; loss of Slimb causes PLK4 accumulation and centriole amplification, and mutations in the Slimb-binding motif also cause centrosome amplification.\",\n      \"method\": \"Co-immunoprecipitation, RNAi, site-directed mutagenesis of Slimb-binding motif in Drosophila\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction, mutagenesis of binding motif, and genetic loss-of-function with defined phenotype; independently replicated (PMID 19171756)\",\n      \"pmids\": [\"19084407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SCF(Slimb) E3 ubiquitin ligase mediates proteolytic degradation of Drosophila Plk4 to prevent centriole reduplication; Plk4 binds Slimb, Plk4 levels are highest at mitosis and absent during S phase, and Slimb regulates Plk4 localization to centrioles during interphase.\",\n      \"method\": \"RNAi screen, co-immunoprecipitation, Slimb-binding mutant expression, immunofluorescence in Drosophila cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, and RNAi with defined phenotype; corroborates PMID 19084407\",\n      \"pmids\": [\"19171756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Plk4 undergoes βTrCP-dependent proteasomal degradation in human cells; kinase-dead Plk4 disrupts Plk4 trans-autophosphorylation within homodimers, shielding endogenous Plk4 from βTrCP recognition, leading to centriole overduplication. Active Plk4 promotes its own degradation by catalyzing βTrCP binding through trans-autophosphorylation.\",\n      \"method\": \"Stable overexpression of kinase-dead Plk4, proteasome inhibitor assays, co-immunoprecipitation in human cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — trans-autophosphorylation mechanism established by kinase-dead dominant negative and Co-IP, two complementary approaches, single lab\",\n      \"pmids\": [\"20516151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cep152 interacts with the cryptic Polo-box of Plk4 via its N-terminal domain; Cep152 is required for Plk4 recruitment to the centrosome and for Plk4-induced centriole overduplication; depletion of Cep152 also prevents CPAP recruitment and leads to monopolar mitotic spindles.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence in human cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and depletion phenotypes replicated in two independent simultaneous publications (PMIDs 21059844 and 21059850)\",\n      \"pmids\": [\"21059844\", \"21059850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cep152 (orthologue of Drosophila Asterless) interacts with Plk4 through residues 1-217 of Cep152 and the crypto Polo-box of Plk4; Cep152 depletion prevents Sas6 localization to the centriole (an early duplication step); Cep152 can be phosphorylated by Plk4 in vitro.\",\n      \"method\": \"Co-immunoprecipitation in human and Xenopus cells, siRNA, in vitro kinase assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vitro kinase assay, siRNA epistasis, confirmed in two organisms\",\n      \"pmids\": [\"21059850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PLK4 phosphorylates FBXW5 at Ser151 to suppress FBXW5-mediated ubiquitylation of HsSAS-6, thereby antagonizing SCF-FBXW5-dependent degradation of the centriolar protein HsSAS-6 and promoting centrosome duplication.\",\n      \"method\": \"In vitro kinase assay, Co-IP, ubiquitylation assay, siRNA/overexpression in human cells\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay identifying phosphorylation site (Ser151), ubiquitylation assay, and Co-IP; multiple orthogonal methods\",\n      \"pmids\": [\"21725316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PP2A(Twins) counteracts Plk4 autophosphorylation, stabilizing Plk4 and promoting centriole duplication; the PP2A regulatory subunit Twins peaks during mitosis and is required for centriole duplication, and SV40 small T antigen mimics Twins function to stabilize Plk4.\",\n      \"method\": \"Genetic and biochemical experiments in Drosophila; Twins RNAi, immunoprecipitation, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PP2A-Twins stabilization of Plk4 shown by RNAi and Co-IP, single lab\",\n      \"pmids\": [\"21987638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GCP6 (a gamma-tubulin ring complex component) interacts with Plk4, is phosphorylated by Plk4 in vitro, and is required for Plk4-induced centriole overduplication; depletion of GCP6 prevents centriole duplication.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, siRNA in human cells, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and in vitro kinase assay with siRNA phenotype, single lab\",\n      \"pmids\": [\"22302995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cep192 and Cep152 cooperate to recruit Plk4 to centrioles; Cep192 binds Plk4 through an N-terminal extension, and double depletion of both completely abolishes Plk4 binding and centriole duplication; Cep192 and Cep152 binding regions are rich in negatively charged residues, suggesting electrostatic interaction with the positively charged polo-box domain.\",\n      \"method\": \"Co-immunoprecipitation, siRNA double depletion, immunofluorescence in human cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-depletion epistasis, reciprocal Co-IP, corroborated by PMID 24277814\",\n      \"pmids\": [\"23641073\", \"24277814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PLK4 is directly phosphorylated and activated by stress-activated protein kinase kinase kinases (SAPKKKs); stress-induced PLK4 activation promotes centrosome duplication whereas SAPK activation opposes it; p53 downregulates PLK4 expression in the late stress response to prevent centrosome amplification.\",\n      \"method\": \"In vitro kinase assay (SAPKKKs phosphorylating PLK4), immunofluorescence, genetic inactivation of MKK4 and p53 in cancer cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus genetic epistasis, single lab\",\n      \"pmids\": [\"23653187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PLK4 is a suicide kinase that trans-autophosphorylates within homodimers on Ser293 and Thr297 within the SCF-Slimb/βTrCP-binding degron and on a phospho-cluster outside the degron (which regulates Thr297 phosphorylation); this multisite mechanism ensures that PLK4 concentration threshold is reached before autodestruction.\",\n      \"method\": \"In vitro kinase assays with phospho-mutants, mass spectrometry, genetic assays in Drosophila soma and germline\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with phospho-site mutagenesis and MS identification, validated in vivo\",\n      \"pmids\": [\"24184099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Drosophila Plk4 phosphorylates four conserved serines in the STAN motif of Ana2 (STIL orthologue); this phosphorylation enables Ana2 to bind and recruit Sas6 for procentriole formation; non-phosphorylatable Ana2 still localizes to the centriole but fails to recruit Sas6.\",\n      \"method\": \"In vitro kinase assay (Plk4 phosphorylating Ana2 STAN motif), mass spectrometry, non-phosphorylatable mutant rescue experiments in Drosophila\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay, phospho-site MS, phospho-mutant in vivo validation, identifies key substrate and mechanism\",\n      \"pmids\": [\"25264260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Plk4 and STIL form a protein complex that recruits HsSAS-6; Plk4 phosphorylates STIL to facilitate the STIL/HsSAS-6 interaction and centriolar loading of HsSAS-6; centriolar STIL provides negative feedback regulating bimodal PLK4 distribution, restricting procentriole formation to one site per parental centriole.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay (PLK4 phosphorylating STIL), STIL-depletion/rescue, immunofluorescence in human cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vitro kinase assay, rescue experiments, multiple orthogonal methods\",\n      \"pmids\": [\"25342035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Plk4 relocalizes from the inner Cep192 ring to the outer Cep152 ring as Cep152 assembles around the daughter centriole; crystal structures show Cep192- and Cep152-derived peptides bind the cryptic polo box (CPB) of Plk4 in opposite orientations and mutually exclusively; the Cep152 peptide binds CPB markedly better and can snatch it from a preformed CPB-Cep192 complex.\",\n      \"method\": \"X-ray crystallography of PLK4-CPB with Cep192/Cep152 peptides, super-resolution microscopy, in vitro competition assay, cancer-mutation functional analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures at atomic resolution with in vitro competition assay and in vivo functional validation of cancer-associated mutant\",\n      \"pmids\": [\"24997597\"],\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 activation loop; Plk4 activity is required for STIL localization to the centriole; Plk4 then phosphorylates STIL to promote STIL's direct binding to the C-terminus of SAS6, driving centriole assembly.\",\n      \"method\": \"Chemical genetic system (analog-sensitive PLK4 in human cells), in vitro kinase assay, Co-IP, phospho-mutant rescue\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chemical genetic inhibition of endogenous PLK4, in vitro kinase assay, phospho-mutant analysis; multiple orthogonal methods\",\n      \"pmids\": [\"26101219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STIL interacts with PLK4 via its coiled-coil region (STIL-CC) binding to Polo-box 3 (PB3) of PLK4 (first identified PB3 interaction partner) and a secondary site in PLK4 L1 region; NMR and crystal structures reveal a novel coiled-coil-mimicking Polo-box–peptide interaction mode; STIL-CC/PLK4 interaction mediates PLK4 activation and stabilization of centriolar PLK4.\",\n      \"method\": \"NMR spectroscopy, X-ray crystallography of PLK4-PB3/STIL-CC complex, in vivo Co-IP, structure-guided mutagenesis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure and NMR with in vivo mutagenesis validation; structural mechanism fully established\",\n      \"pmids\": [\"26188084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STIL is phosphorylated by Plk4 at specific sites within its C-terminal domain; a STIL fragment containing the coiled-coil and STAN motif shows strongest binding to Plk4; STIL phosphorylation by Plk4 is required to trigger centriole duplication.\",\n      \"method\": \"In vitro kinase assay, Co-IP, phospho-site identification, phospho-mutant rescue in human cells\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay and Co-IP with phospho-mutant phenotype, single lab; corroborates PMIDs 25342035, 26101219\",\n      \"pmids\": [\"25701666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KAT2A/KAT2B (GCN5/PCAF) acetyltransferases acetylate PLK4 kinase domain on K45 and K46; molecular dynamics modeling suggests K45/K46 acetylation shifts kinase to inactive conformation; PLK4 kinase activity is reduced upon in vitro acetylation; PLK4 K45R/K46R mutant overexpression does not cause centrosome overamplification; impairing KAT2A/2B activity results in diminished PLK4 phosphorylation and excess centrosome numbers.\",\n      \"method\": \"Mass spectrometry acetylome, in vitro acetylation/kinase assay, molecular dynamics modeling, K45R/K46R mutant overexpression in cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay + mutagenesis + MD modeling + cellular phenotype; multiple orthogonal methods in one study\",\n      \"pmids\": [\"27796307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The E3 ubiquitin ligase Mind bomb 1 (Mib1) interacts with Plk4 and ubiquitylates Plk4 on multiple sites (generating K11-, K29-, and K48-linked chains), controlling Plk4 abundance and its ability to interact with centrosomal proteins, thereby counteracting centriole amplification.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay with linkage-specific analysis (mass spectrometry), immunofluorescence in human cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and in-cell ubiquitylation assay with MS-defined linkages, single lab\",\n      \"pmids\": [\"25795303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PLK4 trans-autoactivation (local concentration-dependent) is a critical event in spatial control of centriole biogenesis; centrioles promote PLK4 activation through local recruitment and accumulation; concentrating PLK4 artificially (e.g. at peroxisomes) is sufficient to rescue centriole amplification in centriole-less cells.\",\n      \"method\": \"PLK4 depletion/rescue, peroxisome tethering assay, Drosophila centriole-removal genetics\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — spatial tethering reconstitution with genetic centriole-removal, single lab\",\n      \"pmids\": [\"26481051\"],\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 and STIL phosphorylation by PLK4, thus inhibiting untimely onset of centriole biogenesis; after CDK1 inactivation at mitotic exit, PLK4 can bind and phosphorylate STIL in G1 to allow pro-centriole assembly in the next S phase.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, cell-cycle-staged analysis in human cells and Drosophila\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of CDK1-STIL complex, in vitro kinase assay showing CDK1 prevents Plk4 phosphorylation of STIL, two organisms\",\n      \"pmids\": [\"27112295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Plk4 interacts with members of the Arp2/3 complex (specifically Arp2) via its Polo-box 1/2 domain; Plk4 phosphorylates Arp2 at T237/T238 (activation site), and this phosphorylation is required for Plk4-driven cell movement and cancer invasion.\",\n      \"method\": \"BioID proximity labeling screen, Co-immunoprecipitation, in vitro kinase assay, phospho-mutant rescue, cell invasion assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID + Co-IP + in vitro kinase assay + phospho-mutant rescue; single lab, multiple methods\",\n      \"pmids\": [\"27872092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Plk4 depletion leads to dispersion of centriolar satellites; Plk4 interacts with the satellite component PCM1 and phosphorylates conserved S372 of PCM1; non-phosphorylatable PCM1 S372A disperses centriolar satellites and perturbs ciliogenesis; phosphomimetic S372E partially rescues satellite organization and ciliogenesis; S372 phosphorylation occurs during G1 and promotes PCM1 dimerization and interaction with other satellite components.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phospho-mutant rescue, ciliogenesis assay in human cells\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay + phospho-mutant rescue + Co-IP; single lab, multiple methods\",\n      \"pmids\": [\"26755742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Plk4 haploinsufficiency disrupts RhoGTPase function during cytokinesis: Plk4+/- MEFs show high primary cytokinesis failure with aberrant actomyosin ring formation, reduced RhoA activation, and failure to localize the RhoA GEF Ect2 to the spindle midbody; Plk4 normally localizes to the midbody and binds to and phosphorylates Ect2 in vitro.\",\n      \"method\": \"Plk4+/- MEF analysis, in vitro kinase assay (Plk4 phosphorylating Ect2), RhoA activation assay, immunofluorescence\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay + functional RhoA assay + midbody localization, single lab\",\n      \"pmids\": [\"20348415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Purified Sak/PLK4 kinase domain has robust kinase activity in vitro; the consensus phosphorylation motif for Sak is [charged]-[Ile/Leu/Val]-Ser/Thr-[large hydrophobic]-[large hydrophobic]-X-[charged/Pro], which differs from the Plk1 consensus motif.\",\n      \"method\": \"In vitro kinase assay on peptide spots arrays with purified Sak kinase domain\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro kinase assay with peptide array determination of consensus motif\",\n      \"pmids\": [\"17174311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Sak serine-threonine kinase acts as an effector of Tec tyrosine kinase: Sak is tyrosine-phosphorylated by Tec and Sak kinase activity is detectable only in the presence of Tec; Tec activity also protects Sak from PEST sequence-dependent proteolysis.\",\n      \"method\": \"Co-immunoprecipitation (yeast two-hybrid identification), in vitro/in vivo kinase assay in HEK293 cells, PEST-deletion mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, kinase activity assay, and protein stability analysis in single study\",\n      \"pmids\": [\"11489907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PLK4 phosphorylates Ana2/STIL in an ordered sequence: first the extreme N-terminus of Ana2, which is critical for subsequent STAN domain modification; central-region phosphorylation then breaks the Plk4-Ana2 interaction; STAN domain phosphorylation recruits Sas6. Disrupting this ordered phosphorylation sequence inhibits centriole duplication and integrity.\",\n      \"method\": \"In vitro kinase assay, phospho-mutant replacement of endogenous Ana2 in Drosophila, mass spectrometry\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of ordered phosphorylation, endogenous gene replacement with phospho-mutants, MS phospho-site identification\",\n      \"pmids\": [\"29496738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"STIL bimodally interacts with Plk4: the short coiled-coil region of STIL protects Plk4 from degradation (positive regulation) while the C-terminal TIM domain of STIL promotes autophosphorylation and degradation of adjacent Plk4 (negative regulation); this bimodal binding limits procentriole formation to a single site per parental centriole.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase/degradation assays, domain-mapping mutants in human cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping, Co-IP, and in vitro kinase assay; single lab, multiple methods\",\n      \"pmids\": [\"29898389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PLK4 self-assembles into condensates in vitro and in Xenopus egg extracts that recruit α/β-tubulin, STIL, and γ-tubulin to form acentriolar MTOCs de novo; this assembly is independent of dynein and suggests PLK4 acts as a self-organizing catalytic scaffold for MTOC formation.\",\n      \"method\": \"Xenopus egg extract reconstitution, in vitro condensate assay, immunofluorescence and live microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution in Xenopus extracts; novel mechanism, single lab\",\n      \"pmids\": [\"30237222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CEP85 directly interacts with STIL through a conserved interface and is required for efficient centriolar targeting of STIL, PLK4 activation, and faithful daughter centriole assembly; structure-guided mutational analyses in vivo confirm the interaction is essential.\",\n      \"method\": \"Protein proximity mapping (BioID), high-resolution structural analysis, Co-immunoprecipitation, structure-guided mutagenesis in human cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID + Co-IP + structure-guided mutagenesis + in vivo phenotype; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29712910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM37 levels determine cellular sensitivity to PLK4 inhibition: elevated TRIM37 inhibits acentrosomal spindle assembly by degrading CEP192, causing mitotic failure upon PLK4 inhibition; low TRIM37 allows PLK4 self-assembly into centrosome-independent condensates serving as ectopic MTOCs; high TRIM37 (amplified in 17q neuroblastoma and breast cancer) renders these cancers highly sensitive to PLK4 inhibition.\",\n      \"method\": \"TRIM37 knockdown/overexpression, PLK4 inhibitor (centrinone) treatment, live-cell imaging, condensate assay, CEP192 degradation assay in human cells and cancer models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell lines, mechanistic dissection of two distinct TRIM37 actions, cancer model validation; high-quality study\",\n      \"pmids\": [\"32908304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PLK4 deubiquitination by the Spata2-CYLD deubiquitinase complex at the centrosome facilitates PLK4 binding to and phosphorylation of NEK7 at Ser204; this NEK7 phosphorylation attenuates the NEK7-NLRP3 interaction required for NLRP3 inflammasome activation, suppressing innate immune signaling.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay (PLK4 phosphorylating NEK7 Ser204), Spata2-KO macrophages, mouse peritonitis model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay + Co-IP + KO model; single lab, multiple methods, novel non-centrosomal function\",\n      \"pmids\": [\"31762063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Plk4 functions upstream of mitotic spindle orientation control in Drosophila neural stem cells by orchestrating centriole symmetry breaking; mechanistically, Plk4 phosphorylates Spd2 (CEP192 orthologue), which induces centriole release from the apical cortex to set centrosome positioning.\",\n      \"method\": \"Drosophila genetics (plk4 mutants), live imaging of asymmetric neural stem cell divisions, phospho-mutant Spd2 rescue\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with phospho-mutant rescue in vivo, single lab\",\n      \"pmids\": [\"31130353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Plk4 is essential for spindle assembly in the absence of centrioles in the early mouse embryo; depletion of maternal Plk4 prevents microtubule nucleation and growth, resulting in monopolar spindles, cytokinesis failure, and developmental arrest; this function depends on Plk4 kinase activity and requires its partner Cep152.\",\n      \"method\": \"Maternal Plk4 depletion in mouse embryos, live imaging, kinase-dead rescue, Cep152-membrane tethering\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo depletion with kinase-dead and Cep152-tethering rescue experiments; single study\",\n      \"pmids\": [\"24268700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PLK4 phosphorylates CP110 at Ser98; phospho-resistant CP110 S98A inhibits centriole assembly, while the phosphomimetic CP110 S98D promotes assembly even under PLK4-limited conditions and augments centrosomal SAS6 levels.\",\n      \"method\": \"In vitro kinase assay (PLK4 phosphorylating CP110), phospho-mutant overexpression in human cells, immunofluorescence\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay + phospho-mutant phenotype; single lab\",\n      \"pmids\": [\"28562169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cdc6 negatively regulates centrosome duplication by binding and inhibiting Sas-6 from forming a stable complex with STIL; PLK4 colocalizes and interacts with Cdc6 at centrosomes during S phase, phosphorylates Cdc6, and disrupts the Sas-6/Cdc6 interaction, thus antagonizing Cdc6-mediated inhibition of centrosome duplication.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phospho-mutant rescue, immunofluorescence in human cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro kinase assay, phospho-mutant rescue; single lab, multiple methods\",\n      \"pmids\": [\"28447620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM46C/TENT5C physically interacts with Plk4, localizes to centrioles, directly inhibits Plk4 kinase activity, and suppresses Plk4-induced centriole duplication independently of FAM46C's nucleotidyl transferase activity.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay (FAM46C inhibiting PLK4), siRNA/overexpression, xenograft model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + in vitro kinase inhibition assay + domain mutant (nucleotidyl-transferase-dead) ruling out alternative mechanism; single lab\",\n      \"pmids\": [\"32807875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TEC tyrosine kinase directly phosphorylates PLK4 at tyrosine 86, stabilizing the PLK4 protein and enhancing PLK4-mediated HCC cell invasion; transcriptome sequencing indicates PLK4 promotes focal adhesion kinase phosphorylation to regulate the focal adhesion pathway in cell migration.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay (TEC phosphorylating PLK4 Y86), phospho-mutant rescue, transcriptome sequencing in HCC cells\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay identifying Y86 site + Co-IP + phospho-mutant; single lab\",\n      \"pmids\": [\"34637843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PLK4 phosphorylates PRMT5 (a histone methyltransferase) in a PLK4/PRMT5/EZH2/H3K27me3 axis in AML cells; PLK4-induced PRMT5 phosphorylation leads to histone modification; in TP53-mutated AML, combined histone modification and PLK4-inhibition-induced polyploidy activates the cGAS-STING pathway, inducing cytokines/chemokines and immune cell activation.\",\n      \"method\": \"In vitro kinase assay (PLK4 phosphorylating PRMT5), Western blot for H3K27me3, cGAS-STING pathway analysis, macrophage/T cell co-culture, in vivo AML model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay + pathway analysis + in vivo model; single lab, multiple methods\",\n      \"pmids\": [\"37738460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PLK4 protein and kinase activity are both required for centriole amplification in multiciliated cells (MCCs); tracheal epithelial cells failing centriole amplification accumulate large centriole protein assemblies and do not undergo apical surface area expansion, linking centriole amplification to surface expansion.\",\n      \"method\": \"Genetically engineered mouse models (PLK4 conditional knockout and kinase-dead knock-in), immunofluorescence, tracheal epithelium analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse models with KO and kinase-dead mutations providing clean genetic evidence\",\n      \"pmids\": [\"35969030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Sak (PLK4) encodes two isoforms (Sak-a and Sak-b) of a putative serine/threonine kinase related to polo-family kinases; Sak expression is associated with mitotic and meiotic cell division in mouse tissues; antisense Sak-a expression suppresses cell growth in CHO cells.\",\n      \"method\": \"cDNA cloning, Northern blot, in situ hybridization in mouse tissues, antisense growth suppression in CHO cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — initial expression-based identification with antisense growth phenotype; no direct biochemical mechanism established\",\n      \"pmids\": [\"8022793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Sak-a transcripts are absent in growth-arrested cells and increase late in G1 through mitosis; Sak-a protein is multiubiquitinated with a half-life of ~2-3 h; overexpression of Sak-a (but not Sak-b or kinase-dead Sak-a D154N) inhibits colony-forming efficiency and increases multinucleated cells, requiring both the kinase domain and the Sak-a-specific C-terminal region.\",\n      \"method\": \"Cell cycle synchronization/Northern blot, HA-tagged protein half-life assay, colony formation assay, multinucleation scoring in CHO cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — kinase domain requirement shown by D154N mutation; ubiquitination shown by immunoprecipitation; but mechanism of multinucleation not established\",\n      \"pmids\": [\"8756623\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLK4 is a serine/threonine kinase that serves as the master regulator of centriole duplication: it is recruited to centrioles hierarchically by Cep192 and then Cep152 (via its cryptic polo box), where it trans-autophosphorylates within homodimers to trigger βTrCP-dependent self-degradation, and is activated by direct binding of STIL (which promotes PLK4 activation-loop self-phosphorylation), whereupon active PLK4 phosphorylates STIL to drive SAS-6 recruitment and cartwheel assembly; its activity is restrained by PP2A-mediated dephosphorylation, by CDK1-CyclinB–mediated prevention of the PLK4-STIL complex in mitosis, by KAT2A/B-mediated acetylation of K45/K46, by SCF-Slimb/βTrCP ubiquitin-mediated degradation, and by the Mib1 E3 ligase; beyond centriole biogenesis, PLK4 phosphorylates Arp2 (T237/T238) to regulate actin cytoskeletal dynamics and cancer invasion, phosphorylates Ect2 to support RhoA activation at the cytokinetic midbody, phosphorylates NEK7 (Ser204) to suppress NLRP3 inflammasome activation, and phosphorylates PRMT5 to remodel histone methylation and activate cGAS-STING signaling in AML.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLK4 is a serine/threonine kinase of the polo family that functions as the master regulator of centriole duplication, where it acts both as the trigger for procentriole assembly and as the rate-limiting determinant of centriole number [#0, #1, #2]. PLK4 is recruited to the centriole hierarchically: Cep192 and Cep152 bind the cryptic polo box, with PLK4 relocalizing from an inner Cep192 ring to an outer Cep152 ring as the daughter centriole matures, a switch enforced by mutually exclusive, oppositely oriented peptide binding in which Cep152 outcompetes Cep192 [#8, #13, #18]. Once positioned, PLK4 is activated through direct binding of STIL, which engages PLK4 polo-box 3 and promotes activation-loop self-phosphorylation; active PLK4 then phosphorylates STIL in an ordered, multisite sequence to drive SAS-6 recruitment and cartwheel assembly [#16, #19, #20, #31]. PLK4 abundance is tightly self-limiting: it trans-autophosphorylates within homodimers on a degron recognized by SCF-Slimb/\\u03b2TrCP, coupling kinase activity to its own ubiquitin-mediated destruction so that a concentration threshold gates centriole formation [#5, #7, #15]. This output is further restrained by PP2A-mediated dephosphorylation, KAT2A/B acetylation of K45/K46, CDK1-CyclinB sequestration of STIL in mitosis, and the Mib1 E3 ligase [#11, #22, #23, #25]. Beyond centriole biogenesis, PLK4 supports cytokinesis by phosphorylating Ect2 to promote RhoA activation at the midbody [#28], organizes centriolar satellites through PCM1 phosphorylation to enable ciliogenesis [#27], drives actin-dependent cell invasion by phosphorylating Arp2 [#26], and is required for centriole amplification during multiciliated cell differentiation [#44]. Differential TRIM37 levels dictate cancer sensitivity to PLK4 inhibition, since PLK4 can self-assemble into centrosome-independent condensates that serve as ectopic microtubule-organizing centers [#33, #35].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established PLK4 (Sak) as a polo-family serine/threonine kinase tied to cell division, opening the question of its specific mitotic function.\",\n      \"evidence\": \"cDNA cloning, expression profiling, and antisense growth suppression in mouse tissues and CHO cells\",\n      \"pmids\": [\"8022793\", \"8756623\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical substrate or pathway defined\", \"Mechanism of growth/multinucleation phenotype unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked PLK4 localization (polo-box domain) and an in vivo requirement to mitotic progression and cyclin B1 destruction, before its centriole role was known.\",\n      \"evidence\": \"Sak-null mouse knockout with cyclin B1/pH3 immunostaining and a polo-box dimerization crystal structure\",\n      \"pmids\": [\"11301255\", \"12352953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not yet connect localization to centriole duplication\", \"Ligand of the interfacial cleft not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified PLK4 as the rate-limiting regulator of centriole duplication, defining its central biological role.\",\n      \"evidence\": \"Reciprocal gain/loss-of-function in human cells and Drosophila mutants with centriole/spindle phenotypes\",\n      \"pmids\": [\"16244668\", \"16326102\", \"17681131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Activating and inhibitory partners not yet mapped\", \"Direct substrates unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved how PLK4 levels are capped, showing kinase activity feeds back onto its own ubiquitin-mediated destruction to prevent centriole amplification.\",\n      \"evidence\": \"Co-IP, Slimb-binding-motif mutagenesis, RNAi, and kinase-dead/proteasome assays in Drosophila and human cells\",\n      \"pmids\": [\"19084407\", \"19171756\", \"20516151\", \"24184099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise degron phospho-site stoichiometry in vivo\", \"Coordination with positive recruitment cues not fully integrated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the centriolar recruitment hierarchy and identified Cep192/Cep152 as the docking platforms binding the PLK4 cryptic polo box.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA double depletion, and in vitro kinase assays in human and Xenopus cells\",\n      \"pmids\": [\"21059844\", \"21059850\", \"23641073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of Cep192-to-Cep152 handoff not yet structurally explained\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Explained the spatial Cep192-to-Cep152 switch structurally, showing the two adaptors bind the cryptic polo box in opposite orientations and mutually exclusively.\",\n      \"evidence\": \"X-ray crystallography of PLK4-CPB with adaptor peptides, super-resolution microscopy, and in vitro competition assay\",\n      \"pmids\": [\"24997597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Timing signals triggering Cep152 engagement during the cycle not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established the STIL-PLK4 activation circuit: STIL binding activates PLK4, and PLK4 phosphorylates STIL to load SAS-6, with STIL bimodal binding restricting duplication to one site.\",\n      \"evidence\": \"Chemical-genetic PLK4 inhibition, in vitro kinase assays, NMR/crystallography of PB3-STIL, and phospho-mutant rescue\",\n      \"pmids\": [\"25342035\", \"26101219\", \"26188084\", \"25701666\", \"29496738\", \"29898389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative model of single-site selection not fully resolved\", \"In vivo phospho-site occupancy incompletely mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Expanded the layers of PLK4 restraint beyond degradation to include dephosphorylation, acetylation, alternative ubiquitin ligases, and cell-cycle sequestration.\",\n      \"evidence\": \"RNAi, Co-IP, in vitro acetylation/kinase assays, MD modeling, and cell-cycle-staged analysis in Drosophila and human cells\",\n      \"pmids\": [\"21987638\", \"27796307\", \"25795303\", \"27112295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each restraint in vivo unquantified\", \"Crosstalk between regulatory modifications unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended PLK4 substrate range beyond centriole biogenesis to cytokinesis, satellite/ciliogenesis control, and actin-driven invasion.\",\n      \"evidence\": \"BioID, Co-IP, in vitro kinase assays, phospho-mutant rescue, and functional assays in MEFs and human cells\",\n      \"pmids\": [\"20348415\", \"26755742\", \"27872092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Some functions rest on single-lab evidence\", \"In vivo significance of non-centriolar substrates not fully tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected PLK4 to therapeutic vulnerability and innate immunity, showing TRIM37-dependent condensate behavior and NEK7 phosphorylation suppressing inflammasome signaling.\",\n      \"evidence\": \"TRIM37 modulation with PLK4 inhibitor, condensate/CEP192 degradation assays, and in vitro kinase assays with KO models\",\n      \"pmids\": [\"32908304\", \"31762063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NEK7/inflammasome arm rests on single-lab evidence\", \"Physiological balance between condensate and centriolar PLK4 unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked PLK4 to chromatin and antitumor immunity via PRMT5 phosphorylation and cGAS-STING activation in AML.\",\n      \"evidence\": \"In vitro kinase assay, H3K27me3 analysis, cGAS-STING readouts, co-culture, and in vivo AML model\",\n      \"pmids\": [\"37738460\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence\", \"Direct PRMT5 phospho-site and structural basis not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PLK4's many non-centriolar substrates are spatially and temporally segregated from its centriole-duplication function within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coordinating centriolar vs. cytoplasmic PLK4 pools\", \"Substrate selection determinants beyond localization unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [16, 17, 19, 26, 28, 29, 36, 39, 43]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [10, 12, 15, 29, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 3, 8, 18]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 3, 25]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 17, 27, 44]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [36, 43]}\n    ],\n    \"complexes\": [\"PLK4 homodimer\"],\n    \"partners\": [\"CEP152\", \"CEP192\", \"STIL\", \"SAS6\", \"BTRC\", \"CEP85\", \"ECT2\", \"PCM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}