Affinage

PLK4

Serine/threonine-protein kinase PLK4 · UniProt O00444

Length
970 aa
Mass
109.0 kDa
Annotated
2026-06-10
100 papers in source corpus 48 papers cited in narrative 47 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1994 Low

    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

    PMID:8022793 PMID:8756623

    Open questions at the time
    • No direct biochemical substrate or pathway defined
    • Mechanism of growth/multinucleation phenotype unresolved
  2. 2001 High

    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

    PMID:11301255 PMID:12352953

    Open questions at the time
    • Did not yet connect localization to centriole duplication
    • Ligand of the interfacial cleft not identified
  3. 2005 High

    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

    PMID:16244668 PMID:16326102 PMID:17681131

    Open questions at the time
    • Activating and inhibitory partners not yet mapped
    • Direct substrates unknown
  4. 2008 High

    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

    PMID:19084407 PMID:19171756 PMID:20516151 PMID:24184099

    Open questions at the time
    • Precise degron phospho-site stoichiometry in vivo
    • Coordination with positive recruitment cues not fully integrated
  5. 2010 High

    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

    PMID:21059844 PMID:21059850 PMID:23641073

    Open questions at the time
    • Order of Cep192-to-Cep152 handoff not yet structurally explained
  6. 2014 High

    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

    PMID:24997597

    Open questions at the time
    • Timing signals triggering Cep152 engagement during the cycle not defined
  7. 2015 High

    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

    PMID:25342035 PMID:25701666 PMID:26101219 PMID:26188084 PMID:29496738 PMID:29898389

    Open questions at the time
    • Quantitative model of single-site selection not fully resolved
    • In vivo phospho-site occupancy incompletely mapped
  8. 2015 Medium

    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

    PMID:21987638 PMID:25795303 PMID:27112295 PMID:27796307

    Open questions at the time
    • Relative contribution of each restraint in vivo unquantified
    • Crosstalk between regulatory modifications unresolved
  9. 2016 Medium

    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

    PMID:20348415 PMID:26755742 PMID:27872092

    Open questions at the time
    • Some functions rest on single-lab evidence
    • In vivo significance of non-centriolar substrates not fully tested
  10. 2019 High

    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

    PMID:31762063 PMID:32908304

    Open questions at the time
    • NEK7/inflammasome arm rests on single-lab evidence
    • Physiological balance between condensate and centriolar PLK4 unclear
  11. 2023 Medium

    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

    PMID:37738460

    Open questions at the time
    • Single-lab evidence
    • Direct PRMT5 phospho-site and structural basis not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PLK4's many non-centriolar substrates are spatially and temporally segregated from its centriole-duplication function within a single cell remains unresolved.
  • No unified model coordinating centriolar vs. cytoplasmic PLK4 pools
  • Substrate selection determinants beyond localization unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016740 transferase activity 5
Localization
GO:0005815 microtubule organizing center 4 GO:0005730 nucleolus 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-168256 Immune System 2
Partners
BTRCCEP152CEP192CEP85ECT2PCM1SAS6STIL
Complex memberships
PLK4 homodimer

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 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. Gain- and loss-of-function (siRNA/overexpression) in human cells; immunofluorescence Nature cell biology High 16244668
2005 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). Drosophila mutation, RNAi in Drosophila and human cells, mathematical modeling of spermatogenesis divisions Current biology : CB High 16326102
2007 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. Plk4 overexpression, siRNA knockdown, immunoelectron microscopy in human cells Developmental cell High 17681131
2001 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. Sak null mouse knockout, live/fixed imaging, cyclin B1/pH3 immunostaining Current biology : CB High 11301255
2002 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. X-ray crystallography (2.0 Å), in vitro and in vivo dimerization assays, subcellular localization by immunofluorescence Nature structural biology High 12352953
2008 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. Co-immunoprecipitation, RNAi, site-directed mutagenesis of Slimb-binding motif in Drosophila Current biology : CB High 19084407
2009 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. RNAi screen, co-immunoprecipitation, Slimb-binding mutant expression, immunofluorescence in Drosophila cells The Journal of cell biology High 19171756
2010 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. Stable overexpression of kinase-dead Plk4, proteasome inhibitor assays, co-immunoprecipitation in human cells Journal of cell science High 20516151
2010 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. Co-immunoprecipitation, siRNA knockdown, immunofluorescence in human cells The Journal of cell biology High 21059844 21059850
2010 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. Co-immunoprecipitation in human and Xenopus cells, siRNA, in vitro kinase assay The Journal of cell biology High 21059850
2011 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. In vitro kinase assay, Co-IP, ubiquitylation assay, siRNA/overexpression in human cells Nature cell biology High 21725316
2011 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. Genetic and biochemical experiments in Drosophila; Twins RNAi, immunoprecipitation, immunofluorescence The Journal of cell biology Medium 21987638
2012 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. Co-immunoprecipitation, in vitro kinase assay, siRNA in human cells, immunofluorescence Journal of cell science Medium 22302995
2013 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. Co-immunoprecipitation, siRNA double depletion, immunofluorescence in human cells Journal of cell science High 23641073 24277814
2013 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. In vitro kinase assay (SAPKKKs phosphorylating PLK4), immunofluorescence, genetic inactivation of MKK4 and p53 in cancer cells Nature communications Medium 23653187
2013 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. In vitro kinase assays with phospho-mutants, mass spectrometry, genetic assays in Drosophila soma and germline Current biology : CB High 24184099
2014 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. In vitro kinase assay (Plk4 phosphorylating Ana2 STAN motif), mass spectrometry, non-phosphorylatable mutant rescue experiments in Drosophila Current biology : CB High 25264260
2014 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. Co-immunoprecipitation, in vitro kinase assay (PLK4 phosphorylating STIL), STIL-depletion/rescue, immunofluorescence in human cells Nature communications High 25342035
2014 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. X-ray crystallography of PLK4-CPB with Cep192/Cep152 peptides, super-resolution microscopy, in vitro competition assay, cancer-mutation functional analysis Nature structural & molecular biology High 24997597
2015 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. Chemical genetic system (analog-sensitive PLK4 in human cells), in vitro kinase assay, Co-IP, phospho-mutant rescue The Journal of cell biology High 26101219
2015 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. NMR spectroscopy, X-ray crystallography of PLK4-PB3/STIL-CC complex, in vivo Co-IP, structure-guided mutagenesis eLife High 26188084
2015 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. In vitro kinase assay, Co-IP, phospho-site identification, phospho-mutant rescue in human cells Biology open Medium 25701666
2015 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. Mass spectrometry acetylome, in vitro acetylation/kinase assay, molecular dynamics modeling, K45R/K46R mutant overexpression in cells Nature communications High 27796307
2015 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. Co-immunoprecipitation, ubiquitylation assay with linkage-specific analysis (mass spectrometry), immunofluorescence in human cells Journal of cell science Medium 25795303
2015 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. PLK4 depletion/rescue, peroxisome tethering assay, Drosophila centriole-removal genetics Developmental cell Medium 26481051
2016 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. Co-immunoprecipitation, in vitro kinase assay, cell-cycle-staged analysis in human cells and Drosophila Current biology : CB High 27112295
2016 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. BioID proximity labeling screen, Co-immunoprecipitation, in vitro kinase assay, phospho-mutant rescue, cell invasion assays Cancer research Medium 27872092
2016 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. Co-immunoprecipitation, in vitro kinase assay, phospho-mutant rescue, ciliogenesis assay in human cells EMBO reports Medium 26755742
2010 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. Plk4+/- MEF analysis, in vitro kinase assay (Plk4 phosphorylating Ect2), RhoA activation assay, immunofluorescence Proceedings of the National Academy of Sciences of the United States of America Medium 20348415
2006 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. In vitro kinase assay on peptide spots arrays with purified Sak kinase domain FEBS letters High 17174311
2001 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. Co-immunoprecipitation (yeast two-hybrid identification), in vitro/in vivo kinase assay in HEK293 cells, PEST-deletion mutant analysis The Journal of biological chemistry Medium 11489907
2018 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. In vitro kinase assay, phospho-mutant replacement of endogenous Ana2 in Drosophila, mass spectrometry The Journal of cell biology High 29496738
2018 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. Co-immunoprecipitation, in vitro kinase/degradation assays, domain-mapping mutants in human cells Cell reports Medium 29898389
2018 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. Xenopus egg extract reconstitution, in vitro condensate assay, immunofluorescence and live microscopy Journal of cell science Medium 30237222
2018 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. Protein proximity mapping (BioID), high-resolution structural analysis, Co-immunoprecipitation, structure-guided mutagenesis in human cells Nature communications Medium 29712910
2019 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. TRIM37 knockdown/overexpression, PLK4 inhibitor (centrinone) treatment, live-cell imaging, condensate assay, CEP192 degradation assay in human cells and cancer models Nature High 32908304
2019 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. Co-immunoprecipitation, in vitro kinase assay (PLK4 phosphorylating NEK7 Ser204), Spata2-KO macrophages, mouse peritonitis model The EMBO journal Medium 31762063
2017 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. Drosophila genetics (plk4 mutants), live imaging of asymmetric neural stem cell divisions, phospho-mutant Spd2 rescue Developmental cell Medium 31130353
2013 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. Maternal Plk4 depletion in mouse embryos, live imaging, kinase-dead rescue, Cep152-membrane tethering Developmental cell Medium 24268700
2017 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. In vitro kinase assay (PLK4 phosphorylating CP110), phospho-mutant overexpression in human cells, immunofluorescence Cell cycle (Georgetown, Tex.) Medium 28562169
2017 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. Co-immunoprecipitation, in vitro kinase assay, phospho-mutant rescue, immunofluorescence in human cells Nature communications Medium 28447620
2020 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. Co-immunoprecipitation, in vitro kinase assay (FAM46C inhibiting PLK4), siRNA/overexpression, xenograft model Communications biology Medium 32807875
2021 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. Co-immunoprecipitation, in vitro kinase assay (TEC phosphorylating PLK4 Y86), phospho-mutant rescue, transcriptome sequencing in HCC cells Cancer letters Medium 34637843
2023 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. In vitro kinase assay (PLK4 phosphorylating PRMT5), Western blot for H3K27me3, cGAS-STING pathway analysis, macrophage/T cell co-culture, in vivo AML model Blood Medium 37738460
2022 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. Genetically engineered mouse models (PLK4 conditional knockout and kinase-dead knock-in), immunofluorescence, tracheal epithelium analysis eLife High 35969030
1994 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. cDNA cloning, Northern blot, in situ hybridization in mouse tissues, antisense growth suppression in CHO cells Proceedings of the National Academy of Sciences of the United States of America Low 8022793
1996 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. Cell cycle synchronization/Northern blot, HA-tagged protein half-life assay, colony formation assay, multinucleation scoring in CHO cells Molecular and cellular biology Low 8756623

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The Polo kinase Plk4 functions in centriole duplication. Nature cell biology 705 16244668
2007 Plk4-induced centriole biogenesis in human cells. Developmental cell 551 17681131
2005 SAK/PLK4 is required for centriole duplication and flagella development. Current biology : CB 507 16326102
2010 Cep152 acts as a scaffold for recruitment of Plk4 and CPAP to the centrosome. The Journal of cell biology 233 21059844
2010 Cep152 interacts with Plk4 and is required for centriole duplication. The Journal of cell biology 230 21059850
2009 The SCF Slimb ubiquitin ligase regulates Plk4/Sak levels to block centriole reduplication. The Journal of cell biology 211 19171756
2008 The SCF/Slimb ubiquitin ligase limits centrosome amplification through degradation of SAK/PLK4. Current biology : CB 205 19084407
2014 Direct interaction of Plk4 with STIL ensures formation of a single procentriole per parental centriole. Nature communications 204 25342035
2013 Human Cep192 and Cep152 cooperate in Plk4 recruitment and centriole duplication. Journal of cell science 196 23641073
2013 Hierarchical recruitment of Plk4 and regulation of centriole biogenesis by two centrosomal scaffolds, Cep192 and Cep152. Proceedings of the National Academy of Sciences of the United States of America 178 24277814
2010 Plk4 trans-autophosphorylation regulates centriole number by controlling betaTrCP-mediated degradation. Journal of cell science 176 20516151
2005 Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis. Nature genetics 171 16025114
2015 Binding of STIL to Plk4 activates kinase activity to promote centriole assembly. The Journal of cell biology 165 26101219
2014 Plk4 phosphorylates Ana2 to trigger Sas6 recruitment and procentriole formation. Current biology : CB 148 25264260
2001 Late mitotic failure in mice lacking Sak, a polo-like kinase. Current biology : CB 140 11301255
2015 Transient PLK4 overexpression accelerates tumorigenesis in p53-deficient epidermis. Nature cell biology 138 26595384
2015 Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse. Open biology 134 26701933
2011 The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication. Nature cell biology 128 21725316
2020 TRIM37 controls cancer-specific vulnerability to PLK4 inhibition. Nature 124 32908304
2002 The Sak polo-box comprises a structural domain sufficient for mitotic subcellular localization. Nature structural biology 124 12352953
2016 Plk4 Promotes Cancer Invasion and Metastasis through Arp2/3 Complex Regulation of the Actin Cytoskeleton. Cancer research 123 27872092
2016 The PLK4-STIL-SAS-6 module at the core of centriole duplication. Biochemical Society transactions 123 27911707
2015 Plk4-dependent phosphorylation of STIL is required for centriole duplication. Biology open 113 25701666
2015 STIL binding to Polo-box 3 of PLK4 regulates centriole duplication. eLife 110 26188084
2013 Regulation of autophosphorylation controls PLK4 self-destruction and centriole number. Current biology : CB 109 24184099
2001 Comparative expression of the mitotic regulators SAK and PLK in colorectal cancer. Annals of surgical oncology 107 11597015
2016 KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification. Nature communications 99 27796307
2014 Molecular basis for unidirectional scaffold switching of human Plk4 in centriole biogenesis. Nature structural & molecular biology 93 24997597
1994 Sak, a murine protein-serine/threonine kinase that is related to the Drosophila polo kinase and involved in cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 91 8022793
2010 Plk4 is required for cytokinesis and maintenance of chromosomal stability. Proceedings of the National Academy of Sciences of the United States of America 89 20348415
2011 The Protein Phosphatase 2A regulatory subunit Twins stabilizes Plk4 to induce centriole amplification. The Journal of cell biology 86 21987638
2019 PLK4 deubiquitination by Spata2-CYLD suppresses NEK7-mediated NLRP3 inflammasome activation at the centrosome. The EMBO journal 81 31762063
2018 MiR-126 negatively regulates PLK-4 to impact the development of hepatocellular carcinoma via ATR/CHEK1 pathway. Cell death & disease 74 30315225
2005 SAK, a new polo-like kinase, is transcriptionally repressed by p53 and induces apoptosis upon RNAi silencing. Neoplasia (New York, N.Y.) 73 15967108
2005 Sak/Plk4 and mitotic fidelity. Oncogene 72 15640847
2012 GCP6 is a substrate of Plk4 and required for centriole duplication. Journal of cell science 69 22302995
2015 PLK4 trans-Autoactivation Controls Centriole Biogenesis in Space. Developmental cell 67 26481051
2016 CDK1 Prevents Unscheduled PLK4-STIL Complex Assembly in Centriole Biogenesis. Current biology : CB 62 27112295
2013 SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress. Nature communications 62 23653187
2016 Expression of Polo-Like Kinase 4(PLK4) in Breast Cancer and Its Response to Taxane-Based Neoadjuvant Chemotherapy. Journal of Cancer 61 27326256
1996 Constitutive expression of murine Sak-a suppresses cell growth and induces multinucleation. Molecular and cellular biology 61 8756623
2019 PLK4: a promising target for cancer therapy. Journal of cancer research and clinical oncology 60 31492983
2017 PLK4: a link between centriole biogenesis and cancer. Expert opinion on therapeutic targets 59 29171762
2013 The discovery of PLK4 inhibitors: (E)-3-((1H-Indazol-6-yl)methylene)indolin-2-ones as novel antiproliferative agents. Journal of medicinal chemistry 57 23829549
2015 The E3 ubiquitin ligase Mib1 regulates Plk4 and centriole biogenesis. Journal of cell science 56 25795303
2013 Spindle formation in the mouse embryo requires Plk4 in the absence of centrioles. Developmental cell 54 24268700
2008 The conserved protein SZY-20 opposes the Plk4-related kinase ZYG-1 to limit centrosome size. Developmental cell 54 19081077
2018 PLK4 is a determinant of temozolomide sensitivity through phosphorylation of IKBKE in glioblastoma. Cancer letters 53 30529153
2018 YLT-11, a novel PLK4 inhibitor, inhibits human breast cancer growth via inducing maladjusted centriole duplication and mitotic defect. Cell death & disease 51 30337519
2016 A non-canonical function of Plk4 in centriolar satellite integrity and ciliogenesis through PCM1 phosphorylation. EMBO reports 51 26755742
2014 PLK4 overexpression and its effect on centrosome regulation and chromosome stability in human gastric cancer. Molecular biology reports 51 24981932
2021 Polo-Like Kinase 4's Critical Role in Cancer Development and Strategies for Plk4-Targeted Therapy. Frontiers in oncology 48 33777739
2018 High PLK4 expression promotes tumor progression and induces epithelial‑mesenchymal transition by regulating the Wnt/β‑catenin signaling pathway in colorectal cancer. International journal of oncology 48 30570110
2014 A novel role for Plk4 in regulating cell spreading and motility. Oncogene 48 25174401
2020 SNHG16 promotes tumorigenesis and cisplatin resistance by regulating miR-338-3p/PLK4 pathway in neuroblastoma cells. Cancer cell international 47 32536824
2012 CAND1 promotes PLK4-mediated centriole overduplication and is frequently disrupted in prostate cancer. Neoplasia (New York, N.Y.) 47 23019411
2018 Bimodal Binding of STIL to Plk4 Controls Proper Centriole Copy Number. Cell reports 42 29898389
2015 A PLK4 mutation causing azoospermia in a man with Sertoli cell-only syndrome. Andrology 42 26452337
2018 An ordered pattern of Ana2 phosphorylation by Plk4 is required for centriole assembly. The Journal of cell biology 40 29496738
2018 Direct binding of CEP85 to STIL ensures robust PLK4 activation and efficient centriole assembly. Nature communications 38 29712910
2018 PLK4 is a microtubule-associated protein that self-assembles promoting de novo MTOC formation. Journal of cell science 38 30237222
2017 DNA replication licensing factor Cdc6 and Plk4 kinase antagonistically regulate centrosome duplication via Sas-6. Nature communications 37 28447620
2003 Clinical development of PEGylated recombinant staphylokinase (PEG-Sak) for bolus thrombolytic treatment of patients with acute myocardial infarction. Advanced drug delivery reviews 37 14499711
2023 Inhibition of PLK4 remodels histone methylation and activates the immune response via the cGAS-STING pathway in TP53-mutated AML. Blood 36 37738460
2019 Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer. International journal of molecular sciences 36 31035676
2001 Sak serine-threonine kinase acts as an effector of Tec tyrosine kinase. The Journal of biological chemistry 36 11489907
2018 Autoamplification and Competition Drive Symmetry Breaking: Initiation of Centriole Duplication by the PLK4-STIL Network. iScience 34 30340068
2019 POLQ Overexpression Is Associated with an Increased Somatic Mutation Load and PLK4 Overexpression in Lung Adenocarcinoma. Cancers 32 31137743
2020 FAM46C/TENT5C functions as a tumor suppressor through inhibition of Plk4 activity. Communications biology 30 32807875
2010 Control of mitotic and meiotic centriole duplication by the Plk4-related kinase ZYG-1. Journal of cell science 30 20144993
2021 Role of Polo-Like Kinase 4 (PLK4) in Epithelial Cancers and Recent Progress in its Small Molecule Targeting for Cancer Management. Molecular cancer therapeutics 29 33402398
2017 Inhibition of polo-like kinase 4 (PLK4): a new therapeutic option for rhabdoid tumors and pediatric medulloblastoma. Oncotarget 29 29340047
2018 Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB). Bioengineering (Basel, Switzerland) 26 30400339
2022 PLK4 is upregulated in prostate cancer and its inhibition reduces centrosome amplification and causes senescence. The Prostate 25 35333404
1981 Physiochemical and immunochemical characterization of gamma-glutamyl transpeptidase from yolk sak tumor and ascitic hepatoma (AH-66) cells. Oncodevelopmental biology and medicine : the journal of the International Society for Oncodevelopmental Biology and Medicine 25 6117836
2022 PLK4 drives centriole amplification and apical surface area expansion in multiciliated cells. eLife 24 35969030
2019 Plk4 Regulates Centriole Asymmetry and Spindle Orientation in Neural Stem Cells. Developmental cell 24 31130353
2023 Autophagy Inhibition Contributes to Apoptosis of PLK4 Downregulation-induced Dormant Cells in Colorectal Cancer. International journal of biological sciences 23 37324947
2020 Inhibition of PLK4 might enhance the anti-tumour effect of bortezomib on glioblastoma via PTEN/PI3K/AKT/mTOR signalling pathway. Journal of cellular and molecular medicine 23 32126150
2020 PLK1- and PLK4-Mediated Asymmetric Mitotic Centrosome Size and Positioning in the Early Zebrafish Embryo. Current biology : CB 23 32916112
2017 Analysis of centrosome and DNA damage response in PLK4 associated Seckel syndrome. European journal of human genetics : EJHG 23 28832566
2016 Cep78 is a new centriolar protein involved in Plk4-induced centriole overduplication. Journal of cell science 23 27246242
2021 TEC kinase stabilizes PLK4 to promote liver cancer metastasis. Cancer letters 22 34637843
2020 A novel lncRNA PLK4 up-regulated by talazoparib represses hepatocellular carcinoma progression by promoting YAP-mediated cell senescence. Journal of cellular and molecular medicine 22 32243714
2020 Use of the Polo-like kinase 4 (PLK4) inhibitor centrinone to investigate intracellular signalling networks using SILAC-based phosphoproteomics. The Biochemical journal 22 32501498
2006 Determination of the Plk4/Sak consensus phosphorylation motif using peptide spots arrays. FEBS letters 22 17174311
2021 Plk4 triggers autonomous de novo centriole biogenesis and maturation. The Journal of cell biology 20 33760919
2020 MiR-654-3p Suppresses Non-Small Cell Lung Cancer Tumourigenesis by Inhibiting PLK4. OncoTargets and therapy 20 32884289
2017 PLK4 phosphorylation of CP110 is required for efficient centriole assembly. Cell cycle (Georgetown, Tex.) 20 28562169
2022 Role of Polo-like Kinases Plk1 and Plk4 in the Initiation of Centriole Duplication-Impact on Cancer. Cells 19 35269408
2022 Fraxetin down-regulates polo-like kinase 4 (PLK4) to inhibit proliferation, migration and invasion of prostate cancer cells through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. Bioengineered 19 35387563
2019 Acto-myosin force organization modulates centriole separation and PLK4 recruitment to ensure centriole fidelity. Nature communications 19 30604763
2000 Role of the N-terminal region of staphylokinase (SAK): evidence for the participation of the N-terminal region of SAK in the enzyme-substrate complex formation. FEBS letters 19 10838076
1996 Sak 57, an intermediate filament keratin present in intercellular bridges of rat primary spermatocytes. Molecular reproduction and development 19 8873075
2022 Design, synthesis, and biological evaluation of novel pyrazolo [3,4-d]pyrimidine derivatives as potent PLK4 inhibitors for the treatment of TRIM37-amplified breast cancer. European journal of medicinal chemistry 18 35576702
2009 Deciphering the function of lactococcal phage ul36 Sak domains. Journal of structural biology 18 20036743
2023 Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype. Cell death & disease 17 36797240
2022 PLK4 is a key molecule in the formation of PGCCs and promotes invasion and migration of progeny cells derived from PGCCs. Journal of Cancer 17 35912011
2022 Centrosomal protein 120 promotes centrosome amplification and gastric cancer progression via USP54-mediated deubiquitination of PLK4. iScience 17 36590171
2021 Down-regulation of Polo-like kinase 4 (PLK4) induces G1 arrest via activation of the p38/p53/p21 signaling pathway in bladder cancer. FEBS open bio 17 34342940

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