KIF18B

KIF18B is a kinesin-8 family plus end-directed motor that controls microtubule dynamics during mitosis by promoting microtubule catastrophe, principally at astral microtubules where it sets spindle position and centering (PMID:29661912, PMID:27559136). It is a highly processive motor that accumulates at growing microtubule plus ends through a C-terminal non-motor microtubule-binding region whose plus-end targeting is governed by direct interaction with the end-binding protein EB1; EB1 knockdown abolishes KIF18B plus-end tracking and KIF18B loss yields excessive, lengthened astral microtubules and spindle defects (PMID:21737685, PMID:29661912). Its depolymerizing output is delivered through a cooperative network with the kinesin-13 MCAK and EB3: KIF18B transports MCAK and EB3 to plus ends via multivalent weak interactions, enabling potent microtubule shortening at low concentrations, with Aurora kinase phosphorylation of MCAK negatively regulating this complex (PMID:21820309, PMID:35502670). This activity is spatially tuned by phosphorylation of the KIF18B C-terminus and by importin α/β, which increase its microtubule lattice on-rate and decrease its off-rate to stimulate destabilization, a regulatory input distinct from that of EB1 (PMID:29661912, PMID:36790918). Through astral microtubule destabilization KIF18B promotes bipolar spindle assembly and, by accumulating at the cell cortex with the LGN/NuMA/dynein-dynactin machinery, directs oriented cell division in vivo (PMID:27354041, PMID:34432485). KIF18B has a separable interphase role: it is constitutively chromatin-bound and, through a central Tudor-interacting motif that binds the 53BP1 Tudor domain and enhances its recognition of H4K20me2, is required—together with its motor function—for 53BP1 focal recruitment to DNA double-strand breaks and telomere fusion (PMID:34192545). In cancer contexts KIF18B is reported to support proliferation, glycolysis, and chemoresistance through transcriptional and signaling effects, but these activities are heterogeneous across the corpus and not yet mechanistically unified (PMID:37190875, PMID:41751942).

1. 2010 Medium

   Established KIF18B as a cell-cycle-regulated, predominantly nuclear interphase protein that associates with astral microtubules in mitosis, defining when and where it acts.

   Evidence Western blotting across the cell cycle, immunocytochemistry, and EGFP-deletion NLS mapping

   PMID:20600703

   Open questions at the time

   • No molecular activity assigned at this stage
   • Mechanism of astral MT association not defined
2. 2011 High

   Resolved how KIF18B reaches microtubule plus ends and what it does there, identifying the EB1 interaction via the C-terminal domain and a depolymerizing/destabilizing role on astral microtubules.

   Evidence Yeast two-hybrid, in vitro C-terminal binding assay, immunofluorescence, and siRNA knockdown phenotypes; reciprocal MCAK Co-IP and Aurora inhibition in a parallel study

   PMID:21737685 PMID:21820309

   Open questions at the time

   • Did not reconstitute the motor activity in vitro
   • Quantitative contribution of MCAK vs KIF18B to depolymerization unresolved
3. 2016 Medium

   Showed that KIF18B-driven astral MT destabilization is spatially biased and functionally required for bipolar spindle assembly and centrosome separation.

   Evidence Genome-wide siRNA screen in Eg5-independent cells and spatial EB1 plus-end tracking of MT dynamics in knockdown cells

   PMID:27354041 PMID:27559136

   Open questions at the time

   • Molecular basis of spatial bias toward cortex-directed MTs not defined
   • Single-lab phenotypes
4. 2018 High

   Established KIF18B as a highly processive motor that increases catastrophe rate, with its C-terminal MT-binding region phosphoregulated to control plus-end accumulation, directly linking motor activity to spindle centering.

   Evidence In vitro reconstitution of single-molecule motility, dynamic MT catastrophe assays, phospho-mimetic mutants, and knockout with spindle positioning readout

   PMID:29661912

   Open questions at the time

   • Identity of the kinase(s) acting on the C-terminus not defined here
   • How catastrophe induction couples to centering forces not fully resolved
5. 2021 High

   Uncovered a mitosis-independent interphase function: KIF18B promotes 53BP1 recruitment to DSBs and telomere fusion via a Tudor-interacting motif that augments 53BP1 binding to H4K20me2.

   Evidence Reciprocal Co-IP, TIM and motor-domain mutagenesis, γH2AX/53BP1 focus assays, and telomere fusion assay

   PMID:34192545

   Open questions at the time

   • Why a microtubule motor function is needed for nuclear DSB repair is unexplained
   • No structure of the TIM–Tudor interaction
6. 2021 Medium

   Connected KIF18B's MT-depolymerizing activity to tissue-level outcomes by showing it localizes to the mitotic cortex with the LGN/NuMA/dynein-dynactin machinery and is required for oriented division and correct cell fate in vivo.

   Evidence Mouse epidermal genetic KO, colocalization with spindle orientation machinery, and cell fate marker analysis

   PMID:34432485

   Open questions at the time

   • Direct biochemical link between KIF18B and the LGN/NuMA complex not established
   • Whether cortical accumulation is depolymerization-dependent unresolved
7. 2022 High

   Reconstituted the depolymerization mechanism, demonstrating that KIF18B transports EB3 and MCAK to plus ends through multivalent weak interactions to drive potent MT shortening at low concentrations.

   Evidence In vitro reconstitution with purified proteins, single-molecule and TIRF imaging

   PMID:35502670

   Open questions at the time

   • Stoichiometry of the KIF18B–EB3–MCAK assembly in cells not defined
   • Cooperativity with phosphoregulation not integrated
8. 2023 High

   Distinguished two regulatory inputs to KIF18B MT binding, showing importin α/β raise lattice affinity (on-rate up, off-rate down) to stimulate destabilization while EB1 promotes destabilization without increasing lattice binding.

   Evidence In vitro MT binding/motility kinetics with purified importins, residue-specific mutagenesis, and cellular localization/monopolar spindle assays

   PMID:36790918

   Open questions at the time

   • How the RanGTP gradient spatially patterns importin regulation in cells not directly shown
   • Crosstalk between importin and phospho-regulation unresolved
9. 2023 Medium

   Linked KIF18B to the mitotic surveillance/p53 pathway, showing its loss blunts vincristine-induced p53 response and confers resistance in lymphoma cells.

   Evidence Genome-wide CRISPR screen and CRISPR/Cas9 KO in two DLBCL cell lines with p53 pathway readout

   PMID:37190875

   Open questions at the time

   • Whether the effect depends on the 53BP1 interaction or motor activity not dissected
   • Mechanism connecting KIF18B to USP28-53BP1-p53 not directly tested
10. 2026 Medium

    Reported additional cancer-context roles placing KIF18B upstream of E2F transcriptional activity, with weaker evidence for Skp2 stabilization/glycolysis, ATR/CHK1 signaling, and other transcriptional effects.

    Evidence Knockdown transcriptomics with luciferase E2F reporter and E2F rescue; ubiquitination/glycolysis assays; Co-IP with ATR/APC/SP1 and promoter analyses

    PMID:31875977 PMID:32587775 PMID:34508743 PMID:41751942 PMID:41977416 PMID:42201394

    Open questions at the time

    • Several rest on single Co-IPs without reciprocal validation
    • Relationship to the established mitotic/DSB functions not reconciled
    • Largely abstract-level mechanistic detail

• How KIF18B's spatially restricted depolymerizing activity, its phospho/importin/EB1 regulatory inputs, and its nuclear 53BP1-dependent DSB role are coordinated within one protein remains unresolved.
• No structural model integrating motor, EB-binding, and TIM regions
• Kinase(s) controlling the C-terminus not identified in the corpus
• Mechanistic basis for diverse cancer phenotypes not unified