{"gene":"KIF13B","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2000,"finding":"GAKIN (KIF13B) binds directly to the guanylate kinase-like (GUK) domain of hDlg (DLG1) and PSD-95, but not p55, among MAGUK family proteins. The interaction was identified by affinity protein purification and peptide sequencing. KIF13B contains a motor domain at the NH2 terminus, a central stalk domain, and a CAP-Gly domain at the COOH terminus. In resting T lymphocytes both proteins are cytoplasmic; upon CD2 receptor cross-linking, hDlg translocates to the lymphocyte cap.","method":"Affinity protein purification, peptide sequencing, cDNA cloning, GST pulldown, immunolocalization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pulldown plus localization, single lab but multiple orthogonal methods","pmids":["10859302"],"is_preprint":false},{"year":2005,"finding":"KIF13B directly interacts with centaurin-alpha1 (an ARF6 GAP and PIP3-binding protein); the interaction is mediated by the GAP domain of centaurin-alpha1 and the stalk domain of KIF13B. KIF13B binding suppresses the ARF6 GAP activity of centaurin-alpha1 in intact cells, and both proteins colocalize at cell-periphery leading edges; a deletion mutant of centaurin-alpha1 lacking the KIF13B-binding site fails to colocalize.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, ARF6 GAP activity assay, immunofluorescence","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Y2H, pulldown, Co-IP, functional assay), single lab","pmids":["15923660"],"is_preprint":false},{"year":2006,"finding":"KIF13B (GAKIN) directly interacts with PIP3BP (a PIP3-interacting protein) and, together with PIP3BP, assembles onto PIP3-containing liposomes and drives their motility along microtubules in vitro. In PC12 cells and hippocampal neurons, KIF13B transport activity promotes PIP3 accumulation at neurite tips; overexpression of KIF13B constructs that alter PIP3 distribution causes loss of axonally differentiated neurites, indicating KIF13B-PIP3BP complex is required for neuronal polarity formation.","method":"In vitro liposome motility assay, co-immunoprecipitation, overexpression/dominant-negative in PC12 cells and hippocampal neurons, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of motor-cargo complex on liposomes plus neuronal functional readouts, multiple orthogonal approaches","pmids":["16864656"],"is_preprint":false},{"year":2007,"finding":"KIF13B (GAKIN) exists in an autoinhibited conformation in solution—it shows potent microtubule gliding activity but minimal microtubule-stimulated ATPase activity. Intramolecular interaction between the MAGUK binding stalk (MBS) domain and the motor domain confers this globular autoinhibited state. Direct binding of the SH3-I3-GUK module of hDlg to the MBS domain of KIF13B activates microtubule-stimulated ATPase activity ~10-fold, demonstrating cargo-mediated relief of autoinhibition.","method":"Microtubule gliding assay, ATPase assay, in vitro binding (pull-down), domain-deletion analysis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with enzymatic assay and domain mutagenesis, rigorous mechanistic dissection","pmids":["17696365"],"is_preprint":false},{"year":2010,"finding":"Par1b/MARK2 phosphorylates KIF13B and is identified as a KIF13B-binding protein. KIF13B accumulates at the distal microtubule tips in axons but not dendrites. Overexpression of KIF13B induces extra axon formation; co-expression of Par1b kinase suppresses this in a kinase-activity-dependent manner. KIF13B siRNA knockdown retards neurite extension and causes an axonless phenotype. The extra-axon phenotype of Par1b siRNA is rescued by KIF13B siRNA, placing KIF13B downstream of Par1b. KIF13B also acts downstream of PI3K signaling via Par1b phosphorylation.","method":"Co-immunoprecipitation, kinase assay, siRNA knockdown, overexpression, epistasis in hippocampal neurons","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis experiments, kinase assay, reciprocal knockdown rescue, multiple orthogonal approaches","pmids":["20194617"],"is_preprint":false},{"year":2010,"finding":"KIF13B (GAKIN) negatively regulates TCR signaling to NF-κB by associating with the scaffold protein CARD11 in a signal-dependent manner and competing with Bcl10 for CARD11 binding. KIF13B dynamically localizes to the immunological synapse and regulates redistribution of CARD11 from the central synapse region to a distal region.","method":"Expression-cloning screen, co-immunoprecipitation, NF-κB reporter assay, immunofluorescence live-cell imaging at immunological synapse","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional screen with Co-IP and signaling assay and localization, single lab","pmids":["21145487"],"is_preprint":false},{"year":2010,"finding":"Xenopus KIF13B (xKIF13B) is required for primordial germ cell (PGC) migration; knockdown inhibits bleb formation and PIP3 accumulation at PGC blebs, causing PGC mismigration in vivo and in vitro. Interference with PIP3 synthesis similarly causes PGC mismigration, linking KIF13B function to polarized PIP3 accumulation for directional cell migration.","method":"Morpholino knockdown in Xenopus embryos, PIP3 imaging, PGC migration assay in vivo and explant","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD with defined cellular phenotype and PIP3 mechanistic link, single lab/organism","pmids":["21029731"],"is_preprint":false},{"year":2012,"finding":"KIF13B transports TRPV1-containing vesicles to the cell surface via its FHA domain. Cdk5 phosphorylates KIF13B at Thr-506 within the FHA domain to promote motor-cargo association; T506A mutation reduces KIF13B-TRPV1 interaction. Cdk5/p35 overexpression promotes and Cdk5 inhibition prevents KIF13B-TRPV1 association. CFA-induced Cdk5 activation increases TRPV1 anterograde transport, contributing to heat hyperalgesia; a cell-permeable TAT-T506 peptide decreases TRPV1 surface localization and alleviates CFA-induced heat hyperalgesia.","method":"Co-immunoprecipitation, kinase assay (Cdk5 phosphorylation of KIF13B), site-directed mutagenesis (T506A), surface biotinylation, TAT peptide delivery in vivo, behavioral pain assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Strong — kinase assay with mutagenesis, multiple functional readouts in vitro and in vivo, mechanistic rescue experiments","pmids":["23077056"],"is_preprint":false},{"year":2014,"finding":"KIF13B enhances caveolin-dependent endocytosis of LRP1 by acting as a scaffold that recruits LRP1 to caveolae via an LRP1–hDLG1–KIF13B–utrophin–caveolae linkage. KIF13B KO mice show elevated serum cholesterol and factor VIII; KO MEFs show decreased LDL uptake. Exogenous KIF13B localizes on the plasma membrane with caveolae and translocates to cytoplasmic vesicles with LRP1 and caveolin-1.","method":"KIF13B knockout mice, co-immunoprecipitation, serum/endocytosis assays in MEFs, live-cell imaging/trafficking","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined phenotype, Co-IP of multi-protein complex, trafficking assay, multiple orthogonal methods","pmids":["24469637"],"is_preprint":false},{"year":2014,"finding":"KIF13B directly interacts with VEGFR2 and mediates its transport from the Golgi to the endothelial cell surface. KIF13B depletion diverts VEGFR2 to lysosomal degradation, prevents VEGF-induced endothelial migration and capillary tube formation, and blocks neovascularization in mice.","method":"Co-immunoprecipitation, KIF13B knockdown, truncation/dominant-negative overexpression, in vitro tube formation assay, in vivo Matrigel plug/neovascularization assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, KD with defined trafficking and functional phenotypes, in vivo model, multiple orthogonal approaches","pmids":["25128562"],"is_preprint":false},{"year":2016,"finding":"KIF13B regulates PNS and CNS myelination through the DLG1 scaffold. In Schwann cells, KIF13B promotes myelination by driving p38γ MAPK-mediated phosphorylation and ubiquitination of DLG1, which downregulates PI3K/AKT signaling (DLG1 is a brake on myelination). In oligodendrocytes, KIF13B negatively regulates myelination by destabilizing DLG1, which in that context enhances AKT activation.","method":"Kif13b conditional knockout mice, co-immunoprecipitation, phosphorylation/ubiquitination assays, myelin analysis in PNS/CNS","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO models with defined phenotypes in two cell types, biochemical pathway dissection, multiple orthogonal methods","pmids":["27070899"],"is_preprint":false},{"year":2016,"finding":"The crystal structure of DLG4 GK domain in complex with the KIF13B MBS (MAGUK binding stalk) domain reveals an atypical MAGUK GK target recognition mode in which the GK domain binds an unphosphorylated, autonomously folded domain (MBS) rather than a phosphopeptide. This structural insight explains the molecular basis of DLG/KIF13B complex formation and autoinhibition relief.","method":"X-ray crystallography, in vitro binding measurements, mutagenesis","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional binding validation and mutagenesis","pmids":["27642159"],"is_preprint":false},{"year":2017,"finding":"KIF13B is a novel member of the RPGRIP1N-C2 domain family and is recruited to the ciliary base by NPHP4, which binds two distinct sites in the KIF13B tail including an RPGRIP1N-C2 domain. KIF13B and NPHP4 are both required for establishing a CAV1-enriched membrane microdomain at the transition zone, which is necessary for Shh-induced ciliary SMO accumulation.","method":"Co-immunoprecipitation, domain mapping, siRNA knockdown, immunofluorescence, SMO accumulation assay, ciliogenesis analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain binding mapping, KD of both components, functional SMO/Shh readout, multiple orthogonal methods","pmids":["28134340"],"is_preprint":false},{"year":2018,"finding":"Drosophila KIF13B ortholog Khc-73 (a plus-end kinesin) regulates sorting of endosomes in larval motor neurons. Loss of Khc-73 impairs retrograde BMP signaling: activated BMP transcription factor Mad nuclear accumulation is reduced, and retrograde-bound endosomes fail to leave the synapse and join the retrograde axonal pathway. Genetic enhancement/suppression with BMP pathway components places Khc-73 in the BMP retrograde signaling pathway.","method":"Drosophila genetics (mutant analysis, epistasis), live imaging of endosomes in motor neurons, pMad immunostaining, electrophysiology","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with genetic pathway placement, live imaging, single organism (Drosophila ortholog)","pmids":["29373576"],"is_preprint":false},{"year":2019,"finding":"Rab10 interacts with KIF13B (and KIF13A) and is required for tubular endosome formation; Rab10 knockout abolishes tubular endosomal structures in HeLaM cells. KIF13B was identified as a Rab10-interacting protein by in silico screening and validated experimentally, and both the Rab10-binding homology domain and the motor domain of KIF13A are required for Rab10-positive tubular endosome formation.","method":"Rab GTPase localization screen, Rab10 knockout (CRISPR), co-immunoprecipitation, domain-deletion analysis, fluorescence microscopy","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO phenotype, Co-IP, domain analysis; some mechanistic detail from KIF13A but KIF13B validated as Rab10 interactor","pmids":["30700496"],"is_preprint":false},{"year":2019,"finding":"The cytoplasmic domain of LRP1 interacts specifically with the alternatively spliced I3 domain of DLG1, which in turn complexes with KIF13B via GUK-MBS domain interaction. The CAP-Gly domain of KIF13B is required for proper subcellular localization of KIF13B and LRP1; mice expressing KIF13B lacking the CAP-Gly domain (KIF13BΔCG) show higher serum cholesterol and reduced LDL uptake. KIF13A null mice show no such cholesterol or factor VIII elevation.","method":"Mouse knockout/truncation models, co-immunoprecipitation, domain-binding assays, serum/endocytosis assays, immunolocalization","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse models (truncation + KO), biochemical domain mapping, functional metabolic phenotype, multiple orthogonal methods","pmids":["31487503"],"is_preprint":false},{"year":2020,"finding":"KIF13B and KIF5B cooperate to transport Rab6-positive secretory vesicles from the Golgi to the cell periphery. KIF13B assists Rab6 vesicles in reaching freshly polymerized microtubule plus ends (where KIF5B binds poorly due to slow MAP7 population). Sub-pixel localization showed both kinesins localize to the vesicle front during plus-end directed transport; upon reversal, KIF13B relocates to the middle while KIF5B shifts to the back, suggesting KIF5B (not KIF13B) undergoes tug-of-war with minus-end motors.","method":"siRNA knockdown, live-cell imaging (TIRF), sub-pixel localization microscopy, kymograph analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — sub-pixel co-localization with multiple kinesins on single vesicles, KD phenotype, multiple orthogonal approaches in single rigorous study","pmids":["33174839"],"is_preprint":false},{"year":2020,"finding":"Netrin-1 induces KIF13B interaction with Myosin X (Myo X); KIF13B mediates anterograde transport of Myo X into axons, which is required for Netrin-1-DCC-regulated axon initiation and contralateral branching in developing mouse neocortex. KIF13B KD results in axon initiation deficits similar to those seen with Myo X KO/KD and Netrin-1 KO.","method":"Proteomic analysis of Myo X binding proteins, co-immunoprecipitation, KIF13B knockdown in embryonic cortical neurons, axon morphology analysis in vivo","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex, KD phenotype in vivo, epistasis; single lab","pmids":["33097641"],"is_preprint":false},{"year":2021,"finding":"EC-specific KIF13B knockout mice demonstrate that endothelial KIF13B is required for VEGF-A-induced vascular leakage, angiogenesis, tumor growth, and cancer metastasis in vivo, confirming KIF13B-mediated VEGFR2 trafficking to the endothelial surface as an essential step in pathological VEGF-A signaling.","method":"Endothelial cell-specific Kif13b conditional knockout mice, VEGF-A vascular leakage assays, tumor growth/metastasis models","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic KO with multiple defined in vivo phenotypes, replicates prior mechanistic findings","pmids":["34670814"],"is_preprint":false},{"year":2022,"finding":"KIF13B undergoes bursts of bidirectional motor-driven movement within primary cilia of human RPE1 cells, with anterograde and retrograde velocities similar to IFT. Intraciliary movement requires KIF13B's own motor domain and appears cell-type specific, representing the first demonstration of intraciliary motor-driven movement by a vertebrate kinesin-3.","method":"Live-cell imaging (TIRF/fluorescence), KIF13B-eGFP constructs including motor-domain mutants, velocity analysis compared to IFT172-eGFP","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with motor-domain mutant, single lab, first demonstration in vertebrate cilia","pmids":["35403186"],"is_preprint":false},{"year":2022,"finding":"Angiomotin isoform 2 (Ap80) is a novel KIF13B interactor that promotes binding of the MAGUK PALS1 to KIF13B. Ap80 concentrates at the ciliary base and recruits PALS1 there. Ap80 depletion leads to elongated primary cilia and reduced SMO ciliary accumulation; Ap80 overexpression causes ciliary shortening, indicating Ap80 activates KIF13B cargo binding at the ciliary base to regulate ciliary length and Hedgehog signaling.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, live-cell imaging, ciliary SMO accumulation assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KD/OE with functional ciliary phenotypes, single lab","pmids":["35673984"],"is_preprint":false},{"year":2023,"finding":"KIF13B mediates recycling of internalized VEGFR2 through Rab11-positive recycling vesicles back to the cell surface. After VEGF stimulation, phosphorylated VEGFR2 at cell-cell junctions is internalized into Rab5-positive early endosomes where it associates with KIF13B. Inhibition of KIF13B attenuates phosphorylation of VEGFR2-Y951, SRC-Y416, and VE-cadherin-Y685 and diverts VEGFR2 to lysosomal degradation.","method":"Co-immunoprecipitation, Rab5/Rab11 vesicle trafficking assays, phospho-specific immunoblotting, KIF13B inhibition (dominant-negative/peptide), live-cell trafficking imaging","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with endosomal markers, signaling readouts, single lab","pmids":["36928770"],"is_preprint":false},{"year":2024,"finding":"KIF13B is recruited to polarized vesicles at the trans-Golgi network through interaction with the heterotetrameric adaptor protein complex AP-1. In hippocampal neurons, KIF13B mediates both dendrite- and axon-selective transport; interference with KIF13B binding to AP-1 disrupts both transport modes.","method":"Live-cell imaging in hippocampal neurons, AP-1 binding domain interference (dominant-negative), KIF13B-fluorescent fusions, kymograph analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with domain-interference approach, single lab, functional polarized transport readout","pmids":["38446634"],"is_preprint":false},{"year":2025,"finding":"KIF13B interacts with AMPKα1 and regulates its phosphorylation, governing mitochondrial homeostasis and suppressing SREBP1-mediated de novo lipogenesis in the liver. Kif13b deficiency increases hepatic lipid synthesis and impairs mitochondrial oxidative phosphorylation; liver-specific Kif13b knockout causes spontaneous hepatic steatosis.","method":"Co-immunoprecipitation, Kif13b whole-body and liver-specific knockout mice, phosphorylation assays, lipid synthesis assays, mitochondrial function assays","journal":"Military Medical Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with AMPKα1, genetic KO models with defined metabolic phenotype, single lab","pmids":["40038775"],"is_preprint":false},{"year":2025,"finding":"In macrophages, KIF13B maintains MERTK expression by enhancing its deubiquitination through interaction with the deubiquitinase USP9X; loss of KIF13B decreases ITCH expression and leads to accelerated CBL-mediated ubiquitination and degradation of MERTK, impairing macrophage efferocytosis and promoting atherosclerosis.","method":"Co-immunoprecipitation (KIF13B-USP9X), Kif13b macrophage-specific knockout mice, MERTK ubiquitination assays, bone marrow transplantation, efferocytosis assays","journal":"European heart journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KO models with pathway placement, ubiquitination assay; single lab","pmids":["40709729"],"is_preprint":false},{"year":2025,"finding":"KIF13B regulates ciliary protein composition and extracellular vesicle (EV) shedding from cilia. KIF13B knockout causes aberrant accumulation of polycystin-2 (PC2) within cilia, increased release of large EVs enriched with CCDC198 and CCDC92, and altered small EV composition. KIF13B acts at centriole distal appendages to limit ciliary protein entry and promote endocytic retrieval downstream of the BBSome, suppressing EV release from cilia.","method":"Kif13b knockout cells, super-resolution microscopy, EV characterization (proteomics), live imaging, PC2 and BBSome localization analysis","journal":"Current biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with proteomic EV characterization and localization analysis, single lab","pmids":["40930094"],"is_preprint":false},{"year":2025,"finding":"In vascular smooth muscle cells (VSMCs), KIF13B facilitates ubiquitination and proteasomal degradation of KLF4 through a KCTD10-dependent pathway. VSMC-specific Kif13b deletion exacerbates atherosclerotic lesion development and impairs plaque stability; adverse effects were rescued by the KLF4 inhibitor Kenpaullone.","method":"VSMC-specific Kif13b KO mice (PCSK9 AAV model), Co-immunoprecipitation (KIF13B-KCTD10), KLF4 ubiquitination/degradation assays, pharmacological rescue","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, cell-type-specific genetic KO, pharmacological rescue; single lab","pmids":["41609725"],"is_preprint":false},{"year":2025,"finding":"KIF13B stabilizes PLIN5 by preventing its lysosomal degradation; loss of KIF13B impairs mitochondrial localization of PLIN5, disrupting cardiac lipid homeostasis and mitochondrial function in sepsis-induced cardiac dysfunction. AAV9-PLIN5 gene therapy rescues cardiac dysfunction in Kif13b KO mice.","method":"Kif13b global KO mice, cardiomyocyte PLIN5 localization assays, lysosomal degradation assays, AAV9-PLIN5 rescue, cardiac function measurements","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO, mechanistic rescue (AAV gene therapy), protein stability assay; single lab","pmids":["41531892"],"is_preprint":false},{"year":2025,"finding":"KIF13B is enriched at photoreceptor synaptic ribbons in addition to the primary photoreceptor cilium. This synaptic localization requires intact synaptic ribbon structure, as shown by loss of KIF13B enrichment at ribbons in RIBEYE knockout mice.","method":"Confocal microscopy, super-resolution SIM, immunogold electron microscopy, RIBEYE KO mice","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple imaging modalities with genetic validation (RIBEYE KO), single lab","pmids":["40649824"],"is_preprint":false},{"year":2026,"finding":"In macrophages, KIF13B loss impairs proteasome-dependent degradation of the glycosyltransferase STT3A, enhancing cathepsin D (CTSD) glycosylation and secretion, which promotes lipid accumulation and inflammatory responses in liver cells via CTSD interaction with hepatocyte THBS1. Transcription factor ZNF384 is identified as an upstream regulator that binds the KIF13B promoter to activate its transcription.","method":"Myeloid-specific Kif13b KO mice, STT3A proteasome degradation assay, CTSD glycosylation/secretion assay, Co-IP (CTSD-THBS1), ZNF384 ChIP/promoter binding assay","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO, biochemical pathway dissection (glycosylation, Co-IP), ChIP; single lab","pmids":["41746601"],"is_preprint":false}],"current_model":"KIF13B is a kinesin-3 family plus-end microtubule motor that exists in a cargo-regulated autoinhibited state (via intramolecular MBS-motor domain interaction) and is activated upon direct binding of DLG1/hDlg (via GUK-MBS interaction); it transports diverse cargos—including PIP3-containing vesicles, VEGFR2, TRPV1, Myosin X, and LRP1—to the cell periphery, with motor-cargo coupling regulated by phosphorylation (Cdk5 at Thr-506; Par1b/MARK2), and it also performs unconventional non-motor scaffold/signaling functions including regulation of ciliary composition and Hedgehog signaling (via NPHP4), myelination (via DLG1-p38γ-AKT), immune synapse organization (via CARD11), and metabolic homeostasis (via AMPKα1, PLIN5, and ubiquitin pathway components)."},"narrative":{"mechanistic_narrative":"KIF13B (GAKIN/Khc-73) is a kinesin-3 plus-end-directed microtubule motor that delivers diverse cargos to the cell periphery and operates under cargo-gated autoinhibition [PMID:17696365, PMID:16864656]. In solution the motor adopts a globular autoinhibited conformation maintained by an intramolecular interaction between its MAGUK-binding stalk (MBS) and the motor domain; direct binding of the SH3-I3-GUK module of DLG1/hDlg to the MBS relieves this inhibition and activates microtubule-stimulated ATPase ~10-fold [PMID:17696365], a recognition mode in which the MAGUK GK domain engages the autonomously folded MBS rather than a phosphopeptide [PMID:27642159]. Through DLG1 and other adaptors, KIF13B transports a defined set of cargos: PIP3-containing vesicles to establish polarized PIP3 accumulation at neurite tips and migrating cells [PMID:16864656, PMID:21029731], VEGFR2 from the Golgi to the endothelial surface and through Rab5/Rab11 recycling, a step essential for VEGF-A-driven angiogenesis, vascular leakage, and tumor metastasis in vivo [PMID:25128562, PMID:34670814, PMID:36928770], TRPV1 vesicles to the cell surface [PMID:23077056], Myosin X into axons during Netrin-1-DCC-regulated axon initiation [PMID:33097641], and LRP1 to caveolae for cholesterol-regulating endocytosis [PMID:24469637, PMID:31487503]. Motor-cargo coupling is tuned by phosphorylation, including Cdk5 at Thr-506 in the FHA domain (promoting TRPV1 binding) and Par1b/MARK2, which acts downstream of PI3K to control axon specification [PMID:23077056, PMID:20194617]. Cargo recruitment is directed by adaptors at distinct membrane sites, including AP-1 at the trans-Golgi network for both axonal and dendritic transport [PMID:38446634] and Rab6/Rab10 for secretory and tubular endosomal carriers [PMID:33174839, PMID:30700496]. Beyond cargo transport, KIF13B performs scaffolding and signaling roles: it is recruited to the ciliary base by NPHP4 and by angiomotin/PALS1 to control a CAV1-enriched transition-zone microdomain, ciliary length, SMO accumulation, and Hedgehog signaling, and it limits ciliary protein entry and EV shedding downstream of the BBSome [PMID:28134340, PMID:35673984, PMID:40930094]; it regulates myelination via a DLG1-p38γ-AKT axis [PMID:27070899]; it antagonizes TCR-to-NF-κB signaling at the immune synapse by competing with Bcl10 for CARD11 [PMID:21145487]; and it governs metabolic and ubiquitin-pathway homeostasis through AMPKα1, PLIN5, and degradation of substrates including KLF4, MERTK, and STT3A in liver, heart, and vascular/macrophage contexts [PMID:40038775, PMID:41531892, PMID:41609725, PMID:40709729, PMID:41746601].","teleology":[{"year":2000,"claim":"Established KIF13B's defining molecular partnership by showing it binds the GUK domain of the MAGUK scaffolds hDlg/DLG1 and PSD-95, framing it as a motor coupled to scaffolding proteins.","evidence":"Affinity purification, peptide sequencing, GST pulldown and immunolocalization in T lymphocytes","pmids":["10859302"],"confidence":"Medium","gaps":["Did not establish what cargo the DLG1-KIF13B complex transports","No demonstration of motor regulation by the interaction"]},{"year":2005,"claim":"Connected KIF13B to peripheral PIP3/ARF6 signaling by identifying centaurin-alpha1 as a stalk-domain partner whose ARF6 GAP activity KIF13B suppresses at leading edges.","evidence":"Yeast two-hybrid, pulldown, Co-IP, ARF6 GAP assay and immunofluorescence","pmids":["15923660"],"confidence":"Medium","gaps":["Physiological consequence of GAP suppression not defined","Single-lab interaction"]},{"year":2006,"claim":"Demonstrated that KIF13B is a bona fide motor for PIP3-containing vesicles and required for neuronal polarity, reconstituting motor-cargo motility in vitro.","evidence":"In vitro liposome motility, Co-IP, dominant-negative perturbation in PC12 cells and hippocampal neurons","pmids":["16864656"],"confidence":"High","gaps":["PIP3BP identity and broader cargo repertoire not fully resolved","How motor engages PIP3 vesicles in vivo not detailed"]},{"year":2007,"claim":"Defined the autoinhibition mechanism, showing KIF13B is held in a globular inactive state by MBS-motor contact that DLG1 binding relieves, explaining cargo-gated motor activation.","evidence":"Microtubule gliding and ATPase assays with domain-deletion analysis","pmids":["17696365"],"confidence":"High","gaps":["Structural basis of MBS-motor contact not solved here","In-cell timing of activation not addressed"]},{"year":2010,"claim":"Placed KIF13B downstream of PI3K-Par1b/MARK2 signaling in axon specification and showed phosphorylation regulates its activity, linking motor function to neuronal polarity decisions.","evidence":"Co-IP, kinase assay, siRNA epistasis and rescue in hippocampal neurons","pmids":["20194617"],"confidence":"High","gaps":["Phosphosite mapping incomplete","Direct effect of phosphorylation on autoinhibition not shown"]},{"year":2010,"claim":"Revealed a non-transport scaffolding role at the immune synapse, where KIF13B competes with Bcl10 for CARD11 to dampen TCR-to-NF-κB signaling.","evidence":"Expression-cloning screen, Co-IP, NF-κB reporter and live-cell synapse imaging","pmids":["21145487"],"confidence":"Medium","gaps":["Whether motor activity is needed for CARD11 redistribution unclear","Single-lab functional model"]},{"year":2010,"claim":"Extended the PIP3-transport role to directional cell migration in vivo, showing KIF13B drives PIP3 accumulation at germ-cell blebs.","evidence":"Morpholino knockdown and PIP3 imaging in Xenopus primordial germ cells","pmids":["21029731"],"confidence":"Medium","gaps":["Ortholog-based; conservation of mechanism in mammals not shown here","Direct cargo at blebs not biochemically defined"]},{"year":2012,"claim":"Identified TRPV1 as a transported cargo and established Cdk5 phosphorylation at FHA-domain Thr-506 as a switch for motor-cargo coupling with in vivo pain relevance.","evidence":"Co-IP, Cdk5 kinase assay, T506A mutagenesis, surface biotinylation, TAT-peptide and behavioral assays","pmids":["23077056"],"confidence":"High","gaps":["Whether FHA phosphorylation also gates other cargos not tested","Structural effect of Thr-506 phosphorylation unresolved"]},{"year":2014,"claim":"Defined a metabolic role via LRP1 trafficking, showing KIF13B scaffolds LRP1-DLG1-utrophin-caveolae linkage and that knockout elevates serum cholesterol and factor VIII.","evidence":"KIF13B KO mice, Co-IP, LDL uptake assays and trafficking imaging in MEFs","pmids":["24469637"],"confidence":"High","gaps":["Relative contribution of motor vs scaffold activity not separated","Tissue specificity of cholesterol phenotype not dissected here"]},{"year":2014,"claim":"Established KIF13B as the motor delivering VEGFR2 from Golgi to the endothelial surface, with depletion diverting VEGFR2 to lysosomal degradation and blocking angiogenesis.","evidence":"Co-IP, knockdown, dominant-negative, tube-formation and in vivo neovascularization assays","pmids":["25128562"],"confidence":"High","gaps":["Adaptor linking KIF13B to VEGFR2 not identified","Recycling vs anterograde roles not yet separated"]},{"year":2016,"claim":"Showed cell-type-divergent control of myelination through DLG1, with KIF13B promoting myelination in Schwann cells but inhibiting it in oligodendrocytes via p38γ-AKT modulation of DLG1.","evidence":"Conditional KO mice, Co-IP, phosphorylation/ubiquitination assays, PNS/CNS myelin analysis","pmids":["27070899"],"confidence":"High","gaps":["Molecular basis of opposite outcomes in two cell types not fully resolved","Whether transport activity is required not isolated"]},{"year":2016,"claim":"Provided the atomic basis of the DLG-KIF13B complex, showing the MAGUK GK domain recognizes the autonomously folded MBS rather than a phosphopeptide.","evidence":"X-ray crystallography of DLG4 GK-KIF13B MBS with binding measurements and mutagenesis","pmids":["27642159"],"confidence":"High","gaps":["Structure of the full autoinhibited motor not solved","Dynamics of activation not captured"]},{"year":2017,"claim":"Uncovered a ciliary-base function, showing NPHP4 recruits KIF13B via its RPGRIP1N-C2 and tail sites to build a CAV1 transition-zone microdomain required for Shh-induced SMO accumulation.","evidence":"Co-IP, domain mapping, siRNA, SMO accumulation and ciliogenesis assays","pmids":["28134340"],"confidence":"High","gaps":["Whether motor activity is needed at the ciliary base unclear","Direct cargo carried to the transition zone not defined"]},{"year":2018,"claim":"Linked the KIF13B ortholog to retrograde signaling endosome sorting, placing Khc-73 in the BMP retrograde pathway at the neuromuscular synapse.","evidence":"Drosophila genetics, epistasis, endosome live imaging, pMad immunostaining and electrophysiology","pmids":["29373576"],"confidence":"Medium","gaps":["Ortholog-based; mammalian equivalence not shown","Direct endosome cargo not identified"]},{"year":2019,"claim":"Identified Rab10 as a partner required for tubular endosome formation, implicating KIF13B in endosomal membrane shaping.","evidence":"Rab localization screen, Rab10 CRISPR KO, Co-IP and domain-deletion analysis","pmids":["30700496"],"confidence":"Medium","gaps":["Some domain detail derived from KIF13A","Direct contribution of KIF13B motor to tubulation not isolated"]},{"year":2019,"claim":"Refined the LRP1 trafficking model by mapping the LRP1-DLG1(I3)-KIF13B(GUK-MBS) linkage and showing the CAP-Gly domain is required for localization and cholesterol control.","evidence":"Mouse KO/truncation models, domain-binding assays, serum/endocytosis assays","pmids":["31487503"],"confidence":"High","gaps":["CAP-Gly binding partner not defined here","KIF13A shown not to substitute, but redundancy elsewhere untested"]},{"year":2020,"claim":"Demonstrated cooperative transport with KIF5B on Rab6 secretory vesicles, with KIF13B specialized for reaching fresh microtubule plus ends.","evidence":"siRNA, TIRF live imaging, sub-pixel localization and kymograph analysis","pmids":["33174839"],"confidence":"High","gaps":["Molecular basis of plus-end-tip preference not fully resolved","Generalizability to other cargos untested"]},{"year":2020,"claim":"Established a Netrin-1-induced KIF13B-Myosin X interaction required for axon initiation and contralateral branching, integrating motor transport with guidance signaling.","evidence":"Proteomics, Co-IP, knockdown in cortical neurons and in vivo axon morphology","pmids":["33097641"],"confidence":"Medium","gaps":["How Netrin-1 triggers the interaction not detailed","Single-lab in vivo model"]},{"year":2021,"claim":"Confirmed endothelial KIF13B-VEGFR2 trafficking as essential for pathological VEGF-A responses in vivo using cell-type-specific knockout.","evidence":"EC-specific conditional KO mice, vascular leakage, tumor growth and metastasis models","pmids":["34670814"],"confidence":"High","gaps":["Did not add new molecular mechanism beyond confirming prior model","Therapeutic targeting feasibility not addressed"]},{"year":2022,"claim":"Showed KIF13B moves bidirectionally within primary cilia using its own motor domain, the first intraciliary motility for a vertebrate kinesin-3.","evidence":"Live-cell imaging with motor-domain mutants and velocity comparison to IFT172","pmids":["35403186"],"confidence":"Medium","gaps":["Functional purpose of intraciliary movement unclear","Source of bidirectionality (retrograde mechanism) unresolved"]},{"year":2022,"claim":"Identified angiomotin Ap80 as an activator that recruits PALS1 to the ciliary base to gate KIF13B cargo binding and control ciliary length and Hedgehog signaling.","evidence":"Co-IP, knockdown/overexpression, live imaging and ciliary SMO assays","pmids":["35673984"],"confidence":"Medium","gaps":["Direct cargo regulated by Ap80-PALS1 not defined","Relationship to NPHP4 ciliary-base mechanism unclear"]},{"year":2024,"claim":"Identified AP-1 as a TGN adaptor recruiting KIF13B for both axonal and dendritic transport in neurons, broadening its polarized-trafficking adaptor repertoire.","evidence":"Live imaging and AP-1 binding-domain interference in hippocampal neurons","pmids":["38446634"],"confidence":"Medium","gaps":["AP-1-bound cargo identities not defined","How directionality of transport is selected unclear"]},{"year":2023,"claim":"Extended VEGFR2 control to recycling, showing KIF13B routes internalized VEGFR2 through Rab5/Rab11 endosomes to sustain downstream phosphorylation rather than lysosomal degradation.","evidence":"Co-IP, Rab5/Rab11 trafficking assays, phospho-immunoblotting and KIF13B inhibition","pmids":["36928770"],"confidence":"Medium","gaps":["Single-lab model","Switch between recycling and degradation not mechanistically defined"]},{"year":2025,"claim":"Defined a metabolic-homeostasis axis through AMPKα1, with hepatic KIF13B suppressing SREBP1-driven lipogenesis and maintaining mitochondrial function.","evidence":"Co-IP, whole-body and liver-specific KO mice, phosphorylation and lipid/mitochondrial assays","pmids":["40038775"],"confidence":"Medium","gaps":["Whether AMPK regulation requires motor activity unknown","Direct vs indirect effect on AMPK phosphorylation unresolved"]},{"year":2025,"claim":"Implicated KIF13B in protein-stability/ubiquitin pathways in vascular and immune cells, controlling degradation of KLF4 (via KCTD10) and MERTK (via USP9X/CBL) with atherosclerosis phenotypes.","evidence":"Cell-type-specific KO mice, Co-IP, ubiquitination/degradation assays and pharmacological/transplant rescue","pmids":["41609725","40709729"],"confidence":"Medium","gaps":["How a kinesin couples to these E3/DUB pathways mechanistically unclear","Whether motor transport underlies the effects untested"]},{"year":2025,"claim":"Expanded ciliary roles, showing KIF13B at centriole distal appendages limits ciliary protein entry (PC2) and EV shedding downstream of the BBSome.","evidence":"KO cells, super-resolution microscopy, EV proteomics and BBSome/PC2 localization","pmids":["40930094"],"confidence":"Medium","gaps":["Mechanism of endocytic retrieval at the ciliary base unclear","Relationship to intraciliary motility not integrated"]},{"year":2025,"claim":"Showed cardiac KIF13B stabilizes PLIN5 against lysosomal degradation to maintain mitochondrial lipid homeostasis, with PLIN5 gene therapy rescuing the KO phenotype.","evidence":"Global KO mice, PLIN5 localization/degradation assays and AAV9-PLIN5 rescue","pmids":["41531892"],"confidence":"Medium","gaps":["Whether KIF13B traffics PLIN5 to mitochondria directly unresolved","Single-lab model"]},{"year":2025,"claim":"Identified ZNF384 as a transcriptional activator of KIF13B and a macrophage STT3A/CTSD glycosylation axis through which KIF13B influences hepatic lipid and inflammatory responses.","evidence":"Myeloid-specific KO mice, proteasome degradation and glycosylation assays, Co-IP and ChIP/promoter assay","pmids":["41746601"],"confidence":"Medium","gaps":["Connection between motor function and STT3A degradation unclear","Generalizability beyond this model untested"]},{"year":2025,"claim":"Documented a non-ciliary neuronal localization, enriching KIF13B at photoreceptor synaptic ribbons in a RIBEYE-dependent manner.","evidence":"Confocal/SIM/immunogold microscopy and RIBEYE KO mice","pmids":["40649824"],"confidence":"Medium","gaps":["Functional role at synaptic ribbons not established","Cargo at ribbons not identified"]},{"year":null,"claim":"It remains unresolved how KIF13B's core motor-transport activity mechanistically connects to its many ubiquitin/protein-stability and signaling-scaffold functions, and whether these require cargo transport, autoinhibition relief, or motor-independent scaffolding.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model separating motor-dependent from scaffold-only functions","Adaptors linking KIF13B to several cargos (e.g., VEGFR2) remain undefined","How phosphorylation integrates with cargo-gated autoinhibition in cells unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[2,3,16,19]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,3,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8,12,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma 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Biology","supporting_discovery_ids":[2,4,17,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,24,29]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8,23,27]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[26,24,29,27]}],"complexes":[],"partners":["DLG1","CARD11","VEGFR2","TRPV1","LRP1","NPHP4","RAB10","AMPKΑ1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NQT8","full_name":"Kinesin-like protein KIF13B","aliases":["Kinesin-like protein GAKIN"],"length_aa":1826,"mass_kda":202.8,"function":"Involved in reorganization of the cortical cytoskeleton. Regulates axon formation by promoting the formation of extra axons. 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KIF5B","url":"https://www.omim.org/entry/602809"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"parathyroid 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The interaction was identified by affinity protein purification and peptide sequencing. KIF13B contains a motor domain at the NH2 terminus, a central stalk domain, and a CAP-Gly domain at the COOH terminus. In resting T lymphocytes both proteins are cytoplasmic; upon CD2 receptor cross-linking, hDlg translocates to the lymphocyte cap.\",\n      \"method\": \"Affinity protein purification, peptide sequencing, cDNA cloning, GST pulldown, immunolocalization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pulldown plus localization, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"10859302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KIF13B directly interacts with centaurin-alpha1 (an ARF6 GAP and PIP3-binding protein); the interaction is mediated by the GAP domain of centaurin-alpha1 and the stalk domain of KIF13B. KIF13B binding suppresses the ARF6 GAP activity of centaurin-alpha1 in intact cells, and both proteins colocalize at cell-periphery leading edges; a deletion mutant of centaurin-alpha1 lacking the KIF13B-binding site fails to colocalize.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, ARF6 GAP activity assay, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Y2H, pulldown, Co-IP, functional assay), single lab\",\n      \"pmids\": [\"15923660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"KIF13B (GAKIN) directly interacts with PIP3BP (a PIP3-interacting protein) and, together with PIP3BP, assembles onto PIP3-containing liposomes and drives their motility along microtubules in vitro. In PC12 cells and hippocampal neurons, KIF13B transport activity promotes PIP3 accumulation at neurite tips; overexpression of KIF13B constructs that alter PIP3 distribution causes loss of axonally differentiated neurites, indicating KIF13B-PIP3BP complex is required for neuronal polarity formation.\",\n      \"method\": \"In vitro liposome motility assay, co-immunoprecipitation, overexpression/dominant-negative in PC12 cells and hippocampal neurons, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of motor-cargo complex on liposomes plus neuronal functional readouts, multiple orthogonal approaches\",\n      \"pmids\": [\"16864656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KIF13B (GAKIN) exists in an autoinhibited conformation in solution—it shows potent microtubule gliding activity but minimal microtubule-stimulated ATPase activity. Intramolecular interaction between the MAGUK binding stalk (MBS) domain and the motor domain confers this globular autoinhibited state. Direct binding of the SH3-I3-GUK module of hDlg to the MBS domain of KIF13B activates microtubule-stimulated ATPase activity ~10-fold, demonstrating cargo-mediated relief of autoinhibition.\",\n      \"method\": \"Microtubule gliding assay, ATPase assay, in vitro binding (pull-down), domain-deletion analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with enzymatic assay and domain mutagenesis, rigorous mechanistic dissection\",\n      \"pmids\": [\"17696365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Par1b/MARK2 phosphorylates KIF13B and is identified as a KIF13B-binding protein. KIF13B accumulates at the distal microtubule tips in axons but not dendrites. Overexpression of KIF13B induces extra axon formation; co-expression of Par1b kinase suppresses this in a kinase-activity-dependent manner. KIF13B siRNA knockdown retards neurite extension and causes an axonless phenotype. The extra-axon phenotype of Par1b siRNA is rescued by KIF13B siRNA, placing KIF13B downstream of Par1b. KIF13B also acts downstream of PI3K signaling via Par1b phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, kinase assay, siRNA knockdown, overexpression, epistasis in hippocampal neurons\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis experiments, kinase assay, reciprocal knockdown rescue, multiple orthogonal approaches\",\n      \"pmids\": [\"20194617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KIF13B (GAKIN) negatively regulates TCR signaling to NF-κB by associating with the scaffold protein CARD11 in a signal-dependent manner and competing with Bcl10 for CARD11 binding. KIF13B dynamically localizes to the immunological synapse and regulates redistribution of CARD11 from the central synapse region to a distal region.\",\n      \"method\": \"Expression-cloning screen, co-immunoprecipitation, NF-κB reporter assay, immunofluorescence live-cell imaging at immunological synapse\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional screen with Co-IP and signaling assay and localization, single lab\",\n      \"pmids\": [\"21145487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Xenopus KIF13B (xKIF13B) is required for primordial germ cell (PGC) migration; knockdown inhibits bleb formation and PIP3 accumulation at PGC blebs, causing PGC mismigration in vivo and in vitro. Interference with PIP3 synthesis similarly causes PGC mismigration, linking KIF13B function to polarized PIP3 accumulation for directional cell migration.\",\n      \"method\": \"Morpholino knockdown in Xenopus embryos, PIP3 imaging, PGC migration assay in vivo and explant\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD with defined cellular phenotype and PIP3 mechanistic link, single lab/organism\",\n      \"pmids\": [\"21029731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KIF13B transports TRPV1-containing vesicles to the cell surface via its FHA domain. Cdk5 phosphorylates KIF13B at Thr-506 within the FHA domain to promote motor-cargo association; T506A mutation reduces KIF13B-TRPV1 interaction. Cdk5/p35 overexpression promotes and Cdk5 inhibition prevents KIF13B-TRPV1 association. CFA-induced Cdk5 activation increases TRPV1 anterograde transport, contributing to heat hyperalgesia; a cell-permeable TAT-T506 peptide decreases TRPV1 surface localization and alleviates CFA-induced heat hyperalgesia.\",\n      \"method\": \"Co-immunoprecipitation, kinase assay (Cdk5 phosphorylation of KIF13B), site-directed mutagenesis (T506A), surface biotinylation, TAT peptide delivery in vivo, behavioral pain assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — kinase assay with mutagenesis, multiple functional readouts in vitro and in vivo, mechanistic rescue experiments\",\n      \"pmids\": [\"23077056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIF13B enhances caveolin-dependent endocytosis of LRP1 by acting as a scaffold that recruits LRP1 to caveolae via an LRP1–hDLG1–KIF13B–utrophin–caveolae linkage. KIF13B KO mice show elevated serum cholesterol and factor VIII; KO MEFs show decreased LDL uptake. Exogenous KIF13B localizes on the plasma membrane with caveolae and translocates to cytoplasmic vesicles with LRP1 and caveolin-1.\",\n      \"method\": \"KIF13B knockout mice, co-immunoprecipitation, serum/endocytosis assays in MEFs, live-cell imaging/trafficking\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined phenotype, Co-IP of multi-protein complex, trafficking assay, multiple orthogonal methods\",\n      \"pmids\": [\"24469637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIF13B directly interacts with VEGFR2 and mediates its transport from the Golgi to the endothelial cell surface. KIF13B depletion diverts VEGFR2 to lysosomal degradation, prevents VEGF-induced endothelial migration and capillary tube formation, and blocks neovascularization in mice.\",\n      \"method\": \"Co-immunoprecipitation, KIF13B knockdown, truncation/dominant-negative overexpression, in vitro tube formation assay, in vivo Matrigel plug/neovascularization assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, KD with defined trafficking and functional phenotypes, in vivo model, multiple orthogonal approaches\",\n      \"pmids\": [\"25128562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIF13B regulates PNS and CNS myelination through the DLG1 scaffold. In Schwann cells, KIF13B promotes myelination by driving p38γ MAPK-mediated phosphorylation and ubiquitination of DLG1, which downregulates PI3K/AKT signaling (DLG1 is a brake on myelination). In oligodendrocytes, KIF13B negatively regulates myelination by destabilizing DLG1, which in that context enhances AKT activation.\",\n      \"method\": \"Kif13b conditional knockout mice, co-immunoprecipitation, phosphorylation/ubiquitination assays, myelin analysis in PNS/CNS\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO models with defined phenotypes in two cell types, biochemical pathway dissection, multiple orthogonal methods\",\n      \"pmids\": [\"27070899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The crystal structure of DLG4 GK domain in complex with the KIF13B MBS (MAGUK binding stalk) domain reveals an atypical MAGUK GK target recognition mode in which the GK domain binds an unphosphorylated, autonomously folded domain (MBS) rather than a phosphopeptide. This structural insight explains the molecular basis of DLG/KIF13B complex formation and autoinhibition relief.\",\n      \"method\": \"X-ray crystallography, in vitro binding measurements, mutagenesis\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional binding validation and mutagenesis\",\n      \"pmids\": [\"27642159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KIF13B is a novel member of the RPGRIP1N-C2 domain family and is recruited to the ciliary base by NPHP4, which binds two distinct sites in the KIF13B tail including an RPGRIP1N-C2 domain. KIF13B and NPHP4 are both required for establishing a CAV1-enriched membrane microdomain at the transition zone, which is necessary for Shh-induced ciliary SMO accumulation.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, siRNA knockdown, immunofluorescence, SMO accumulation assay, ciliogenesis analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain binding mapping, KD of both components, functional SMO/Shh readout, multiple orthogonal methods\",\n      \"pmids\": [\"28134340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Drosophila KIF13B ortholog Khc-73 (a plus-end kinesin) regulates sorting of endosomes in larval motor neurons. Loss of Khc-73 impairs retrograde BMP signaling: activated BMP transcription factor Mad nuclear accumulation is reduced, and retrograde-bound endosomes fail to leave the synapse and join the retrograde axonal pathway. Genetic enhancement/suppression with BMP pathway components places Khc-73 in the BMP retrograde signaling pathway.\",\n      \"method\": \"Drosophila genetics (mutant analysis, epistasis), live imaging of endosomes in motor neurons, pMad immunostaining, electrophysiology\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with genetic pathway placement, live imaging, single organism (Drosophila ortholog)\",\n      \"pmids\": [\"29373576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rab10 interacts with KIF13B (and KIF13A) and is required for tubular endosome formation; Rab10 knockout abolishes tubular endosomal structures in HeLaM cells. KIF13B was identified as a Rab10-interacting protein by in silico screening and validated experimentally, and both the Rab10-binding homology domain and the motor domain of KIF13A are required for Rab10-positive tubular endosome formation.\",\n      \"method\": \"Rab GTPase localization screen, Rab10 knockout (CRISPR), co-immunoprecipitation, domain-deletion analysis, fluorescence microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO phenotype, Co-IP, domain analysis; some mechanistic detail from KIF13A but KIF13B validated as Rab10 interactor\",\n      \"pmids\": [\"30700496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The cytoplasmic domain of LRP1 interacts specifically with the alternatively spliced I3 domain of DLG1, which in turn complexes with KIF13B via GUK-MBS domain interaction. The CAP-Gly domain of KIF13B is required for proper subcellular localization of KIF13B and LRP1; mice expressing KIF13B lacking the CAP-Gly domain (KIF13BΔCG) show higher serum cholesterol and reduced LDL uptake. KIF13A null mice show no such cholesterol or factor VIII elevation.\",\n      \"method\": \"Mouse knockout/truncation models, co-immunoprecipitation, domain-binding assays, serum/endocytosis assays, immunolocalization\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse models (truncation + KO), biochemical domain mapping, functional metabolic phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"31487503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KIF13B and KIF5B cooperate to transport Rab6-positive secretory vesicles from the Golgi to the cell periphery. KIF13B assists Rab6 vesicles in reaching freshly polymerized microtubule plus ends (where KIF5B binds poorly due to slow MAP7 population). Sub-pixel localization showed both kinesins localize to the vesicle front during plus-end directed transport; upon reversal, KIF13B relocates to the middle while KIF5B shifts to the back, suggesting KIF5B (not KIF13B) undergoes tug-of-war with minus-end motors.\",\n      \"method\": \"siRNA knockdown, live-cell imaging (TIRF), sub-pixel localization microscopy, kymograph analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — sub-pixel co-localization with multiple kinesins on single vesicles, KD phenotype, multiple orthogonal approaches in single rigorous study\",\n      \"pmids\": [\"33174839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Netrin-1 induces KIF13B interaction with Myosin X (Myo X); KIF13B mediates anterograde transport of Myo X into axons, which is required for Netrin-1-DCC-regulated axon initiation and contralateral branching in developing mouse neocortex. KIF13B KD results in axon initiation deficits similar to those seen with Myo X KO/KD and Netrin-1 KO.\",\n      \"method\": \"Proteomic analysis of Myo X binding proteins, co-immunoprecipitation, KIF13B knockdown in embryonic cortical neurons, axon morphology analysis in vivo\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex, KD phenotype in vivo, epistasis; single lab\",\n      \"pmids\": [\"33097641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EC-specific KIF13B knockout mice demonstrate that endothelial KIF13B is required for VEGF-A-induced vascular leakage, angiogenesis, tumor growth, and cancer metastasis in vivo, confirming KIF13B-mediated VEGFR2 trafficking to the endothelial surface as an essential step in pathological VEGF-A signaling.\",\n      \"method\": \"Endothelial cell-specific Kif13b conditional knockout mice, VEGF-A vascular leakage assays, tumor growth/metastasis models\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic KO with multiple defined in vivo phenotypes, replicates prior mechanistic findings\",\n      \"pmids\": [\"34670814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIF13B undergoes bursts of bidirectional motor-driven movement within primary cilia of human RPE1 cells, with anterograde and retrograde velocities similar to IFT. Intraciliary movement requires KIF13B's own motor domain and appears cell-type specific, representing the first demonstration of intraciliary motor-driven movement by a vertebrate kinesin-3.\",\n      \"method\": \"Live-cell imaging (TIRF/fluorescence), KIF13B-eGFP constructs including motor-domain mutants, velocity analysis compared to IFT172-eGFP\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with motor-domain mutant, single lab, first demonstration in vertebrate cilia\",\n      \"pmids\": [\"35403186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Angiomotin isoform 2 (Ap80) is a novel KIF13B interactor that promotes binding of the MAGUK PALS1 to KIF13B. Ap80 concentrates at the ciliary base and recruits PALS1 there. Ap80 depletion leads to elongated primary cilia and reduced SMO ciliary accumulation; Ap80 overexpression causes ciliary shortening, indicating Ap80 activates KIF13B cargo binding at the ciliary base to regulate ciliary length and Hedgehog signaling.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, live-cell imaging, ciliary SMO accumulation assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KD/OE with functional ciliary phenotypes, single lab\",\n      \"pmids\": [\"35673984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIF13B mediates recycling of internalized VEGFR2 through Rab11-positive recycling vesicles back to the cell surface. After VEGF stimulation, phosphorylated VEGFR2 at cell-cell junctions is internalized into Rab5-positive early endosomes where it associates with KIF13B. Inhibition of KIF13B attenuates phosphorylation of VEGFR2-Y951, SRC-Y416, and VE-cadherin-Y685 and diverts VEGFR2 to lysosomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, Rab5/Rab11 vesicle trafficking assays, phospho-specific immunoblotting, KIF13B inhibition (dominant-negative/peptide), live-cell trafficking imaging\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with endosomal markers, signaling readouts, single lab\",\n      \"pmids\": [\"36928770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIF13B is recruited to polarized vesicles at the trans-Golgi network through interaction with the heterotetrameric adaptor protein complex AP-1. In hippocampal neurons, KIF13B mediates both dendrite- and axon-selective transport; interference with KIF13B binding to AP-1 disrupts both transport modes.\",\n      \"method\": \"Live-cell imaging in hippocampal neurons, AP-1 binding domain interference (dominant-negative), KIF13B-fluorescent fusions, kymograph analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with domain-interference approach, single lab, functional polarized transport readout\",\n      \"pmids\": [\"38446634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KIF13B interacts with AMPKα1 and regulates its phosphorylation, governing mitochondrial homeostasis and suppressing SREBP1-mediated de novo lipogenesis in the liver. Kif13b deficiency increases hepatic lipid synthesis and impairs mitochondrial oxidative phosphorylation; liver-specific Kif13b knockout causes spontaneous hepatic steatosis.\",\n      \"method\": \"Co-immunoprecipitation, Kif13b whole-body and liver-specific knockout mice, phosphorylation assays, lipid synthesis assays, mitochondrial function assays\",\n      \"journal\": \"Military Medical Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with AMPKα1, genetic KO models with defined metabolic phenotype, single lab\",\n      \"pmids\": [\"40038775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In macrophages, KIF13B maintains MERTK expression by enhancing its deubiquitination through interaction with the deubiquitinase USP9X; loss of KIF13B decreases ITCH expression and leads to accelerated CBL-mediated ubiquitination and degradation of MERTK, impairing macrophage efferocytosis and promoting atherosclerosis.\",\n      \"method\": \"Co-immunoprecipitation (KIF13B-USP9X), Kif13b macrophage-specific knockout mice, MERTK ubiquitination assays, bone marrow transplantation, efferocytosis assays\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KO models with pathway placement, ubiquitination assay; single lab\",\n      \"pmids\": [\"40709729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KIF13B regulates ciliary protein composition and extracellular vesicle (EV) shedding from cilia. KIF13B knockout causes aberrant accumulation of polycystin-2 (PC2) within cilia, increased release of large EVs enriched with CCDC198 and CCDC92, and altered small EV composition. KIF13B acts at centriole distal appendages to limit ciliary protein entry and promote endocytic retrieval downstream of the BBSome, suppressing EV release from cilia.\",\n      \"method\": \"Kif13b knockout cells, super-resolution microscopy, EV characterization (proteomics), live imaging, PC2 and BBSome localization analysis\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with proteomic EV characterization and localization analysis, single lab\",\n      \"pmids\": [\"40930094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In vascular smooth muscle cells (VSMCs), KIF13B facilitates ubiquitination and proteasomal degradation of KLF4 through a KCTD10-dependent pathway. VSMC-specific Kif13b deletion exacerbates atherosclerotic lesion development and impairs plaque stability; adverse effects were rescued by the KLF4 inhibitor Kenpaullone.\",\n      \"method\": \"VSMC-specific Kif13b KO mice (PCSK9 AAV model), Co-immunoprecipitation (KIF13B-KCTD10), KLF4 ubiquitination/degradation assays, pharmacological rescue\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, cell-type-specific genetic KO, pharmacological rescue; single lab\",\n      \"pmids\": [\"41609725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KIF13B stabilizes PLIN5 by preventing its lysosomal degradation; loss of KIF13B impairs mitochondrial localization of PLIN5, disrupting cardiac lipid homeostasis and mitochondrial function in sepsis-induced cardiac dysfunction. AAV9-PLIN5 gene therapy rescues cardiac dysfunction in Kif13b KO mice.\",\n      \"method\": \"Kif13b global KO mice, cardiomyocyte PLIN5 localization assays, lysosomal degradation assays, AAV9-PLIN5 rescue, cardiac function measurements\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO, mechanistic rescue (AAV gene therapy), protein stability assay; single lab\",\n      \"pmids\": [\"41531892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KIF13B is enriched at photoreceptor synaptic ribbons in addition to the primary photoreceptor cilium. This synaptic localization requires intact synaptic ribbon structure, as shown by loss of KIF13B enrichment at ribbons in RIBEYE knockout mice.\",\n      \"method\": \"Confocal microscopy, super-resolution SIM, immunogold electron microscopy, RIBEYE KO mice\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple imaging modalities with genetic validation (RIBEYE KO), single lab\",\n      \"pmids\": [\"40649824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In macrophages, KIF13B loss impairs proteasome-dependent degradation of the glycosyltransferase STT3A, enhancing cathepsin D (CTSD) glycosylation and secretion, which promotes lipid accumulation and inflammatory responses in liver cells via CTSD interaction with hepatocyte THBS1. Transcription factor ZNF384 is identified as an upstream regulator that binds the KIF13B promoter to activate its transcription.\",\n      \"method\": \"Myeloid-specific Kif13b KO mice, STT3A proteasome degradation assay, CTSD glycosylation/secretion assay, Co-IP (CTSD-THBS1), ZNF384 ChIP/promoter binding assay\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO, biochemical pathway dissection (glycosylation, Co-IP), ChIP; single lab\",\n      \"pmids\": [\"41746601\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIF13B is a kinesin-3 family plus-end microtubule motor that exists in a cargo-regulated autoinhibited state (via intramolecular MBS-motor domain interaction) and is activated upon direct binding of DLG1/hDlg (via GUK-MBS interaction); it transports diverse cargos—including PIP3-containing vesicles, VEGFR2, TRPV1, Myosin X, and LRP1—to the cell periphery, with motor-cargo coupling regulated by phosphorylation (Cdk5 at Thr-506; Par1b/MARK2), and it also performs unconventional non-motor scaffold/signaling functions including regulation of ciliary composition and Hedgehog signaling (via NPHP4), myelination (via DLG1-p38γ-AKT), immune synapse organization (via CARD11), and metabolic homeostasis (via AMPKα1, PLIN5, and ubiquitin pathway components).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIF13B (GAKIN/Khc-73) is a kinesin-3 plus-end-directed microtubule motor that delivers diverse cargos to the cell periphery and operates under cargo-gated autoinhibition [#3, #2]. In solution the motor adopts a globular autoinhibited conformation maintained by an intramolecular interaction between its MAGUK-binding stalk (MBS) and the motor domain; direct binding of the SH3-I3-GUK module of DLG1/hDlg to the MBS relieves this inhibition and activates microtubule-stimulated ATPase ~10-fold [#3], a recognition mode in which the MAGUK GK domain engages the autonomously folded MBS rather than a phosphopeptide [#11]. Through DLG1 and other adaptors, KIF13B transports a defined set of cargos: PIP3-containing vesicles to establish polarized PIP3 accumulation at neurite tips and migrating cells [#2, #6], VEGFR2 from the Golgi to the endothelial surface and through Rab5/Rab11 recycling, a step essential for VEGF-A-driven angiogenesis, vascular leakage, and tumor metastasis in vivo [#9, #18, #21], TRPV1 vesicles to the cell surface [#7], Myosin X into axons during Netrin-1-DCC-regulated axon initiation [#17], and LRP1 to caveolae for cholesterol-regulating endocytosis [#8, #15]. Motor-cargo coupling is tuned by phosphorylation, including Cdk5 at Thr-506 in the FHA domain (promoting TRPV1 binding) and Par1b/MARK2, which acts downstream of PI3K to control axon specification [#7, #4]. Cargo recruitment is directed by adaptors at distinct membrane sites, including AP-1 at the trans-Golgi network for both axonal and dendritic transport [#22] and Rab6/Rab10 for secretory and tubular endosomal carriers [#16, #14]. Beyond cargo transport, KIF13B performs scaffolding and signaling roles: it is recruited to the ciliary base by NPHP4 and by angiomotin/PALS1 to control a CAV1-enriched transition-zone microdomain, ciliary length, SMO accumulation, and Hedgehog signaling, and it limits ciliary protein entry and EV shedding downstream of the BBSome [#12, #20, #25]; it regulates myelination via a DLG1-p38\\u03b3-AKT axis [#10]; it antagonizes TCR-to-NF-\\u03baB signaling at the immune synapse by competing with Bcl10 for CARD11 [#5]; and it governs metabolic and ubiquitin-pathway homeostasis through AMPK\\u03b11, PLIN5, and degradation of substrates including KLF4, MERTK, and STT3A in liver, heart, and vascular/macrophage contexts [#23, #27, #26, #24, #29].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established KIF13B's defining molecular partnership by showing it binds the GUK domain of the MAGUK scaffolds hDlg/DLG1 and PSD-95, framing it as a motor coupled to scaffolding proteins.\",\n      \"evidence\": \"Affinity purification, peptide sequencing, GST pulldown and immunolocalization in T lymphocytes\",\n      \"pmids\": [\"10859302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish what cargo the DLG1-KIF13B complex transports\", \"No demonstration of motor regulation by the interaction\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected KIF13B to peripheral PIP3/ARF6 signaling by identifying centaurin-alpha1 as a stalk-domain partner whose ARF6 GAP activity KIF13B suppresses at leading edges.\",\n      \"evidence\": \"Yeast two-hybrid, pulldown, Co-IP, ARF6 GAP assay and immunofluorescence\",\n      \"pmids\": [\"15923660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological consequence of GAP suppression not defined\", \"Single-lab interaction\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that KIF13B is a bona fide motor for PIP3-containing vesicles and required for neuronal polarity, reconstituting motor-cargo motility in vitro.\",\n      \"evidence\": \"In vitro liposome motility, Co-IP, dominant-negative perturbation in PC12 cells and hippocampal neurons\",\n      \"pmids\": [\"16864656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PIP3BP identity and broader cargo repertoire not fully resolved\", \"How motor engages PIP3 vesicles in vivo not detailed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the autoinhibition mechanism, showing KIF13B is held in a globular inactive state by MBS-motor contact that DLG1 binding relieves, explaining cargo-gated motor activation.\",\n      \"evidence\": \"Microtubule gliding and ATPase assays with domain-deletion analysis\",\n      \"pmids\": [\"17696365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MBS-motor contact not solved here\", \"In-cell timing of activation not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed KIF13B downstream of PI3K-Par1b/MARK2 signaling in axon specification and showed phosphorylation regulates its activity, linking motor function to neuronal polarity decisions.\",\n      \"evidence\": \"Co-IP, kinase assay, siRNA epistasis and rescue in hippocampal neurons\",\n      \"pmids\": [\"20194617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosite mapping incomplete\", \"Direct effect of phosphorylation on autoinhibition not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed a non-transport scaffolding role at the immune synapse, where KIF13B competes with Bcl10 for CARD11 to dampen TCR-to-NF-\\u03baB signaling.\",\n      \"evidence\": \"Expression-cloning screen, Co-IP, NF-\\u03baB reporter and live-cell synapse imaging\",\n      \"pmids\": [\"21145487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether motor activity is needed for CARD11 redistribution unclear\", \"Single-lab functional model\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended the PIP3-transport role to directional cell migration in vivo, showing KIF13B drives PIP3 accumulation at germ-cell blebs.\",\n      \"evidence\": \"Morpholino knockdown and PIP3 imaging in Xenopus primordial germ cells\",\n      \"pmids\": [\"21029731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog-based; conservation of mechanism in mammals not shown here\", \"Direct cargo at blebs not biochemically defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified TRPV1 as a transported cargo and established Cdk5 phosphorylation at FHA-domain Thr-506 as a switch for motor-cargo coupling with in vivo pain relevance.\",\n      \"evidence\": \"Co-IP, Cdk5 kinase assay, T506A mutagenesis, surface biotinylation, TAT-peptide and behavioral assays\",\n      \"pmids\": [\"23077056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FHA phosphorylation also gates other cargos not tested\", \"Structural effect of Thr-506 phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a metabolic role via LRP1 trafficking, showing KIF13B scaffolds LRP1-DLG1-utrophin-caveolae linkage and that knockout elevates serum cholesterol and factor VIII.\",\n      \"evidence\": \"KIF13B KO mice, Co-IP, LDL uptake assays and trafficking imaging in MEFs\",\n      \"pmids\": [\"24469637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of motor vs scaffold activity not separated\", \"Tissue specificity of cholesterol phenotype not dissected here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established KIF13B as the motor delivering VEGFR2 from Golgi to the endothelial surface, with depletion diverting VEGFR2 to lysosomal degradation and blocking angiogenesis.\",\n      \"evidence\": \"Co-IP, knockdown, dominant-negative, tube-formation and in vivo neovascularization assays\",\n      \"pmids\": [\"25128562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adaptor linking KIF13B to VEGFR2 not identified\", \"Recycling vs anterograde roles not yet separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed cell-type-divergent control of myelination through DLG1, with KIF13B promoting myelination in Schwann cells but inhibiting it in oligodendrocytes via p38\\u03b3-AKT modulation of DLG1.\",\n      \"evidence\": \"Conditional KO mice, Co-IP, phosphorylation/ubiquitination assays, PNS/CNS myelin analysis\",\n      \"pmids\": [\"27070899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of opposite outcomes in two cell types not fully resolved\", \"Whether transport activity is required not isolated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the atomic basis of the DLG-KIF13B complex, showing the MAGUK GK domain recognizes the autonomously folded MBS rather than a phosphopeptide.\",\n      \"evidence\": \"X-ray crystallography of DLG4 GK-KIF13B MBS with binding measurements and mutagenesis\",\n      \"pmids\": [\"27642159\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full autoinhibited motor not solved\", \"Dynamics of activation not captured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Uncovered a ciliary-base function, showing NPHP4 recruits KIF13B via its RPGRIP1N-C2 and tail sites to build a CAV1 transition-zone microdomain required for Shh-induced SMO accumulation.\",\n      \"evidence\": \"Co-IP, domain mapping, siRNA, SMO accumulation and ciliogenesis assays\",\n      \"pmids\": [\"28134340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether motor activity is needed at the ciliary base unclear\", \"Direct cargo carried to the transition zone not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked the KIF13B ortholog to retrograde signaling endosome sorting, placing Khc-73 in the BMP retrograde pathway at the neuromuscular synapse.\",\n      \"evidence\": \"Drosophila genetics, epistasis, endosome live imaging, pMad immunostaining and electrophysiology\",\n      \"pmids\": [\"29373576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog-based; mammalian equivalence not shown\", \"Direct endosome cargo not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified Rab10 as a partner required for tubular endosome formation, implicating KIF13B in endosomal membrane shaping.\",\n      \"evidence\": \"Rab localization screen, Rab10 CRISPR KO, Co-IP and domain-deletion analysis\",\n      \"pmids\": [\"30700496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Some domain detail derived from KIF13A\", \"Direct contribution of KIF13B motor to tubulation not isolated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Refined the LRP1 trafficking model by mapping the LRP1-DLG1(I3)-KIF13B(GUK-MBS) linkage and showing the CAP-Gly domain is required for localization and cholesterol control.\",\n      \"evidence\": \"Mouse KO/truncation models, domain-binding assays, serum/endocytosis assays\",\n      \"pmids\": [\"31487503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CAP-Gly binding partner not defined here\", \"KIF13A shown not to substitute, but redundancy elsewhere untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated cooperative transport with KIF5B on Rab6 secretory vesicles, with KIF13B specialized for reaching fresh microtubule plus ends.\",\n      \"evidence\": \"siRNA, TIRF live imaging, sub-pixel localization and kymograph analysis\",\n      \"pmids\": [\"33174839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of plus-end-tip preference not fully resolved\", \"Generalizability to other cargos untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a Netrin-1-induced KIF13B-Myosin X interaction required for axon initiation and contralateral branching, integrating motor transport with guidance signaling.\",\n      \"evidence\": \"Proteomics, Co-IP, knockdown in cortical neurons and in vivo axon morphology\",\n      \"pmids\": [\"33097641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How Netrin-1 triggers the interaction not detailed\", \"Single-lab in vivo model\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed endothelial KIF13B-VEGFR2 trafficking as essential for pathological VEGF-A responses in vivo using cell-type-specific knockout.\",\n      \"evidence\": \"EC-specific conditional KO mice, vascular leakage, tumor growth and metastasis models\",\n      \"pmids\": [\"34670814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not add new molecular mechanism beyond confirming prior model\", \"Therapeutic targeting feasibility not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed KIF13B moves bidirectionally within primary cilia using its own motor domain, the first intraciliary motility for a vertebrate kinesin-3.\",\n      \"evidence\": \"Live-cell imaging with motor-domain mutants and velocity comparison to IFT172\",\n      \"pmids\": [\"35403186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional purpose of intraciliary movement unclear\", \"Source of bidirectionality (retrograde mechanism) unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified angiomotin Ap80 as an activator that recruits PALS1 to the ciliary base to gate KIF13B cargo binding and control ciliary length and Hedgehog signaling.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression, live imaging and ciliary SMO assays\",\n      \"pmids\": [\"35673984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cargo regulated by Ap80-PALS1 not defined\", \"Relationship to NPHP4 ciliary-base mechanism unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified AP-1 as a TGN adaptor recruiting KIF13B for both axonal and dendritic transport in neurons, broadening its polarized-trafficking adaptor repertoire.\",\n      \"evidence\": \"Live imaging and AP-1 binding-domain interference in hippocampal neurons\",\n      \"pmids\": [\"38446634\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AP-1-bound cargo identities not defined\", \"How directionality of transport is selected unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended VEGFR2 control to recycling, showing KIF13B routes internalized VEGFR2 through Rab5/Rab11 endosomes to sustain downstream phosphorylation rather than lysosomal degradation.\",\n      \"evidence\": \"Co-IP, Rab5/Rab11 trafficking assays, phospho-immunoblotting and KIF13B inhibition\",\n      \"pmids\": [\"36928770\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab model\", \"Switch between recycling and degradation not mechanistically defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a metabolic-homeostasis axis through AMPK\\u03b11, with hepatic KIF13B suppressing SREBP1-driven lipogenesis and maintaining mitochondrial function.\",\n      \"evidence\": \"Co-IP, whole-body and liver-specific KO mice, phosphorylation and lipid/mitochondrial assays\",\n      \"pmids\": [\"40038775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AMPK regulation requires motor activity unknown\", \"Direct vs indirect effect on AMPK phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated KIF13B in protein-stability/ubiquitin pathways in vascular and immune cells, controlling degradation of KLF4 (via KCTD10) and MERTK (via USP9X/CBL) with atherosclerosis phenotypes.\",\n      \"evidence\": \"Cell-type-specific KO mice, Co-IP, ubiquitination/degradation assays and pharmacological/transplant rescue\",\n      \"pmids\": [\"41609725\", \"40709729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a kinesin couples to these E3/DUB pathways mechanistically unclear\", \"Whether motor transport underlies the effects untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded ciliary roles, showing KIF13B at centriole distal appendages limits ciliary protein entry (PC2) and EV shedding downstream of the BBSome.\",\n      \"evidence\": \"KO cells, super-resolution microscopy, EV proteomics and BBSome/PC2 localization\",\n      \"pmids\": [\"40930094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of endocytic retrieval at the ciliary base unclear\", \"Relationship to intraciliary motility not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed cardiac KIF13B stabilizes PLIN5 against lysosomal degradation to maintain mitochondrial lipid homeostasis, with PLIN5 gene therapy rescuing the KO phenotype.\",\n      \"evidence\": \"Global KO mice, PLIN5 localization/degradation assays and AAV9-PLIN5 rescue\",\n      \"pmids\": [\"41531892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KIF13B traffics PLIN5 to mitochondria directly unresolved\", \"Single-lab model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified ZNF384 as a transcriptional activator of KIF13B and a macrophage STT3A/CTSD glycosylation axis through which KIF13B influences hepatic lipid and inflammatory responses.\",\n      \"evidence\": \"Myeloid-specific KO mice, proteasome degradation and glycosylation assays, Co-IP and ChIP/promoter assay\",\n      \"pmids\": [\"41746601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Connection between motor function and STT3A degradation unclear\", \"Generalizability beyond this model untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Documented a non-ciliary neuronal localization, enriching KIF13B at photoreceptor synaptic ribbons in a RIBEYE-dependent manner.\",\n      \"evidence\": \"Confocal/SIM/immunogold microscopy and RIBEYE KO mice\",\n      \"pmids\": [\"40649824\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role at synaptic ribbons not established\", \"Cargo at ribbons not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how KIF13B's core motor-transport activity mechanistically connects to its many ubiquitin/protein-stability and signaling-scaffold functions, and whether these require cargo transport, autoinhibition relief, or motor-independent scaffolding.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model separating motor-dependent from scaffold-only functions\", \"Adaptors linking KIF13B to several cargos (e.g., VEGFR2) remain undefined\", \"How phosphorylation integrates with cargo-gated autoinhibition in cells unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [2, 3, 16, 19]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 3, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8, 12, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 8, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [12, 19, 20, 25]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [25]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [9, 16, 22]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [14, 21]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 4, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 9, 7, 8, 22]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [8, 16, 14, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 12, 18, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 4, 17, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 24, 29]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8, 23, 27]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [26, 24, 29, 27]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DLG1\", \"CARD11\", \"VEGFR2\", \"TRPV1\", \"LRP1\", \"NPHP4\", \"Rab10\", \"AMPK\\u03b11\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}