{"gene":"KIF1C","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1998,"finding":"KIF1C was identified as a new kinesin-like protein (Unc104 subfamily) localized primarily at the Golgi apparatus; overexpression of catalytically inactive KIF1C inhibited brefeldin A-induced retrograde flow of Golgi membranes into the ER, implicating KIF1C in Golgi-to-ER vesicle transport. KIF1C was identified via yeast two-hybrid using the ezrin domain of PTPD1 as bait, and was found to be tyrosine-phosphorylated after peroxovanadate stimulation.","method":"Yeast two-hybrid, immunofluorescence, dominant-negative overexpression in 293/NIH3T3/C2C12 cells, brefeldin A treatment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative overexpression with specific organelle phenotype, immunofluorescence localization, single lab with two orthogonal methods","pmids":["9685376"],"is_preprint":false},{"year":1999,"finding":"KIF1C dimerizes and associates with 14-3-3 proteins (beta, gamma, epsilon, zeta) via phosphorylation of Ser1092 (in a canonical 14-3-3 binding sequence). Ser1092 is a substrate for casein kinase II in vitro; inhibition of casein kinase II in cells reduced KIF1C–14-3-3γ association.","method":"Yeast two-hybrid, transient overexpression, co-immunoprecipitation, in vitro kinase assay, casein kinase II inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay identifying CK2 as writer, reciprocal co-IP confirming 14-3-3 interaction dependent on pSer1092, and cellular rescue by inhibitor; single lab but multiple orthogonal methods","pmids":["10559254"],"is_preprint":false},{"year":2001,"finding":"Kif1C alleles determine resistance or susceptibility of mouse macrophages to anthrax lethal toxin (LeTx). Brefeldin A treatment (which alters KIF1C cellular localization) converts resistant macrophages to susceptibility; ectopic expression of a resistance allele in susceptible macrophages increases survival. KIF1C acts downstream of toxin entry/processing (MKK3 cleavage still occurs in resistant cells), likely influencing a post-entry step.","method":"Genetic mapping, allele overexpression, brefeldin A treatment, LeTx susceptibility assay, MKK3 cleavage assay","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with allele-specific rescue and localization perturbation, single lab, multiple approaches","pmids":["11591317"],"is_preprint":false},{"year":2002,"finding":"KIF1C knockout mice are viable with no obvious abnormalities; primary lung fibroblasts from kif1C−/− mice show no significant difference in Golgi distribution or brefeldin A-induced Golgi-to-ER retrograde transport, indicating KIF1C is dispensable for this retrograde transport in vivo.","method":"Gene knockout (knock-in of beta-gal into motor domain), immunocytochemistry, time-lapse analysis of BFA-induced transport","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with time-lapse functional readout; negates earlier proposed Golgi-to-ER transport role, replicated across multiple cell/tissue types","pmids":["11784862"],"is_preprint":false},{"year":2006,"finding":"KIF1C is a microtubule plus-end-enriched kinesin that targets podosome turnover regions in primary human macrophages; KIF1C depletion (siRNA/shRNA) or expression of dominant-negative constructs decreases podosome dynamics and causes podosome deficiency. KIF1C binds non-muscle myosin IIA via its PTPD-binding domain, linking actin and tubulin cytoskeletons.","method":"siRNA/shRNA knockdown, dominant-negative overexpression, protein interaction studies (co-IP), live-cell imaging, immunofluorescence in primary human macrophages","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KD with specific podosome phenotype, protein interaction confirmed by co-IP, plus-end localization by live imaging; single lab but multiple orthogonal methods","pmids":["16554367"],"is_preprint":false},{"year":2012,"finding":"KIF1C mediates transport of α5β1-integrins to trailing focal adhesions, which is required for maturation of these adhesions and resistance to tail retraction during directional cell migration. Loss of KIF1C leads to impaired rear stabilization and reduced directional persistence; the phenotype is suppressed by myosin II inhibition.","method":"Kif1C depletion (siRNA), live-cell migration assays, integrin trafficking assays, myosin II inhibition epistasis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KD with defined cargo (α5β1 integrin), specific cellular phenotype (tail retraction/directionality), genetic epistasis with myosin II inhibition; single lab, multiple orthogonal approaches","pmids":["23237952"],"is_preprint":false},{"year":2014,"finding":"Rab6A binds to both the motor domain and the C-terminus of KIF1C; Rab6A binding to the motor domain inhibits microtubule interaction in vitro and in cells, reducing the pool of motile KIF1C. KIF1C depletion slows protein delivery to the cell surface, disrupts vesicle motility, and triggers Golgi fragmentation. Protection of Golgi from fragmentation requires Rab6A-binding at both ends but not KIF1C motor activity.","method":"In vitro microtubule binding assay, co-IP, KIF1C depletion (siRNA), live-cell imaging of vesicle motility, Golgi fragmentation assay, rescue with deletion constructs","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution of Rab6A inhibition of motor domain MT binding, plus cellular KD with specific cargo/organelle phenotype and domain-mapping rescue; single lab, multiple orthogonal methods","pmids":["25821985"],"is_preprint":false},{"year":2014,"finding":"KIF1C translocation to the cell periphery is dependent on CLASP proteins; upon PKC-induced podosome formation, KIF1C accumulates near CLASPs at peripheral microtubule plus ends. Chimeric mitochondrially-targeted CLASP2 recruits KIF1C, indicating a direct transient CLASP–KIF1C association that is required for KIF1C trafficking and podosome formation.","method":"CLASP siRNA knockdown, PKC activation, live-cell imaging, chimeric CLASP2 mitochondrial targeting assay, immunofluorescence","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chimeric targeting experiment directly recruits KIF1C to mitochondria via CLASP2, plus KD phenotype; single lab, two orthogonal methods","pmids":["25344256"],"is_preprint":false},{"year":2014,"finding":"Microtubule acetylation (regulated by MEC-17 acetyltransferase) influences the subcellular distribution, directionality, velocity, and run length of KIF1C-associated vesicles in primary human macrophages, as well as the targeting frequency of microtubule plus ends to podosomes.","method":"MEC-17 overexpression/siRNA, tubacin (deacetylase inhibitor) treatment, live-cell imaging of KIF1C vesicle dynamics, immunofluorescence","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct measurement of KIF1C vesicle parameters under tubulin acetylation perturbations, single lab, two orthogonal methods (genetic and pharmacological)","pmids":["25151635"],"is_preprint":false},{"year":2019,"finding":"KIF1C is autoinhibited through an interaction between its microtubule-binding surface (motor domain) and its stalk. This autoinhibition is released by binding of PTPN21's FERM domain or the cargo adaptor Hook3 to the KIF1C tail. In vitro, full-length human KIF1C is a processive, plus-end-directed motor; its landing rate onto microtubules increases in the presence of PTPN21 FERM domain or Hook3. PTPN21 FERM domain stimulates dense core vesicle transport in primary hippocampal neurons and rescues integrin trafficking in KIF1C-depleted cells.","method":"In vitro single-molecule motility assay with purified full-length KIF1C, domain-binding assays, neuronal DCV transport assay, integrin trafficking rescue in KIF1C-depleted cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified full-length motor establishing autoinhibition mechanism and activator-induced landing rate increase, corroborated by neuronal transport and integrin rescue assays; single lab, multiple orthogonal methods","pmids":["31217419"],"is_preprint":false},{"year":2019,"finding":"Hook3 acts as a scaffold that simultaneously binds dynein/dynactin (activating its motility) and the tail of KIF1C (without activating KIF1C). This trimeric complex allows dynein to transport KIF1C toward the minus end and KIF1C to transport dynein toward the plus end; in cells, KIF1C can recruit Hook3 to the cell periphery.","method":"In vitro reconstitution with purified components (dynein/dynactin, Hook3, KIF1C), single-molecule motility assays, mass spectrometry, co-IP, live-cell imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of tri-partite complex with purified components plus single-molecule motility, supported by MS interactome and cellular imaging; single lab but multiple orthogonal Tier-1 methods","pmids":["31320392"],"is_preprint":false},{"year":2021,"finding":"KIF1C interacts with APC-dependent mRNAs and is required for their active transport to cytoplasmic protrusions along microtubules. Two-color live-cell imaging directly showed single mRNAs transported by single KIF1C motors; the mRNA 3'UTR is sufficient for KIF1C-dependent transport. KIF1C also maintains peripheral multimeric mRNA clusters and transports its own mRNA.","method":"Live-cell single-molecule imaging (two-color), siRNA KIF1C depletion, mRNA localization assay, 3'UTR sufficiency experiment","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct two-color single-molecule visualization of mRNA-motor co-transport, KD with specific mRNA localization phenotype, 3'UTR domain mapping; single lab, multiple orthogonal methods","pmids":["34493599"],"is_preprint":false},{"year":2019,"finding":"Kif1c regulates actin ring formation and osteoclastic bone resorption downstream of p130Cas (and upstream of c-Src). Kif1c shRNA knockdown in wild-type osteoclasts suppressed actin ring formation; Kif1c overexpression rescued bone resorption in p130CasΔOCL−/− osteoclasts but not in c-Src−/− osteoclasts, placing Kif1c between p130Cas and c-Src in this signaling pathway.","method":"shRNA knockdown, overexpression rescue epistasis, cDNA microarray for pathway placement, bone resorption assay","journal":"Cell biochemistry and function","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with KD and overexpression rescue in two distinct KO backgrounds establishing pathway position; single lab","pmids":["31887784"],"is_preprint":false},{"year":2022,"finding":"c-Src phosphorylates tyrosine residues within the stalk domain of KIF1C, enhancing its association with PTPD1, which in turn activates KIF1C's microtubule-binding ability, likely by relieving autoinhibitory motor–stalk interactions. KIF1C localizes to invadopodium tips and is required for invadopodia elongation and cancer cell invasion.","method":"c-Src overexpression/inhibition, phospho-mutant constructs, co-IP, microtubule-binding assay, invadopodia elongation assay, invasion assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-mutant constructs and co-IP demonstrating c-Src-mediated stalk phosphorylation and PTPD1 recruitment, plus functional invadopodia phenotype; single lab, multiple methods","pmids":["35654143"],"is_preprint":false},{"year":2022,"finding":"In neuronal cells, KIF1C interacts with all core components of the exon junction complex (EJC) in an RNA-mediated manner (abolished by RNase treatment); expression of mutant KIF1C causes loss of distal neurite EJC localization and pericentrosomal accumulation of EJC components, suggesting KIF1C transports mRNA in an EJC-bound state along neurites.","method":"Affinity proteomics (AP-MS) in SH-SY5Y cells, co-immunoprecipitation, RNase treatment, immunostaining of mutant KIF1C-expressing cells, UV-crosslinking RNA-protein extraction","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS with co-IP validation and RNase sensitivity test plus subcellular mislocalization phenotype; single lab, multiple orthogonal methods","pmids":["36316088"],"is_preprint":false},{"year":2023,"finding":"Localization of Kif1c mRNA to cell protrusions does not regulate KIF1C protein abundance or distribution but is required for directed cell migration and controls the specificity of KIF1C protein–protein interactions; mRNA mislocalization dramatically dysregulates the number and identity of KIF1C binding partners as determined by mass spectrometry.","method":"Kif1c mRNA mislocalization (genetic perturbation), mass spectrometry of endogenous KIF1C interactors, directed migration assays","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous KIF1C interactome by MS under mRNA mislocalization condition, functional migration readout; single lab, two orthogonal methods","pmids":["36859340"],"is_preprint":false},{"year":2024,"finding":"KIF1C's C-terminal tail contains an intrinsically disordered region (IDR) that drives liquid-liquid phase separation (LLPS). KIF1C forms dynamic liquid condensates in cellular protrusions that incorporate RNA molecules in a sequence-selective manner. Purified KIF1C tail constructs undergo LLPS in vitro at near-endogenous nM concentrations without crowding agents and directly recruit RNA. IDR-dependent LLPS is required for enrichment of mRNA cargoes at the cell periphery.","method":"In vitro LLPS with purified KIF1C tail, live-cell condensate imaging (FRAP, fluorescence recovery), IDR deletion mutants, RNA recruitment assay in vitro and in cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of LLPS with purified protein plus domain-deletion mutants and cellular functional consequence; single lab but Tier-1 methods with multiple orthogonal validations","pmids":["38898313"],"is_preprint":false},{"year":2024,"finding":"KIF1C unexpectedly supports retrograde transport of lysosomes toward the nucleus via dynein, without requiring its own motor activity (which is actually inhibitory for this process). Mechanistically, KIF1C interacts with dynein-activating adaptor Hook3, which associates with the lysosome-anchored protein RUFY3, thereby activating dynein-driven lysosomal transport. This non-motor role of KIF1C is required for efficient autophagic and endocytic cargo degradation.","method":"KIF1C depletion, motor-dead KIF1C mutant, co-IP (KIF1C–Hook3–RUFY3), lysosome positioning assay, autophagic/endocytic degradation assays","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — motor-dead mutant epistasis plus co-IP of trimeric complex with functional organelle positioning and degradation readout; single lab, multiple orthogonal methods","pmids":["39394274"],"is_preprint":false},{"year":2025,"finding":"Crystal structure of the Hook3(553–624)–KIF1C(714–809) complex was determined, revealing the molecular basis for Hook3–KIF1C interaction. Structure-based mutations in this interface abolish binding between full-length proteins in HEK293T cells and abrogate Hook3/KIF1C-mediated anterograde transport in RPE1 cells, demonstrating the complex is necessary and sufficient for Hook3-activated KIF1C transport.","method":"Crystal structure determination, structure-based mutagenesis, co-IP in HEK293T cells, anterograde transport assay in RPE1 cells","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with structure-based mutagenesis validated by co-IP and functional transport assay; single lab but Tier-1 structural method with functional corroboration","pmids":["40312563"],"is_preprint":false},{"year":2025,"finding":"CNBP (RNA-binding protein) binds directly to GA-rich sequences in the 3'UTR of protrusion-targeted mRNAs and interacts with KIF1C; CNBP is required for KIF1C recruitment to mRNA cargo and for active mRNA transport on microtubules to the cell periphery, defining a KIF1C–CNBP motor-adaptor complex for mRNA transport.","method":"RNA pulldown, co-IP (CNBP–KIF1C), siRNA depletion, live-cell mRNA transport assay, 3'UTR binding assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding, protein co-IP, KD with specific mRNA trafficking phenotype; single lab, multiple orthogonal methods","pmids":["39982819"],"is_preprint":false},{"year":2025,"finding":"Liquid-liquid phase separation of KIF1C generates multi-kinesin clusters that entangle neighboring microtubules and impose mechanical stress sufficient to cause microtubule breakage and disassembly in cells. Microtubule fragmentation requires a highly processive motor domain, a stiff clustering mechanism (IDR-driven LLPS), and sufficient drag force.","method":"Live-cell imaging of microtubule breakage, computational simulations, IDR/motor domain mutants, in vitro LLPS","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro LLPS combined with live-cell breakage imaging and computational modeling; preprint, single lab, not yet peer-reviewed","pmids":["bio_10.1101_2025.01.31.635950"],"is_preprint":true}],"current_model":"KIF1C is an autoinhibited kinesin-3 (Unc104 subfamily) plus-end-directed motor whose activity is suppressed by an intramolecular interaction between its motor domain and stalk, and is released by binding of PTPN21/FERM or the dynein-activating adaptor Hook3 to its tail; once active, it transports diverse cargoes—including Rab6A-positive Golgi/secretory vesicles, α5β1-integrins to trailing focal adhesions, dense core vesicles in neurons, and APC-dependent mRNAs to cell protrusions via a CNBP motor-adaptor complex—along microtubules toward the plus end, while its C-terminal IDR drives liquid-liquid phase separation that enables sequence-selective mRNA clustering at the periphery; it also scaffolds bidirectional transport by binding Hook3 together with dynein/dynactin, and in a non-motor capacity activates dynein-driven retrograde lysosomal transport through Hook3–RUFY3; its activity and localization are further regulated by casein kinase II phosphorylation of Ser1092 (enabling 14-3-3 binding), c-Src-mediated tyrosine phosphorylation of its stalk (enhancing PTPD1 association), Rab6A binding to its motor domain (inhibiting microtubule interaction), CLASP-dependent microtubule track selection, and tubulin acetylation status."},"narrative":{"mechanistic_narrative":"KIF1C is a plus-end-directed kinesin-3 motor that transports diverse membranous and ribonucleoprotein cargoes along microtubules and additionally scaffolds dynein-driven transport in both motor-dependent and non-motor capacities [PMID:31217419, PMID:31320392]. The motor is held inactive by an intramolecular interaction between its microtubule-binding motor domain and stalk; this autoinhibition is relieved when the FERM domain of PTPN21 or the cargo adaptor Hook3 binds the KIF1C tail, increasing its landing rate on microtubules and converting it into a processive motor [PMID:31217419]. Activation is further tuned by phosphorylation: casein kinase II phosphorylation of Ser1092 generates a 14-3-3 binding site [PMID:10559254], and c-Src-mediated tyrosine phosphorylation of the stalk enhances PTPD1 association to relieve autoinhibition [PMID:35654143], while Rab6A binding to the motor domain inhibits microtubule engagement [PMID:25821985]. Once active, KIF1C delivers Rab6A-positive secretory vesicles to the cell surface and protects Golgi integrity [PMID:25821985], traffics α5β1-integrins to trailing focal adhesions to stabilize the cell rear during directional migration [PMID:23237952], and supports podosome and invadopodia dynamics in macrophages and cancer cells [PMID:16554367, PMID:35654143]. KIF1C is also an mRNA transport motor: it carries APC-dependent and EJC-bound transcripts to cytoplasmic protrusions, with cargo specificity conferred by the RNA-binding adaptor CNBP recognizing GA-rich 3'UTR sequences [PMID:34493599, PMID:36316088, PMID:39982819]. Its C-terminal intrinsically disordered region drives liquid-liquid phase separation that sequence-selectively clusters mRNA at the periphery [PMID:38898313]. Beyond carrying cargo itself, KIF1C bridges dynein/dynactin via Hook3 to enable bidirectional transport [PMID:31320392], and in a non-motor mode activates dynein-driven retrograde lysosomal transport through a Hook3–RUFY3 link required for autophagic and endocytic degradation [PMID:39394274]. The structural basis of the Hook3–KIF1C interaction has been resolved, defining an interface necessary for Hook3-activated anterograde transport [PMID:40312563].","teleology":[{"year":1998,"claim":"Established KIF1C as a kinesin-like protein and proposed a first cellular role, framing it as a Golgi-associated motor potentially driving Golgi-to-ER retrograde transport.","evidence":"Yeast two-hybrid with PTPD1 ezrin domain, immunofluorescence localization, and dominant-negative overexpression with brefeldin A in cultured cells","pmids":["9685376"],"confidence":"Medium","gaps":["Dominant-negative phenotype not confirmed by loss-of-function genetics","Direct motor activity not demonstrated","Cargo identity unresolved"]},{"year":1999,"claim":"Identified phosphoregulation of KIF1C, showing CK2 phosphorylation of Ser1092 creates a 14-3-3 docking site, the first regulatory input on the motor.","evidence":"In vitro CK2 kinase assay, co-IP of 14-3-3 isoforms, and CK2 inhibition in cells","pmids":["10559254"],"confidence":"High","gaps":["Functional consequence of 14-3-3 binding for transport not defined","Connection to cargo selection unknown"]},{"year":2002,"claim":"Linked KIF1C function and localization to a physiological output, anthrax lethal toxin susceptibility in macrophages, acting at a post-entry step.","evidence":"Genetic mapping, allele-specific overexpression rescue, brefeldin A perturbation, and MKK3 cleavage assays","pmids":["11591317"],"confidence":"Medium","gaps":["Molecular mechanism downstream of KIF1C not defined","Relevance to human cells unclear"]},{"year":2002,"claim":"Overturned the proposed Golgi-to-ER retrograde role by showing KIF1C knockout mice are viable with normal retrograde transport, redirecting the field toward other functions.","evidence":"Gene knockout with beta-gal knock-in and time-lapse BFA-induced transport analysis in primary fibroblasts","pmids":["11784862"],"confidence":"High","gaps":["Did not identify the true physiological cargo or function","Possible redundancy with other motors not tested"]},{"year":2006,"claim":"Repositioned KIF1C as a plus-end-enriched motor at podosomes that physically bridges actin and microtubule cytoskeletons via non-muscle myosin IIA.","evidence":"siRNA/shRNA knockdown, dominant-negative constructs, co-IP, and live imaging in primary human macrophages","pmids":["16554367"],"confidence":"High","gaps":["Cargo transported to podosomes not identified","Directness of myosin IIA interaction at structural level not resolved"]},{"year":2012,"claim":"Defined a concrete cargo and migration function: KIF1C transports α5β1-integrins to the trailing edge to stabilize the rear during directional cell migration.","evidence":"siRNA depletion, integrin trafficking and migration assays, and myosin II inhibition epistasis","pmids":["23237952"],"confidence":"High","gaps":["Adaptor coupling KIF1C to integrin cargo not defined","Mechanism of rear-specific targeting unclear"]},{"year":2014,"claim":"Revealed Rab6A as a dual regulator/cargo factor whose binding to the motor domain inhibits microtubule interaction, while KIF1C is required for surface delivery and Golgi integrity.","evidence":"In vitro microtubule binding assays, co-IP, siRNA depletion, live vesicle imaging, and domain-deletion rescue in eLife study","pmids":["25821985"],"confidence":"High","gaps":["How Rab6A inhibition is relieved in vivo not defined","Motor-independent Golgi protection mechanism unresolved"]},{"year":2014,"claim":"Showed KIF1C peripheral targeting depends on CLASP proteins and on microtubule acetylation, identifying track-selection inputs governing where KIF1C operates.","evidence":"CLASP siRNA, chimeric mitochondrial CLASP2 recruitment, MEC-17 perturbation, tubacin treatment, and live imaging in macrophages","pmids":["25344256","25151635"],"confidence":"Medium","gaps":["Molecular nature of CLASP–KIF1C contact not mapped","Whether acetylation acts on motor or track recruitment unresolved"]},{"year":2019,"claim":"Established the core activation mechanism: full-length KIF1C is autoinhibited via a motor–stalk interaction that is released by PTPN21 FERM or Hook3 binding to the tail, converting it to a processive motor.","evidence":"Single-molecule motility with purified full-length KIF1C, domain-binding assays, neuronal DCV transport, and integrin trafficking rescue","pmids":["31217419"],"confidence":"High","gaps":["Structural detail of the autoinhibited conformation not resolved","How phosphorylation integrates with adaptor-mediated release unclear"]},{"year":2019,"claim":"Demonstrated Hook3 scaffolds bidirectional transport, simultaneously binding dynein/dynactin and the KIF1C tail to couple opposing motors.","evidence":"In vitro reconstitution with purified dynein/dynactin, Hook3 and KIF1C, single-molecule motility, mass spectrometry, co-IP and live imaging","pmids":["31320392"],"confidence":"High","gaps":["How directionality of the trimeric complex is biased in cells not defined","Cargo carried by the bidirectional complex not identified"]},{"year":2019,"claim":"Placed Kif1c in an osteoclast signaling pathway between p130Cas and c-Src controlling actin ring formation and bone resorption.","evidence":"shRNA knockdown, overexpression rescue in p130Cas and c-Src knockout backgrounds, and bone resorption assays","pmids":["31887784"],"confidence":"Medium","gaps":["Molecular target of KIF1C in this pathway not defined","Whether motor activity is required not tested"]},{"year":2021,"claim":"Identified KIF1C as a direct mRNA transport motor carrying APC-dependent transcripts and its own mRNA to protrusions, with 3'UTR sufficiency for transport.","evidence":"Two-color single-molecule live imaging, siRNA depletion, mRNA localization and 3'UTR sufficiency assays","pmids":["34493599"],"confidence":"High","gaps":["RNA-binding adaptor not yet identified in this study","Selectivity for specific transcripts unexplained"]},{"year":2022,"claim":"Extended the mRNA cargo model by showing RNA-dependent association of KIF1C with the exon junction complex during neurite transport.","evidence":"AP-MS in SH-SY5Y cells, co-IP with RNase sensitivity, and mutant KIF1C mislocalization imaging","pmids":["36316088"],"confidence":"Medium","gaps":["Direct versus RNA-bridged EJC contact not distinguished","Functional consequence of EJC mislocalization for translation not assessed"]},{"year":2022,"claim":"Connected c-Src tyrosine phosphorylation of the stalk to PTPD1 recruitment and autoinhibition relief, linking the motor to invadopodia-driven cancer invasion.","evidence":"c-Src perturbation, phospho-mutant constructs, co-IP, microtubule-binding and invadopodia/invasion assays","pmids":["35654143"],"confidence":"Medium","gaps":["Specific phosphorylated tyrosines and structural effect not mapped","Quantitative contribution relative to adaptor activation unknown"]},{"year":2023,"claim":"Showed that localization of Kif1c mRNA itself, rather than protein abundance, dictates the identity and number of KIF1C protein interactions and supports directed migration.","evidence":"mRNA mislocalization genetic perturbation, mass spectrometry of endogenous interactors, and migration assays","pmids":["36859340"],"confidence":"Medium","gaps":["Mechanism coupling local translation to interaction specificity unresolved","Which mislocalized interactions are functionally decisive not defined"]},{"year":2024,"claim":"Demonstrated that the KIF1C C-terminal IDR drives liquid-liquid phase separation that sequence-selectively recruits and clusters mRNA at the periphery.","evidence":"In vitro LLPS with purified tail at near-endogenous concentrations, FRAP, IDR-deletion mutants, and RNA recruitment assays","pmids":["38898313"],"confidence":"High","gaps":["How LLPS is spatially restricted to protrusions unclear","Relationship between condensate state and motility not fully defined"]},{"year":2024,"claim":"Uncovered a non-motor role in which KIF1C activates dynein-driven retrograde lysosomal transport via a Hook3–RUFY3 axis required for cargo degradation.","evidence":"KIF1C depletion, motor-dead mutant, co-IP of KIF1C–Hook3–RUFY3, lysosome positioning and degradation assays","pmids":["39394274"],"confidence":"Medium","gaps":["How the same Hook3 scaffold switches between anterograde and retrograde modes not resolved","Stoichiometry of the KIF1C–Hook3–RUFY3 complex unknown"]},{"year":2025,"claim":"Defined the molecular CNBP–KIF1C motor-adaptor that couples GA-rich 3'UTR recognition to active mRNA transport, supplying the missing RNA-binding link.","evidence":"RNA pulldown, co-IP, siRNA depletion, and live-cell mRNA transport and 3'UTR binding assays","pmids":["39982819"],"confidence":"Medium","gaps":["Whether CNBP acts within KIF1C condensates not tested","Generality across all protrusion mRNAs unresolved"]},{"year":2025,"claim":"Resolved the structural basis of Hook3-activated transport, defining the Hook3–KIF1C interface necessary and sufficient for anterograde motility.","evidence":"Crystal structure of Hook3(553–624)–KIF1C(714–809), structure-based mutagenesis, co-IP and anterograde transport assays","pmids":["40312563"],"confidence":"High","gaps":["Structure of the autoinhibited full-length motor still lacking","How adaptor binding mechanically relieves autoinhibition not visualized"]},{"year":2025,"claim":"Proposed that KIF1C LLPS-driven multi-kinesin clusters generate mechanical force that fragments microtubules, implying an active role in cytoskeletal remodeling.","evidence":"Live-cell microtubule breakage imaging, computational simulation, IDR/motor mutants, and in vitro LLPS (preprint)","pmids":["bio_10.1101_2025.01.31.635950"],"confidence":"Medium","gaps":["Not yet peer-reviewed","Physiological role of microtubule breakage unconfirmed","Whether this occurs at endogenous expression levels unclear"]},{"year":null,"claim":"It remains unresolved how the multiple activating inputs (phosphorylation, adaptor binding, Rab6A inhibition, mRNA localization) are integrated to select cargo, direction, and condensate state at specific subcellular sites.","evidence":"Open question synthesized across the timeline","pmids":[],"confidence":"Medium","gaps":["No unified model coupling autoinhibition release to specific cargo classes","Structure of the full autoinhibited motor unknown","Switch between anterograde motor and non-motor dynein-activating modes undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[9,10,11]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[9]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,6]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[11,16,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,17]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[4,8,20]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11,16]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6,9,10]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[11,16,19]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[5]}],"complexes":["KIF1C–Hook3–dynein/dynactin complex","KIF1C–Hook3–RUFY3 complex","KIF1C–CNBP mRNA motor-adaptor complex"],"partners":["HOOK3","PTPN21","RAB6A","PTPD1","CNBP","RUFY3","14-3-3","CLASP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43896","full_name":"Kinesin-like protein KIF1C","aliases":[],"length_aa":1103,"mass_kda":122.9,"function":"Motor required for the retrograde transport of Golgi vesicles to the endoplasmic reticulum. 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KIF1C was identified via yeast two-hybrid using the ezrin domain of PTPD1 as bait, and was found to be tyrosine-phosphorylated after peroxovanadate stimulation.\",\n      \"method\": \"Yeast two-hybrid, immunofluorescence, dominant-negative overexpression in 293/NIH3T3/C2C12 cells, brefeldin A treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative overexpression with specific organelle phenotype, immunofluorescence localization, single lab with two orthogonal methods\",\n      \"pmids\": [\"9685376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"KIF1C dimerizes and associates with 14-3-3 proteins (beta, gamma, epsilon, zeta) via phosphorylation of Ser1092 (in a canonical 14-3-3 binding sequence). Ser1092 is a substrate for casein kinase II in vitro; inhibition of casein kinase II in cells reduced KIF1C–14-3-3γ association.\",\n      \"method\": \"Yeast two-hybrid, transient overexpression, co-immunoprecipitation, in vitro kinase assay, casein kinase II inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay identifying CK2 as writer, reciprocal co-IP confirming 14-3-3 interaction dependent on pSer1092, and cellular rescue by inhibitor; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"10559254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Kif1C alleles determine resistance or susceptibility of mouse macrophages to anthrax lethal toxin (LeTx). Brefeldin A treatment (which alters KIF1C cellular localization) converts resistant macrophages to susceptibility; ectopic expression of a resistance allele in susceptible macrophages increases survival. KIF1C acts downstream of toxin entry/processing (MKK3 cleavage still occurs in resistant cells), likely influencing a post-entry step.\",\n      \"method\": \"Genetic mapping, allele overexpression, brefeldin A treatment, LeTx susceptibility assay, MKK3 cleavage assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with allele-specific rescue and localization perturbation, single lab, multiple approaches\",\n      \"pmids\": [\"11591317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"KIF1C knockout mice are viable with no obvious abnormalities; primary lung fibroblasts from kif1C−/− mice show no significant difference in Golgi distribution or brefeldin A-induced Golgi-to-ER retrograde transport, indicating KIF1C is dispensable for this retrograde transport in vivo.\",\n      \"method\": \"Gene knockout (knock-in of beta-gal into motor domain), immunocytochemistry, time-lapse analysis of BFA-induced transport\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with time-lapse functional readout; negates earlier proposed Golgi-to-ER transport role, replicated across multiple cell/tissue types\",\n      \"pmids\": [\"11784862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"KIF1C is a microtubule plus-end-enriched kinesin that targets podosome turnover regions in primary human macrophages; KIF1C depletion (siRNA/shRNA) or expression of dominant-negative constructs decreases podosome dynamics and causes podosome deficiency. KIF1C binds non-muscle myosin IIA via its PTPD-binding domain, linking actin and tubulin cytoskeletons.\",\n      \"method\": \"siRNA/shRNA knockdown, dominant-negative overexpression, protein interaction studies (co-IP), live-cell imaging, immunofluorescence in primary human macrophages\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with specific podosome phenotype, protein interaction confirmed by co-IP, plus-end localization by live imaging; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"16554367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KIF1C mediates transport of α5β1-integrins to trailing focal adhesions, which is required for maturation of these adhesions and resistance to tail retraction during directional cell migration. Loss of KIF1C leads to impaired rear stabilization and reduced directional persistence; the phenotype is suppressed by myosin II inhibition.\",\n      \"method\": \"Kif1C depletion (siRNA), live-cell migration assays, integrin trafficking assays, myosin II inhibition epistasis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cargo (α5β1 integrin), specific cellular phenotype (tail retraction/directionality), genetic epistasis with myosin II inhibition; single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"23237952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rab6A binds to both the motor domain and the C-terminus of KIF1C; Rab6A binding to the motor domain inhibits microtubule interaction in vitro and in cells, reducing the pool of motile KIF1C. KIF1C depletion slows protein delivery to the cell surface, disrupts vesicle motility, and triggers Golgi fragmentation. Protection of Golgi from fragmentation requires Rab6A-binding at both ends but not KIF1C motor activity.\",\n      \"method\": \"In vitro microtubule binding assay, co-IP, KIF1C depletion (siRNA), live-cell imaging of vesicle motility, Golgi fragmentation assay, rescue with deletion constructs\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution of Rab6A inhibition of motor domain MT binding, plus cellular KD with specific cargo/organelle phenotype and domain-mapping rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25821985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIF1C translocation to the cell periphery is dependent on CLASP proteins; upon PKC-induced podosome formation, KIF1C accumulates near CLASPs at peripheral microtubule plus ends. Chimeric mitochondrially-targeted CLASP2 recruits KIF1C, indicating a direct transient CLASP–KIF1C association that is required for KIF1C trafficking and podosome formation.\",\n      \"method\": \"CLASP siRNA knockdown, PKC activation, live-cell imaging, chimeric CLASP2 mitochondrial targeting assay, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chimeric targeting experiment directly recruits KIF1C to mitochondria via CLASP2, plus KD phenotype; single lab, two orthogonal methods\",\n      \"pmids\": [\"25344256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Microtubule acetylation (regulated by MEC-17 acetyltransferase) influences the subcellular distribution, directionality, velocity, and run length of KIF1C-associated vesicles in primary human macrophages, as well as the targeting frequency of microtubule plus ends to podosomes.\",\n      \"method\": \"MEC-17 overexpression/siRNA, tubacin (deacetylase inhibitor) treatment, live-cell imaging of KIF1C vesicle dynamics, immunofluorescence\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct measurement of KIF1C vesicle parameters under tubulin acetylation perturbations, single lab, two orthogonal methods (genetic and pharmacological)\",\n      \"pmids\": [\"25151635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KIF1C is autoinhibited through an interaction between its microtubule-binding surface (motor domain) and its stalk. This autoinhibition is released by binding of PTPN21's FERM domain or the cargo adaptor Hook3 to the KIF1C tail. In vitro, full-length human KIF1C is a processive, plus-end-directed motor; its landing rate onto microtubules increases in the presence of PTPN21 FERM domain or Hook3. PTPN21 FERM domain stimulates dense core vesicle transport in primary hippocampal neurons and rescues integrin trafficking in KIF1C-depleted cells.\",\n      \"method\": \"In vitro single-molecule motility assay with purified full-length KIF1C, domain-binding assays, neuronal DCV transport assay, integrin trafficking rescue in KIF1C-depleted cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified full-length motor establishing autoinhibition mechanism and activator-induced landing rate increase, corroborated by neuronal transport and integrin rescue assays; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31217419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Hook3 acts as a scaffold that simultaneously binds dynein/dynactin (activating its motility) and the tail of KIF1C (without activating KIF1C). This trimeric complex allows dynein to transport KIF1C toward the minus end and KIF1C to transport dynein toward the plus end; in cells, KIF1C can recruit Hook3 to the cell periphery.\",\n      \"method\": \"In vitro reconstitution with purified components (dynein/dynactin, Hook3, KIF1C), single-molecule motility assays, mass spectrometry, co-IP, live-cell imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of tri-partite complex with purified components plus single-molecule motility, supported by MS interactome and cellular imaging; single lab but multiple orthogonal Tier-1 methods\",\n      \"pmids\": [\"31320392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KIF1C interacts with APC-dependent mRNAs and is required for their active transport to cytoplasmic protrusions along microtubules. Two-color live-cell imaging directly showed single mRNAs transported by single KIF1C motors; the mRNA 3'UTR is sufficient for KIF1C-dependent transport. KIF1C also maintains peripheral multimeric mRNA clusters and transports its own mRNA.\",\n      \"method\": \"Live-cell single-molecule imaging (two-color), siRNA KIF1C depletion, mRNA localization assay, 3'UTR sufficiency experiment\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct two-color single-molecule visualization of mRNA-motor co-transport, KD with specific mRNA localization phenotype, 3'UTR domain mapping; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34493599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Kif1c regulates actin ring formation and osteoclastic bone resorption downstream of p130Cas (and upstream of c-Src). Kif1c shRNA knockdown in wild-type osteoclasts suppressed actin ring formation; Kif1c overexpression rescued bone resorption in p130CasΔOCL−/− osteoclasts but not in c-Src−/− osteoclasts, placing Kif1c between p130Cas and c-Src in this signaling pathway.\",\n      \"method\": \"shRNA knockdown, overexpression rescue epistasis, cDNA microarray for pathway placement, bone resorption assay\",\n      \"journal\": \"Cell biochemistry and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with KD and overexpression rescue in two distinct KO backgrounds establishing pathway position; single lab\",\n      \"pmids\": [\"31887784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"c-Src phosphorylates tyrosine residues within the stalk domain of KIF1C, enhancing its association with PTPD1, which in turn activates KIF1C's microtubule-binding ability, likely by relieving autoinhibitory motor–stalk interactions. KIF1C localizes to invadopodium tips and is required for invadopodia elongation and cancer cell invasion.\",\n      \"method\": \"c-Src overexpression/inhibition, phospho-mutant constructs, co-IP, microtubule-binding assay, invadopodia elongation assay, invasion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-mutant constructs and co-IP demonstrating c-Src-mediated stalk phosphorylation and PTPD1 recruitment, plus functional invadopodia phenotype; single lab, multiple methods\",\n      \"pmids\": [\"35654143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In neuronal cells, KIF1C interacts with all core components of the exon junction complex (EJC) in an RNA-mediated manner (abolished by RNase treatment); expression of mutant KIF1C causes loss of distal neurite EJC localization and pericentrosomal accumulation of EJC components, suggesting KIF1C transports mRNA in an EJC-bound state along neurites.\",\n      \"method\": \"Affinity proteomics (AP-MS) in SH-SY5Y cells, co-immunoprecipitation, RNase treatment, immunostaining of mutant KIF1C-expressing cells, UV-crosslinking RNA-protein extraction\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS with co-IP validation and RNase sensitivity test plus subcellular mislocalization phenotype; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36316088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Localization of Kif1c mRNA to cell protrusions does not regulate KIF1C protein abundance or distribution but is required for directed cell migration and controls the specificity of KIF1C protein–protein interactions; mRNA mislocalization dramatically dysregulates the number and identity of KIF1C binding partners as determined by mass spectrometry.\",\n      \"method\": \"Kif1c mRNA mislocalization (genetic perturbation), mass spectrometry of endogenous KIF1C interactors, directed migration assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous KIF1C interactome by MS under mRNA mislocalization condition, functional migration readout; single lab, two orthogonal methods\",\n      \"pmids\": [\"36859340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIF1C's C-terminal tail contains an intrinsically disordered region (IDR) that drives liquid-liquid phase separation (LLPS). KIF1C forms dynamic liquid condensates in cellular protrusions that incorporate RNA molecules in a sequence-selective manner. Purified KIF1C tail constructs undergo LLPS in vitro at near-endogenous nM concentrations without crowding agents and directly recruit RNA. IDR-dependent LLPS is required for enrichment of mRNA cargoes at the cell periphery.\",\n      \"method\": \"In vitro LLPS with purified KIF1C tail, live-cell condensate imaging (FRAP, fluorescence recovery), IDR deletion mutants, RNA recruitment assay in vitro and in cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of LLPS with purified protein plus domain-deletion mutants and cellular functional consequence; single lab but Tier-1 methods with multiple orthogonal validations\",\n      \"pmids\": [\"38898313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIF1C unexpectedly supports retrograde transport of lysosomes toward the nucleus via dynein, without requiring its own motor activity (which is actually inhibitory for this process). Mechanistically, KIF1C interacts with dynein-activating adaptor Hook3, which associates with the lysosome-anchored protein RUFY3, thereby activating dynein-driven lysosomal transport. This non-motor role of KIF1C is required for efficient autophagic and endocytic cargo degradation.\",\n      \"method\": \"KIF1C depletion, motor-dead KIF1C mutant, co-IP (KIF1C–Hook3–RUFY3), lysosome positioning assay, autophagic/endocytic degradation assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — motor-dead mutant epistasis plus co-IP of trimeric complex with functional organelle positioning and degradation readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39394274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Crystal structure of the Hook3(553–624)–KIF1C(714–809) complex was determined, revealing the molecular basis for Hook3–KIF1C interaction. Structure-based mutations in this interface abolish binding between full-length proteins in HEK293T cells and abrogate Hook3/KIF1C-mediated anterograde transport in RPE1 cells, demonstrating the complex is necessary and sufficient for Hook3-activated KIF1C transport.\",\n      \"method\": \"Crystal structure determination, structure-based mutagenesis, co-IP in HEK293T cells, anterograde transport assay in RPE1 cells\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with structure-based mutagenesis validated by co-IP and functional transport assay; single lab but Tier-1 structural method with functional corroboration\",\n      \"pmids\": [\"40312563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CNBP (RNA-binding protein) binds directly to GA-rich sequences in the 3'UTR of protrusion-targeted mRNAs and interacts with KIF1C; CNBP is required for KIF1C recruitment to mRNA cargo and for active mRNA transport on microtubules to the cell periphery, defining a KIF1C–CNBP motor-adaptor complex for mRNA transport.\",\n      \"method\": \"RNA pulldown, co-IP (CNBP–KIF1C), siRNA depletion, live-cell mRNA transport assay, 3'UTR binding assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding, protein co-IP, KD with specific mRNA trafficking phenotype; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39982819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Liquid-liquid phase separation of KIF1C generates multi-kinesin clusters that entangle neighboring microtubules and impose mechanical stress sufficient to cause microtubule breakage and disassembly in cells. Microtubule fragmentation requires a highly processive motor domain, a stiff clustering mechanism (IDR-driven LLPS), and sufficient drag force.\",\n      \"method\": \"Live-cell imaging of microtubule breakage, computational simulations, IDR/motor domain mutants, in vitro LLPS\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro LLPS combined with live-cell breakage imaging and computational modeling; preprint, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.01.31.635950\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"KIF1C is an autoinhibited kinesin-3 (Unc104 subfamily) plus-end-directed motor whose activity is suppressed by an intramolecular interaction between its motor domain and stalk, and is released by binding of PTPN21/FERM or the dynein-activating adaptor Hook3 to its tail; once active, it transports diverse cargoes—including Rab6A-positive Golgi/secretory vesicles, α5β1-integrins to trailing focal adhesions, dense core vesicles in neurons, and APC-dependent mRNAs to cell protrusions via a CNBP motor-adaptor complex—along microtubules toward the plus end, while its C-terminal IDR drives liquid-liquid phase separation that enables sequence-selective mRNA clustering at the periphery; it also scaffolds bidirectional transport by binding Hook3 together with dynein/dynactin, and in a non-motor capacity activates dynein-driven retrograde lysosomal transport through Hook3–RUFY3; its activity and localization are further regulated by casein kinase II phosphorylation of Ser1092 (enabling 14-3-3 binding), c-Src-mediated tyrosine phosphorylation of its stalk (enhancing PTPD1 association), Rab6A binding to its motor domain (inhibiting microtubule interaction), CLASP-dependent microtubule track selection, and tubulin acetylation status.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIF1C is a plus-end-directed kinesin-3 motor that transports diverse membranous and ribonucleoprotein cargoes along microtubules and additionally scaffolds dynein-driven transport in both motor-dependent and non-motor capacities [#9, #10]. The motor is held inactive by an intramolecular interaction between its microtubule-binding motor domain and stalk; this autoinhibition is relieved when the FERM domain of PTPN21 or the cargo adaptor Hook3 binds the KIF1C tail, increasing its landing rate on microtubules and converting it into a processive motor [#9]. Activation is further tuned by phosphorylation: casein kinase II phosphorylation of Ser1092 generates a 14-3-3 binding site [#1], and c-Src-mediated tyrosine phosphorylation of the stalk enhances PTPD1 association to relieve autoinhibition [#13], while Rab6A binding to the motor domain inhibits microtubule engagement [#6]. Once active, KIF1C delivers Rab6A-positive secretory vesicles to the cell surface and protects Golgi integrity [#6], traffics \\u03b15\\u03b21-integrins to trailing focal adhesions to stabilize the cell rear during directional migration [#5], and supports podosome and invadopodia dynamics in macrophages and cancer cells [#4, #13]. KIF1C is also an mRNA transport motor: it carries APC-dependent and EJC-bound transcripts to cytoplasmic protrusions, with cargo specificity conferred by the RNA-binding adaptor CNBP recognizing GA-rich 3'UTR sequences [#11, #14, #19]. Its C-terminal intrinsically disordered region drives liquid-liquid phase separation that sequence-selectively clusters mRNA at the periphery [#16]. Beyond carrying cargo itself, KIF1C bridges dynein/dynactin via Hook3 to enable bidirectional transport [#10], and in a non-motor mode activates dynein-driven retrograde lysosomal transport through a Hook3\\u2013RUFY3 link required for autophagic and endocytic degradation [#17]. The structural basis of the Hook3\\u2013KIF1C interaction has been resolved, defining an interface necessary for Hook3-activated anterograde transport [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established KIF1C as a kinesin-like protein and proposed a first cellular role, framing it as a Golgi-associated motor potentially driving Golgi-to-ER retrograde transport.\",\n      \"evidence\": \"Yeast two-hybrid with PTPD1 ezrin domain, immunofluorescence localization, and dominant-negative overexpression with brefeldin A in cultured cells\",\n      \"pmids\": [\"9685376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dominant-negative phenotype not confirmed by loss-of-function genetics\", \"Direct motor activity not demonstrated\", \"Cargo identity unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified phosphoregulation of KIF1C, showing CK2 phosphorylation of Ser1092 creates a 14-3-3 docking site, the first regulatory input on the motor.\",\n      \"evidence\": \"In vitro CK2 kinase assay, co-IP of 14-3-3 isoforms, and CK2 inhibition in cells\",\n      \"pmids\": [\"10559254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of 14-3-3 binding for transport not defined\", \"Connection to cargo selection unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked KIF1C function and localization to a physiological output, anthrax lethal toxin susceptibility in macrophages, acting at a post-entry step.\",\n      \"evidence\": \"Genetic mapping, allele-specific overexpression rescue, brefeldin A perturbation, and MKK3 cleavage assays\",\n      \"pmids\": [\"11591317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism downstream of KIF1C not defined\", \"Relevance to human cells unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Overturned the proposed Golgi-to-ER retrograde role by showing KIF1C knockout mice are viable with normal retrograde transport, redirecting the field toward other functions.\",\n      \"evidence\": \"Gene knockout with beta-gal knock-in and time-lapse BFA-induced transport analysis in primary fibroblasts\",\n      \"pmids\": [\"11784862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the true physiological cargo or function\", \"Possible redundancy with other motors not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Repositioned KIF1C as a plus-end-enriched motor at podosomes that physically bridges actin and microtubule cytoskeletons via non-muscle myosin IIA.\",\n      \"evidence\": \"siRNA/shRNA knockdown, dominant-negative constructs, co-IP, and live imaging in primary human macrophages\",\n      \"pmids\": [\"16554367\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo transported to podosomes not identified\", \"Directness of myosin IIA interaction at structural level not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a concrete cargo and migration function: KIF1C transports \\u03b15\\u03b21-integrins to the trailing edge to stabilize the rear during directional cell migration.\",\n      \"evidence\": \"siRNA depletion, integrin trafficking and migration assays, and myosin II inhibition epistasis\",\n      \"pmids\": [\"23237952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adaptor coupling KIF1C to integrin cargo not defined\", \"Mechanism of rear-specific targeting unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed Rab6A as a dual regulator/cargo factor whose binding to the motor domain inhibits microtubule interaction, while KIF1C is required for surface delivery and Golgi integrity.\",\n      \"evidence\": \"In vitro microtubule binding assays, co-IP, siRNA depletion, live vesicle imaging, and domain-deletion rescue in eLife study\",\n      \"pmids\": [\"25821985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Rab6A inhibition is relieved in vivo not defined\", \"Motor-independent Golgi protection mechanism unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed KIF1C peripheral targeting depends on CLASP proteins and on microtubule acetylation, identifying track-selection inputs governing where KIF1C operates.\",\n      \"evidence\": \"CLASP siRNA, chimeric mitochondrial CLASP2 recruitment, MEC-17 perturbation, tubacin treatment, and live imaging in macrophages\",\n      \"pmids\": [\"25344256\", \"25151635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular nature of CLASP\\u2013KIF1C contact not mapped\", \"Whether acetylation acts on motor or track recruitment unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established the core activation mechanism: full-length KIF1C is autoinhibited via a motor\\u2013stalk interaction that is released by PTPN21 FERM or Hook3 binding to the tail, converting it to a processive motor.\",\n      \"evidence\": \"Single-molecule motility with purified full-length KIF1C, domain-binding assays, neuronal DCV transport, and integrin trafficking rescue\",\n      \"pmids\": [\"31217419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the autoinhibited conformation not resolved\", \"How phosphorylation integrates with adaptor-mediated release unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated Hook3 scaffolds bidirectional transport, simultaneously binding dynein/dynactin and the KIF1C tail to couple opposing motors.\",\n      \"evidence\": \"In vitro reconstitution with purified dynein/dynactin, Hook3 and KIF1C, single-molecule motility, mass spectrometry, co-IP and live imaging\",\n      \"pmids\": [\"31320392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How directionality of the trimeric complex is biased in cells not defined\", \"Cargo carried by the bidirectional complex not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed Kif1c in an osteoclast signaling pathway between p130Cas and c-Src controlling actin ring formation and bone resorption.\",\n      \"evidence\": \"shRNA knockdown, overexpression rescue in p130Cas and c-Src knockout backgrounds, and bone resorption assays\",\n      \"pmids\": [\"31887784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target of KIF1C in this pathway not defined\", \"Whether motor activity is required not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified KIF1C as a direct mRNA transport motor carrying APC-dependent transcripts and its own mRNA to protrusions, with 3'UTR sufficiency for transport.\",\n      \"evidence\": \"Two-color single-molecule live imaging, siRNA depletion, mRNA localization and 3'UTR sufficiency assays\",\n      \"pmids\": [\"34493599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-binding adaptor not yet identified in this study\", \"Selectivity for specific transcripts unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the mRNA cargo model by showing RNA-dependent association of KIF1C with the exon junction complex during neurite transport.\",\n      \"evidence\": \"AP-MS in SH-SY5Y cells, co-IP with RNase sensitivity, and mutant KIF1C mislocalization imaging\",\n      \"pmids\": [\"36316088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus RNA-bridged EJC contact not distinguished\", \"Functional consequence of EJC mislocalization for translation not assessed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected c-Src tyrosine phosphorylation of the stalk to PTPD1 recruitment and autoinhibition relief, linking the motor to invadopodia-driven cancer invasion.\",\n      \"evidence\": \"c-Src perturbation, phospho-mutant constructs, co-IP, microtubule-binding and invadopodia/invasion assays\",\n      \"pmids\": [\"35654143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific phosphorylated tyrosines and structural effect not mapped\", \"Quantitative contribution relative to adaptor activation unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed that localization of Kif1c mRNA itself, rather than protein abundance, dictates the identity and number of KIF1C protein interactions and supports directed migration.\",\n      \"evidence\": \"mRNA mislocalization genetic perturbation, mass spectrometry of endogenous interactors, and migration assays\",\n      \"pmids\": [\"36859340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling local translation to interaction specificity unresolved\", \"Which mislocalized interactions are functionally decisive not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that the KIF1C C-terminal IDR drives liquid-liquid phase separation that sequence-selectively recruits and clusters mRNA at the periphery.\",\n      \"evidence\": \"In vitro LLPS with purified tail at near-endogenous concentrations, FRAP, IDR-deletion mutants, and RNA recruitment assays\",\n      \"pmids\": [\"38898313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LLPS is spatially restricted to protrusions unclear\", \"Relationship between condensate state and motility not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered a non-motor role in which KIF1C activates dynein-driven retrograde lysosomal transport via a Hook3\\u2013RUFY3 axis required for cargo degradation.\",\n      \"evidence\": \"KIF1C depletion, motor-dead mutant, co-IP of KIF1C\\u2013Hook3\\u2013RUFY3, lysosome positioning and degradation assays\",\n      \"pmids\": [\"39394274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the same Hook3 scaffold switches between anterograde and retrograde modes not resolved\", \"Stoichiometry of the KIF1C\\u2013Hook3\\u2013RUFY3 complex unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the molecular CNBP\\u2013KIF1C motor-adaptor that couples GA-rich 3'UTR recognition to active mRNA transport, supplying the missing RNA-binding link.\",\n      \"evidence\": \"RNA pulldown, co-IP, siRNA depletion, and live-cell mRNA transport and 3'UTR binding assays\",\n      \"pmids\": [\"39982819\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CNBP acts within KIF1C condensates not tested\", \"Generality across all protrusion mRNAs unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the structural basis of Hook3-activated transport, defining the Hook3\\u2013KIF1C interface necessary and sufficient for anterograde motility.\",\n      \"evidence\": \"Crystal structure of Hook3(553\\u2013624)\\u2013KIF1C(714\\u2013809), structure-based mutagenesis, co-IP and anterograde transport assays\",\n      \"pmids\": [\"40312563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the autoinhibited full-length motor still lacking\", \"How adaptor binding mechanically relieves autoinhibition not visualized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed that KIF1C LLPS-driven multi-kinesin clusters generate mechanical force that fragments microtubules, implying an active role in cytoskeletal remodeling.\",\n      \"evidence\": \"Live-cell microtubule breakage imaging, computational simulation, IDR/motor mutants, and in vitro LLPS (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.01.31.635950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not yet peer-reviewed\", \"Physiological role of microtubule breakage unconfirmed\", \"Whether this occurs at endogenous expression levels unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the multiple activating inputs (phosphorylation, adaptor binding, Rab6A inhibition, mRNA localization) are integrated to select cargo, direction, and condensate state at specific subcellular sites.\",\n      \"evidence\": \"Open question synthesized across the timeline\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coupling autoinhibition release to specific cargo classes\", \"Structure of the full autoinhibited motor unknown\", \"Switch between anterograde motor and non-motor dynein-activating modes undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [9, 10, 11]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [11, 16, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [4, 8, 20]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11, 16]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6, 9, 10]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [11, 16, 19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"KIF1C\\u2013Hook3\\u2013dynein/dynactin complex\",\n      \"KIF1C\\u2013Hook3\\u2013RUFY3 complex\",\n      \"KIF1C\\u2013CNBP mRNA motor-adaptor complex\"\n    ],\n    \"partners\": [\n      \"Hook3\",\n      \"PTPN21\",\n      \"Rab6A\",\n      \"PTPD1\",\n      \"CNBP\",\n      \"RUFY3\",\n      \"14-3-3\",\n      \"CLASP2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}