{"gene":"CLIP1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1992,"finding":"CLIP-170 links endocytic carrier vesicles to microtubules in vitro; its N-terminal domain contains a novel tandem-repeat motif responsible for microtubule binding, and the protein forms a homodimer with a long central coiled-coil domain connecting the N-terminal microtubule-binding domain to the C-terminal organelle-interacting domain.","method":"cDNA cloning, in vitro vesicle-microtubule binding assay, domain analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of vesicle-MT binding, structural domain identification, founding paper replicated by subsequent work","pmids":["1356075"],"is_preprint":false},{"year":1994,"finding":"The tandem repeat in the N-terminal domain of CLIP-170 is essential for microtubule binding in vivo; the C-terminal domain is required for anchoring microtubules to peripheral cytoplasmic structures (cargo-binding function), and overexpression of intact CLIP-170 causes microtubule bundling dependent on the C-terminal domain.","method":"Transient expression of intact and deletion/mutation mutants in HeLa and Vero cells, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mutagenesis in cells with clear phenotypic readouts, replicated across labs","pmids":["7983157"],"is_preprint":false},{"year":1999,"finding":"CLIP-170 dynamically treadmills on growing microtubule plus ends in vivo at rates matching microtubule elongation (~0.15–0.4 µm/s), highlighting newly polymerized tubulin; microtubule-drug treatment rapidly abolishes this movement, indicating that plus-end association is coupled to active polymerization.","method":"GFP-CLIP-170 live-cell imaging, fluorescent speckle microscopy, pharmacological perturbation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative live imaging, drug perturbation, independently replicated","pmids":["10052454"],"is_preprint":false},{"year":1999,"finding":"CLIP-170 plus-end targeting is closely linked to tubulin polymerization: the N-terminal microtubule-interacting domain alone localizes to plus ends; CLIP-170 associates with newly formed microtubules traced by biotinylated tubulin and cross-links/sediments with non-polymerized tubulin in vitro.","method":"Biotin-tubulin microinjection, in vitro co-sedimentation, cross-linking, transfection of domain fragments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple in vitro assays plus live-cell tracing, replicated concept","pmids":["9885247"],"is_preprint":false},{"year":1999,"finding":"CLIP-170 recruits dynactin to microtubule plus ends via its C-terminal putative cargo-binding domain; overexpression of p150(Glued) and mutant CLIP-170 forms indicate that CLIP-170 is upstream of dynactin in endosomal cargo loading at microtubule ends.","method":"Colocalization immunofluorescence, overexpression of wild-type and mutant CLIP-170 and p150(Glued), endosomal trafficking assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression/localization studies in cells, single lab, two orthogonal approaches","pmids":["10588646"],"is_preprint":false},{"year":1999,"finding":"Dynactin and CLIP-170 colocalize along distal segments of interphase microtubules; dynactin (Arp1 subunit) can be removed from microtubules by dynamitin overexpression without affecting CLIP-170, indicating they use partially distinct microtubule-association mechanisms.","method":"Multi-antibody immunofluorescence, dynamitin overexpression, temperature-shift experiments","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-antibody approach, single lab, colocalization-based","pmids":["10212138"],"is_preprint":false},{"year":1999,"finding":"CLIP-170 is a thin 135-nm homodimer with two kinks in its coiled-coil rod; the N-terminal domain binds microtubules with a stoichiometry of one dimeric head per four tubulin heterodimers; the rod and tail domains reduce microtubule-binding stoichiometry of the full-length protein.","method":"Purification of authentic CLIP-170, electron microscopy (glycerol spray/rotary shadowing), in vitro microtubule-binding stoichiometry assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — purified protein, EM structural characterization, quantitative in vitro binding assays","pmids":["10464331"],"is_preprint":false},{"year":1998,"finding":"CLIP-170 transiently localizes to prometaphase kinetochores and codistributes with dynein and dynactin there; overexpression of the C-terminal domain displaces endogenous CLIP-170 from kinetochores and causes a prometaphase delay; dynamitin overexpression reduces CLIP-170 at kinetochores, suggesting dynein/dynactin-dependent kinetochore targeting of CLIP-170.","method":"Immunofluorescence, transient overexpression of C-terminal CLIP-170 fragment, dynamitin overexpression","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain overexpression with functional readout, single lab","pmids":["9585405"],"is_preprint":false},{"year":2002,"finding":"IQGAP1 (an effector of Rac1/Cdc42) directly interacts with CLIP-170, and activated Rac1/Cdc42, IQGAP1, and CLIP-170 form a tripartite complex. Expression of C-terminal IQGAP1 fragment (containing the CLIP-170 binding region) delocalizes GFP-CLIP-170 from microtubule tips and alters microtubule arrays; IQGAP1 mutant defective in Rac1/Cdc42 binding induces multiple leading edges.","method":"Co-immunoprecipitation, pulldown, GFP live imaging, dominant-negative overexpression in Vero cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional dominant-negative, live imaging, replicated concept","pmids":["12110184"],"is_preprint":false},{"year":2002,"finding":"CLIP-170 directly interacts with LIS1 via the distal zinc finger motif of CLIP-170's C-terminal domain; LIS1 is required for CLIP-170 kinetochore recruitment, and LIS1 acts as a regulated adapter between CLIP-170 and cytoplasmic dynein. Overexpression of CLIP-170 causes zinc finger-dependent co-localization of phospho-LIS1 and dynactin on microtubule bundles.","method":"Co-immunoprecipitation, colocalization, domain mutant overexpression, indirect immunofluorescence","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction mapped to specific domain, functional consequence in cells, replicated by other labs","pmids":["11940666"],"is_preprint":false},{"year":2002,"finding":"LIS1 WD-repeat domain overexpression displaces CLIP-170 from kinetochores without affecting dynein/dynactin; LIS1 NH2-terminal overexpression displaces endogenous LIS1 with no effect on CLIP-170, dynein, or dynactin; dynamitin overexpression removes both CLIP-170 and LIS1. LIS1 interacts directly with dynein heavy chain (AAA1 domain) and intermediate chain, and with dynamitin.","method":"Co-expression/co-immunoprecipitation, two-hybrid assay, domain overexpression, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP + two-hybrid + domain dissection, replicated","pmids":["11889140"],"is_preprint":false},{"year":2002,"finding":"FRAP/mTOR interacts with CLIP-170 and phosphorylates it in vitro at rapamycin-sensitive sites; rapamycin inhibits CLIP-170 binding to microtubules in vivo, indicating that mTOR-mediated phosphorylation positively regulates CLIP-170 microtubule-binding activity.","method":"Co-immunoprecipitation, in vitro kinase assay, rapamycin treatment, microtubule-binding assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus cellular microtubule-binding assay, single lab with two orthogonal methods","pmids":["12231510"],"is_preprint":false},{"year":2003,"finding":"CLIP-170 interacts with dynactin via the second metal-binding (zinc finger) motif of its C-terminal tail, and with EB1 via a mechanism requiring neither metal-binding motif; these interactions are separable, and CLIP-170 can target dynactin to microtubule plus ends independently of EB1.","method":"Site-directed mutagenesis, transfection/colocalization assay in mammalian cells","journal":"Cell motility and the cytoskeleton","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with localization readout, single lab","pmids":["12789661"],"is_preprint":false},{"year":2004,"finding":"CLIP-170 N-terminal domain (H2) promotes microtubule rescues and stimulates nucleation in vitro; by cryo-EM, H2 induces tubulin ring formation in solution and curved oligomers at microtubule plus ends, suggesting CLIP-170 copolymerizes with tubulin and modulates dynamics through tubulin-oligomer intermediates.","method":"In vitro microtubule dynamics assay (pure tubulin + centrosomes), electron cryomicroscopy","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro dynamics assay plus cryo-EM structural data, single lab","pmids":["15589150"],"is_preprint":false},{"year":2004,"finding":"CLIP-170 undergoes an intramolecular autoinhibitory interaction between its N-terminal microtubule-binding domain (first metal-binding motif) and its C-terminal domain, as shown by scanning force microscopy and FRET. This intramolecular folding reduces MT-binding. The NH2 terminus of p150(Glued) binds the CLIP-170 C-terminus (second metal-binding motif); p150(Glued) and LIS1 compete for binding to the CLIP-170 C-terminus. RNAi depletion of CLIP-170 strongly reduces dynactin accumulation at MT tips.","method":"Scanning force microscopy, FRET, RNAi knockdown, direct binding assays (GST pulldown/co-IP), immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — FRET + SFM structural evidence + RNAi functional assay + direct binding, single comprehensive study with multiple orthogonal methods","pmids":["15381688"],"is_preprint":false},{"year":2005,"finding":"CLIP-170 has stronger affinity for tubulin dimer than polymer and can distinguish GTP- from GDP-tubulin; the second CAP-Gly domain with adjacent serine-rich region is the minimal plus-end tracking unit capable of both +TIP behavior in vivo and tubulin polymerization promotion in vitro, whereas the first CAP-Gly domain alone is incompetent for either activity.","method":"In vitro biochemistry (sedimentation, affinity assays), live-cell imaging of CLIP-170 CAP-Gly domain fragments","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemistry + live-cell domain mapping, single lab with two orthogonal methods","pmids":["16120651"],"is_preprint":false},{"year":2005,"finding":"CLIP-170 localizes dynamically to the outermost part of unattached kinetochores and to growing microtubule ends; RNAi depletion of CLIP-170 causes defective chromosome congression and diminished kinetochore-microtubule attachments without detectably affecting microtubule dynamics or k-fiber stability.","method":"High-resolution immunofluorescence, RNAi depletion, live-cell imaging","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with specific mitotic phenotype readout, single lab","pmids":["16362039"],"is_preprint":false},{"year":2005,"finding":"CLIP-170 is essential for male fertility and spermatogenesis; in spermatids it associates with the manchette and centrosomes and transitions from a mobile plus-end tracking protein to a relatively immobile structural protein, indicating a structural role in spermatid differentiation and sperm head shaping.","method":"CLIP-170 knockout and GFP knock-in mice, live testis imaging, FRAP","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with specific fertility phenotype + GFP knock-in live imaging + FRAP in physiological tissue","pmids":["16230537"],"is_preprint":false},{"year":2006,"finding":"EB1 is required for plus-end localization of CLIP-170, which in turn is required to localize p150(Glued) to plus ends; CLIP-170 depletion causes defects in microtubule dynamics and cell polarization after scratch wounding. However, removal of p150(Glued) from plus ends by EB1 or CLIP-170 depletion does not affect organelle distribution or membrane traffic, indicating that CLIP-170/p150(Glued) plus-end function is not required for general membrane trafficking.","method":"RNAi depletion (EB1, CLIP-170, p150Glued), immunofluorescence, membrane trafficking assays (transferrin uptake, ER-Golgi transport), live-cell imaging","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi epistasis hierarchy established with multiple functional readouts, positive and negative findings","pmids":["16772339"],"is_preprint":false},{"year":2008,"finding":"CLIP-170 requires EB1 for microtubule plus-end tracking; reconstituted in vitro at single-molecule resolution, EB1 autonomously tracks growing ends while CLIP-170 alone shows lattice diffusion and fails to selectively track ends. EB1 addition is both necessary and sufficient to mediate CLIP-170 plus-end tracking. GTP hydrolysis is required for end-specificity.","method":"In vitro reconstitution with TIRF single-molecule microscopy, pharmacological (GMPCPP) perturbation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — single-molecule reconstitution in vitro with orthogonal pharmacological control, replicated by Bieling et al. 2008","pmids":["19126680"],"is_preprint":false},{"year":2008,"finding":"EB1 autonomously recognizes specific binding sites at growing microtubule ends; CLIP-170 does not end-track by itself but requires EB1 and recognizes composite binding sites constituted by end-accumulated EB1 and tyrosinated α-tubulin; unlike fission yeast Tip1, mammalian CLIP-170 end-tracking does not require motor activity.","method":"In vitro reconstitution with purified proteins, TIRF microscopy, tubulin tyrosination manipulation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — full reconstitution in vitro, multiple protein variants tested, orthogonal chemical/biochemical controls","pmids":["19103809"],"is_preprint":false},{"year":2008,"finding":"GFP-CLIP-170 turns over rapidly on microtubule plus ends (rate-limited by diffusion); growing microtubule ends contain a surplus of relatively low-affinity CLIP-170 binding sites. The apparent comet fluorescence loss does not reflect single-molecule behavior but overall structural changes at the MT end.","method":"Quantitative fluorescence microscopy, FRAP, single-molecule analysis of GFP-CLIP-170 and GFP-EB3","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP + quantitative imaging, single lab","pmids":["18283108"],"is_preprint":false},{"year":2008,"finding":"CLIP-170 is specifically required for efficient CR3/αMβ2-integrin-triggered phagocytosis in macrophages; it directly interacts with the formin homology 2 (FH2) domain of mDia1 via a direct protein-protein interaction, controls mDia1 recruitment to phagocytic cups, and thereby regulates actin polymerization essential for phagocytosis. This interaction is negatively regulated during αMβ2-mediated phagocytosis.","method":"RNAi knockdown, dominant-negative expression, direct binding assay, immunofluorescence, phagocytosis assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding confirmed, RNAi phenotype in primary macrophages, multiple orthogonal approaches, single lab","pmids":["19114595"],"is_preprint":false},{"year":2008,"finding":"Dynein, Lis1, and CLIP-170 counteract Eg5-dependent centrosome separation during bipolar spindle assembly; CLIP-170 depletion allows spindle bipolarity with less Eg5 activity, a function mediated through CLIP-170's interaction with dynein (not shared by CLIP-115, which lacks the dynein-dynactin interaction domain).","method":"RNAi depletion in human cells, spindle bipolarity assay, Eg5 inhibitor (monastrol) titration","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi epistasis with paralog (CLIP-115) comparison, single lab","pmids":["19020519"],"is_preprint":false},{"year":2009,"finding":"CLIP-170 initiates minus-end-directed transport of membrane organelles (melanosomes) in Xenopus melanophores by capturing organelles at growing microtubule plus ends; inhibition of MT dynamics or loss of CLIP-170 from MT tips dramatically inhibits pigment aggregation.","method":"Live-cell imaging in Xenopus melanophores, MT dynamics inhibition, CLIP-170 dominant-negative expression","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — live-cell organelle transport assay with pharmacological and genetic perturbation, clear mechanistic readout","pmids":["19758557"],"is_preprint":false},{"year":2009,"finding":"CLIP-170 binds to both α-tubulin and β-tubulin (not only the acidic C-terminal tails) including H12 helices of both tubulins, as shown by chemical cross-linking/mass spectrometry. CLIP-170 can use its multiple tubulin-binding sites to bind EB1 and microtubules simultaneously.","method":"Chemical cross-linking, mass spectrometry, in vitro binding assays","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — chemical cross-linking MS reveals binding contacts, in vitro assays, single lab","pmids":["19913027"],"is_preprint":false},{"year":2010,"finding":"AMPK directly phosphorylates CLIP-170; phosphorylation is required for proper microtubule dynamics and directional cell migration. Non-phosphorylatable CLIP-170 causes prolonged MT-tip accumulation and slower tubulin polymerization; these phenotypes are rescued by phosphomimetic CLIP-170. AMPK inhibition impairs MT stabilization and directional migration, also rescued by phosphomimetic CLIP-170.","method":"In vitro kinase assay, expression of phosphomimetic/non-phosphorylatable CLIP-170 mutants, live-cell microtubule imaging, cell migration assay (wound healing)","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay + rescue with phosphomimetic in cells, multiple phenotypic readouts, replicated by subsequent work","pmids":["20495555"],"is_preprint":false},{"year":2010,"finding":"Polo-like kinase 1 (Plk1) phosphorylates CLIP-170 at S195, and casein kinase 2 (CK2) phosphorylates it at S1318; Plk1 phosphorylation enhances CLIP-170 association with CK2; CK2 phosphorylation is required for CLIP-170 interaction with dynactin and kinetochore localization. Both phosphorylation events are required for timely formation of kinetochore-microtubule attachments.","method":"In vitro kinase assay, phospho-site mapping, co-immunoprecipitation, expression of phosphomutants, kinetochore-fiber assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay + site mapping + phosphomutant rescue, single lab with multiple orthogonal methods","pmids":["20664522"],"is_preprint":false},{"year":2009,"finding":"Cdc2 (CDK1) phosphorylates CLIP-170 at Thr287 in vivo; expression of non-phosphorylatable T287A causes CLIP-170 mislocalization, accumulation of Plk1 and cyclin B, and G2/M block; depletion of CLIP-170 leads to centrosome reduplication, and Cdc2 phosphorylation of CLIP-170 is required to prevent it.","method":"Co-immunoprecipitation, in vivo phosphorylation assay, T287A phosphomutant expression, centrosome counting, cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo phosphorylation + mutant phenotype, single lab","pmids":["19687009"],"is_preprint":false},{"year":2011,"finding":"CLIP-170 and IQGAP1 cooperatively regulate dendrite morphology in neurons; mTOR kinase interacts with CLIP-170 and is required for efficient formation of a CLIP-170/IQGAP1 complex; dynamic microtubules, CLIP-170, and IQGAP1 are required for proper dendritic arbor morphology and PI3K-mTOR-induced dendritic complexity.","method":"Co-immunoprecipitation, RNAi knockdown, live-cell imaging of dendritic dynamics, morphometric analysis in rat neurons","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + RNAi + morphometric analysis, single lab","pmids":["21430156"],"is_preprint":false},{"year":2011,"finding":"EB1 and a minimal CLIP-170 fragment (ClipCG12 with two non-interacting CAP-Gly domains) cooperatively regulate microtubule dynamic instability; together at 250 nM they modulate dynamics and deplete stably bound Pi at microtubule ends, suggesting they modify the stabilizing GTP cap by cooperative action.","method":"In vitro microtubule dynamics assay, SAXS, analytical ultracentrifugation, [γ-32P]GTP pulsing","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with multiple biophysical methods (SAXS, AUC, dynamics assay, radioisotope), single lab","pmids":["22424550"],"is_preprint":false},{"year":2013,"finding":"Pregnenolone (P5) directly binds CLIP-170 at its coiled-coil domain, changing it to an extended (active) conformation that increases CLIP-170 interactions with microtubules, dynactin p150(Glued), and LIS1, promoting CLIP-170-dependent microtubule polymerization and cell migration.","method":"Photoaffinity probe capture from embryonic extract, direct binding assay, conformational analysis, in vivo zebrafish epiboly assay, mammalian cell migration assay","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — photoaffinity capture + direct binding + conformational change + in vivo genetic rescue, multiple orthogonal methods","pmids":["23955365"],"is_preprint":false},{"year":2014,"finding":"CLIP-170 colocalizes with PLK1 at kinetochores during early mitosis; CLIP-170 depletion reduces PLK1 kinetochore recruitment, causing kinetochore-fiber instability and chromosome misalignment. CDK1-dependent phosphorylation at T287 is required: non-phosphorylatable T287A fails to restore PLK1 kinetochore localization or rescue chromosome alignment defects.","method":"RNAi depletion, immunofluorescence, phosphomutant (T287A) rescue assay, kinetochore-fiber stability assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi + phosphomutant rescue with multiple mitotic phenotypic readouts, single lab with orthogonal methods","pmids":["24777477"],"is_preprint":false},{"year":2014,"finding":"LRRK1 phosphorylates CLIP-170 at Thr1384 in its C-terminal zinc knuckle motif; this promotes CLIP-170 association with dynein-dynactin complexes and causes accumulation of p150(Glued) at microtubule plus ends, thereby facilitating migration of EGFR-containing endosomes.","method":"In vitro kinase assay, phospho-site mapping, co-immunoprecipitation, live-cell EGFR trafficking assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay + site mapping + Co-IP + transport assay, single lab with multiple orthogonal methods","pmids":["25413345"],"is_preprint":false},{"year":2014,"finding":"Plk1 phosphorylates CLIP-170 at Ser312 during mitosis; in vitro phosphorylation by Plk1 diminishes CLIP-170 binding to microtubule ends and lattice without affecting EB3 binding; proper Ser312 phosphorylation/dephosphorylation cycling is required for stable kinetochore-microtubule attachment and chromosome alignment.","method":"In vitro kinase/binding assay with purified CLIP-170 N-terminal fragment, phospho-site mapping, mitotic phenotype analysis with phosphomutants","journal":"Cell structure and function","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase + binding assay + phosphomutant phenotype, single lab with two orthogonal methods","pmids":["24451569"],"is_preprint":false},{"year":2015,"finding":"CLIP-170 at microtubule plus ends is required to initiate retrograde transport of herpes simplex virus (HSV-1) particles in primary human cells; CLIP-170 functions in a +TIP complex with EB1 and DCTN1 to capture incoming virus particles. Depletion of CLIP-170 completely blocks long-range retrograde transport and suppresses infection ~5000-fold without affecting transferrin uptake or dynein-dependent organelle movement.","method":"RNAi depletion, dominant-negative expression, live-cell imaging, infection assay in primary human cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi + dominant-negative, quantitative infection assay, multiple controls distinguishing CLIP-170-specific vs. general dynein function","pmids":["26504169"],"is_preprint":false},{"year":2016,"finding":"CLIP-170 phosphorylation and α-tubulin tyrosination cooperatively control initiation of dynein-driven retrograde transport in the distal axon; CLIP-170 primarily regulates the time to microtubule encounter, while tyrosination of the lattice regulates the probability of binding.","method":"In vitro single-molecule reconstitution, live-cell transport assay in primary neurons, computational simulation, pharmacological manipulation of tubulin PTMs","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — single-molecule reconstitution + neuronal transport assay + simulation, multiple orthogonal methods","pmids":["26972003"],"is_preprint":false},{"year":2017,"finding":"CLIP-170 is required for redeployment of ninein from centrosomes to non-centrosomal microtubule organizing centres (n-MTOCs) during epithelial differentiation, thereby enabling apico-basal microtubule array formation; IQGAP1 and active Rac1 cooperate with CLIP-170 in this process. Confirmed using CLIP-170/CLIP-115 double KO intestinal tissue and organoids.","method":"RNAi depletion, KO mouse tissue (Clip1/Clip2 double KO), organoid culture, immunofluorescence","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO + RNAi in multiple model systems with defined organelle-redistribution phenotype","pmids":["28179500"],"is_preprint":false},{"year":2017,"finding":"CLIP170 interacts with the TLR2/TLR4 adaptor TIRAP, induces its ubiquitination and subsequent proteasomal degradation, and thereby negatively regulates TLR4-mediated proinflammatory cytokine (IL-6, TNF-α) production in macrophages.","method":"Co-immunoprecipitation, overexpression/knockdown (siRNA), ubiquitination assay, cytokine ELISA, in vivo siRNA delivery in mice","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + ubiquitination assay + in vivo knockdown, single lab","pmids":["29222167"],"is_preprint":false},{"year":2018,"finding":"CLIP-170 contains multiple EB1-binding modules in its N-terminal region: two CAP-Gly domains (engaging EB1's C-terminal EEY motif only), a bridging SXIP motif, and an array of divergent SXIP-like motifs N-terminal to the first CAP-Gly domain. These modules act multivalently to strengthen the CLIP-170-EB1 interaction.","method":"Isothermal titration calorimetry, size-exclusion chromatography, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative biophysical binding measurements with mutational dissection, single lab","pmids":["30455356"],"is_preprint":false},{"year":2018,"finding":"CLIP-170 phosphorylation (by AMPK) is essential for MTOC repositioning to the immunological synapse during T cell activation; T cell stimulation induces dynein co-localization with CLIP-170 and plus-end tracking, and phosphorylated CLIP-170 is required for dynein recruitment to plus-end tracking and subsequent dynein relocation to the contact surface.","method":"Fluorescence imaging, CLIP-170 phosphorylation inhibition (dominant-negative AMPK/phosphomutant), single-molecule tracking of dynein","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging + phosphomutant approach, single lab","pmids":["30487641"],"is_preprint":false},{"year":2019,"finding":"CLIP-170 associates with MT plus ends to coordinate recycling and outward transport of Met RTK-containing endosomes (Rab4-positive); HGF stimulation induces GGA3 and CLIP-170 recruitment to an activated Met RTK complex, and CLIP-170 is required for net outward movement of Met-positive vesicles toward the cell cortex and lamellipodia.","method":"Co-immunoprecipitation, live-cell imaging, dominant-negative CLIP-170, RNAi knockdown, endosome trafficking assay","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + live imaging + genetic perturbation, single lab","pmids":["30537020"],"is_preprint":false},{"year":2020,"finding":"JNK directly phosphorylates CLIP-170 in its microtubule-binding domain upon cell stress, increasing CLIP-170's rescue-promoting activity; phosphomimetic CLIP-170 enhances rescue events in vitro and in cells, and increases CLIP-170 remnant occurrence on the microtubule lattice at potential future rescue sites.","method":"In vitro kinase assay, in vitro microtubule dynamics assay, phosphomimetic/non-phosphorylatable mutants, live-cell imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase + dynamics assay + cellular imaging with phosphomutants, single lab with multiple methods","pmids":["32491151"],"is_preprint":false},{"year":2020,"finding":"AMPK-mediated phosphorylation of CLIP-170 at Ser311 regulates microtubule turnover at intercalated disks in cardiomyocytes; inhibition of this phosphorylation (S311A transgenic mice) causes MT accumulation at intercalated disks, cardiomyocyte elongation, and progressive decline in cardiac contraction.","method":"CLIP-170 S311A transgenic mouse, time-lapse imaging, pharmacological (MYK-461) modulation of AMPK localization","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic mouse model + live imaging + pharmacological perturbation with cardiac function readout","pmids":["33251722"],"is_preprint":false},{"year":2021,"finding":"CLIP-170 directly interacts with TIRAP (TLR adaptor) and CLIP-170 induces TIRAP ubiquitination and degradation, negatively regulating TLR4 signaling; TFPI2 inhibits CLIP-170-mediated TIRAP ubiquitination by binding the CLIP-170 R24 residue of TFPI2's KD1 domain, and HOPE (hypothermic oxygenated perfusion) exerts anti-inflammatory effects by modulating the TFPI2/CLIP-170/TIRAP axis.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, rat liver IRI model, Western blot","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + ubiquitination assay + in vivo model, single lab","pmids":["39617791"],"is_preprint":false},{"year":2021,"finding":"DCTN1 (dynactin-1) competes with CLIP-170 for binding to incoming HIV-1 particles; outside its dynactin role, DCTN1 functions as a +TIP that sequesters CLIP-170 from viral cores, inhibiting early HIV-1 infection. Deletion of the zinc knuckle domain of CLIP-170 increases its binding to virus particles but does not promote infection, indicating this Zn domain mediates a critical proviral CLIP-170 function blocked by DCTN1.","method":"RNAi knockdown of DCTN1, CLIP-170 Zn-domain deletion mutant, virus particle co-immunoprecipitation, infectivity assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with viral particles + infectivity assay + domain mutant, single lab","pmids":["34686593"],"is_preprint":false},{"year":2021,"finding":"SOCS3 interacts with CLIP-170 (and CLASP2) via its N-terminal domain; the SOCS3-CLIP-170/CLASP2 complex is essential for maximal anti-inflammatory SOCS3 effects in lung endothelium. Knockdown of CLIP-170 impairs SOCS3-JAK2 interaction and abolishes SOCS3's protective effects against IL-6 and bacterial pathogen-induced barrier dysfunction.","method":"Co-immunoprecipitation, endothelial cell KD, EC-specific SOCS3 KO mice, lung permeability/inflammation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + genetic KO + KD with functional barrier readout, single lab","pmids":["33372035"],"is_preprint":false},{"year":2022,"finding":"The CLIP-170 N-terminal domain directly binds filamentous actin (F-actin) with relatively weak affinity; the F-actin-binding region overlaps with the microtubule-binding region; in vitro competition assays show that CLIP-170-F-actin and CLIP-170-MT interactions are mutually exclusive.","method":"High-speed co-sedimentation assays, CLIP-170 fragment/mutant analysis, in vitro competition assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with domain mapping and competition assay, single lab","pmids":["35283190"],"is_preprint":false},{"year":2021,"finding":"Overexpression of CLIP-170 in cells induces large patch structures with hallmarks of biomolecular condensates (phase-separated liquid droplets): they contain CLIP-170 and other +TIP network proteins, are dynamic by FRAP, and exclude other known condensate markers; bioinformatic analysis confirms conserved intrinsically disordered regions in key +TIPs.","method":"Video microscopy, immunofluorescence, FRAP, bioinformatic disorder prediction","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP + imaging evidence for condensate properties, supported by bioinformatics, single lab","pmids":["34890409"],"is_preprint":false}],"current_model":"CLIP-170 (CLIP1) is a homodimeric microtubule plus-end tracking protein (+TIP) that binds growing microtubule ends via its N-terminal CAP-Gly domains in an EB1-dependent manner (EB1 is necessary and sufficient for CLIP-170 end-tracking), uses its C-terminal zinc-finger/metal-binding motifs to recruit dynactin (p150Glued) and interact with LIS1 and dynein, and undergoes extensive phospho-regulation by multiple kinases (mTOR, AMPK, CDK1/Cdc2, Plk1, CK2, JNK, LRRK1) that control its microtubule affinity, conformation (autoinhibited closed vs. open extended state), and ability to link organelle capture at growing MT ends to minus-end-directed dynein transport, facilitate kinetochore-microtubule attachments in mitosis, coordinate microtubule-actin cross-talk via IQGAP1 and formins, and regulate TLR4 signaling by promoting TIRAP degradation."},"narrative":{"mechanistic_narrative":"CLIP1 (CLIP-170) is a homodimeric microtubule plus-end tracking protein (+TIP) that links growing microtubule ends to organelle capture, minus-end-directed transport, and microtubule dynamics regulation [PMID:1356075, PMID:10052454, PMID:19758557]. It is a thin 135-nm homodimer in which a long coiled-coil rod connects an N-terminal microtubule/tubulin-binding region — built from tandem CAP-Gly modules, with the second CAP-Gly domain and adjacent serine-rich region constituting the minimal plus-end tracking and polymerization-promoting unit — to a C-terminal cargo/metal-binding domain [PMID:1356075, PMID:10464331, PMID:16120651]. Plus-end tracking is not autonomous: CLIP-170 alone diffuses on the lattice, and EB1 is necessary and sufficient to confer end-specificity, with CLIP-170 recognizing composite sites formed by end-accumulated EB1 and tyrosinated α-tubulin through multivalent CAP-Gly and SXIP-like modules [PMID:19126680, PMID:19103809, PMID:30455356]. At the plus end CLIP-170 promotes microtubule rescue and nucleation via curved tubulin-oligomer intermediates and, with EB1, cooperatively tunes the stabilizing GTP cap [PMID:15589150, PMID:22424550]. Through its C-terminal zinc-finger motifs, CLIP-170 recruits dynactin (p150Glued) and binds LIS1, which together couple it to cytoplasmic dynein; p150Glued and LIS1 compete for the same C-terminal site, and an intramolecular fold between the N- and C-termini autoinhibits microtubule binding [PMID:11940666, PMID:12789661, PMID:15381688]. This +TIP-to-dynein relay drives capture of membrane organelles at growing ends and initiation of retrograde transport — of melanosomes, EGFR- and Met-containing endosomes, and incoming herpesvirus particles — and positions CLIP-170 at unattached kinetochores where it supports chromosome congression, kinetochore-microtubule attachment, and PLK1 recruitment during mitosis [PMID:16362039, PMID:19758557, PMID:25413345, PMID:26504169, PMID:30537020, PMID:24777477]. CLIP-170 activity is extensively controlled by phosphorylation: mTOR, AMPK, JNK, CDK1, Plk1, CK2, and LRRK1 phosphorylate distinct sites to regulate its microtubule affinity, rescue activity, dynactin/dynein engagement, and kinetochore function, governing directional cell migration, cardiomyocyte microtubule turnover, and MTOC repositioning [PMID:12231510, PMID:20495555, PMID:32491151, PMID:20664522, PMID:24451569, PMID:25413345, PMID:33251722]. CLIP-170 also coordinates microtubule-actin cross-talk through direct, mutually exclusive binding to F-actin and via IQGAP1 and the formin mDia1, supporting cell polarization, dendrite morphology, phagocytosis, and non-centrosomal MTOC assembly [PMID:35283190, PMID:12110184, PMID:19114595, PMID:21430156, PMID:28179500], and negatively regulates TLR4 signaling by promoting ubiquitination and degradation of the adaptor TIRAP [PMID:29222167]. Genetic knockout establishes that CLIP-170 is essential for spermatogenesis and male fertility [PMID:16230537].","teleology":[{"year":1992,"claim":"Established CLIP-170 as the founding molecular linker between membranous organelles and microtubules, defining the modular architecture that all later mechanism rests on.","evidence":"cDNA cloning, in vitro vesicle-microtubule binding assay, and domain analysis","pmids":["1356075"],"confidence":"High","gaps":["Did not define how plus-end specificity arises","C-terminal cargo partners not yet identified"]},{"year":1994,"claim":"Mapped the division of labor between domains — N-terminal tandem repeat for microtubule binding and C-terminal domain for peripheral cargo anchoring — converting the structural model into a functional one.","evidence":"Domain/deletion mutant expression in HeLa and Vero cells with immunofluorescence","pmids":["7983157"],"confidence":"High","gaps":["Mechanism of end-tracking vs lattice binding unresolved","No direct partner identification"]},{"year":1999,"claim":"Discovered that CLIP-170 treadmills on growing plus ends coupled to active polymerization and biochemically characterized the homodimer and its tubulin/plus-end binding, establishing the +TIP behavior and its link to newly polymerized tubulin.","evidence":"GFP live-cell imaging, biotin-tubulin tracing, in vitro co-sedimentation/cross-linking, and EM of purified protein","pmids":["10052454","9885247","10464331"],"confidence":"High","gaps":["Whether end-tracking is autonomous or requires partners unknown","Binding stoichiometry to dimer vs polymer not fully resolved"]},{"year":1999,"claim":"Placed CLIP-170 upstream of dynactin at plus ends, linking +TIP behavior to the dynein transport machinery for endosomal cargo loading.","evidence":"Colocalization and overexpression of WT/mutant CLIP-170 and p150Glued with endosomal trafficking assays","pmids":["10588646","10212138"],"confidence":"Medium","gaps":["Direct binding site not yet mapped","Overexpression-based; physiological requirement unestablished"]},{"year":1998,"claim":"Identified CLIP-170 at prometaphase kinetochores codistributing with dynein/dynactin, extending its role from interphase trafficking to mitotic chromosome segregation.","evidence":"Immunofluorescence, C-terminal fragment and dynamitin overexpression","pmids":["9585405"],"confidence":"Medium","gaps":["Targeting mechanism inferred from dynamitin, not directly demonstrated","Functional contribution to attachment not yet tested by depletion"]},{"year":2002,"claim":"Mapped the C-terminal zinc-finger to LIS1 and dynactin binding and connected CLIP-170 to Rac1/Cdc42-IQGAP1 signaling, defining how it couples to dynein and to actin-based polarity cues.","evidence":"Reciprocal Co-IP, two-hybrid, domain mutagenesis, and live imaging in cells","pmids":["11940666","11889140","12110184"],"confidence":"High","gaps":["How LIS1/dynactin binding is coordinated in time unclear","Direct vs indirect IQGAP1 contact at residue level not defined"]},{"year":2002,"claim":"Showed mTOR directly phosphorylates CLIP-170 to positively regulate its microtubule binding, opening the theme of kinase control of +TIP activity.","evidence":"Co-IP, in vitro kinase assay, rapamycin treatment, and microtubule-binding assay","pmids":["12231510"],"confidence":"High","gaps":["Phospho-sites not mapped","In vivo physiological context undefined"]},{"year":2004,"claim":"Resolved how CLIP-170 modulates dynamics and how its own activity is gated — promoting rescue/nucleation via curved tubulin oligomers while an intramolecular fold autoinhibits microtubule binding and sets up p150Glued/LIS1 competition.","evidence":"In vitro dynamics assay, cryo-EM, scanning force microscopy, FRET, RNAi, and direct binding assays","pmids":["15589150","15381688"],"confidence":"High","gaps":["What relieves autoinhibition in vivo not established here","Structural basis of oligomer induction at atomic resolution lacking"]},{"year":2005,"claim":"Defined the minimal plus-end tracking unit (second CAP-Gly + serine-rich region) and CLIP-170's preference for GTP-tubulin dimer, and demonstrated its functional requirement at kinetochores for chromosome congression.","evidence":"In vitro biochemistry, live-cell domain imaging, and RNAi with mitotic readouts","pmids":["16120651","16362039"],"confidence":"High","gaps":["Kinetochore study Medium confidence, single lab","How GTP-tubulin discrimination is achieved structurally unclear"]},{"year":2005,"claim":"Demonstrated genetically that CLIP-170 is essential for male fertility and undergoes a +TIP-to-structural transition in spermatids, establishing an organismal, non-trafficking role.","evidence":"Knockout and GFP knock-in mice, live testis imaging, and FRAP","pmids":["16230537"],"confidence":"High","gaps":["Molecular basis of the mobility transition unknown","Manchette/centrosome binding partners in spermatids unidentified"]},{"year":2008,"claim":"Resolved the long-standing question of plus-end specificity: in vitro single-molecule reconstitution showed EB1 is necessary and sufficient for CLIP-170 end-tracking, which depends on EB1 plus tyrosinated α-tubulin and GTP hydrolysis, not motor activity.","evidence":"TIRF single-molecule reconstitution with purified proteins and GMPCPP/tyrosination controls","pmids":["19126680","19103809","18283108"],"confidence":"High","gaps":["How EB1 dependence integrates with intrinsic tubulin affinity in cells unclear","Stoichiometry of the composite binding site not fully defined"]},{"year":2008,"claim":"Extended CLIP-170 function into innate immunity, spindle bipolarity, and actin regulation — direct mDia1 binding for phagocytosis, dynein-dependent counteraction of Eg5, and CR3-triggered actin polymerization.","evidence":"RNAi, dominant-negative expression, direct binding assays, and phagocytosis/spindle assays","pmids":["19114595","19020519"],"confidence":"High","gaps":["mDia1 binding interface not residue-mapped","Eg5-counteraction study Medium confidence"]},{"year":2009,"claim":"Demonstrated CLIP-170 initiates minus-end-directed organelle transport by capturing cargo at growing plus ends, and that it contacts both α- and β-tubulin H12 helices, mechanistically linking +TIP capture to dynein transport.","evidence":"Live melanophore imaging with MT-dynamics inhibition, plus cross-linking/mass spectrometry of tubulin contacts","pmids":["19758557","19913027"],"confidence":"High","gaps":["Handoff step from CLIP-170 capture to dynein motility not directly visualized","Tubulin contact study Medium confidence"]},{"year":2009,"claim":"Initiated the cell-cycle kinase control theme by showing CDK1/Cdc2 phosphorylates CLIP-170 at Thr287 to control localization, mitotic progression, and prevention of centrosome reduplication.","evidence":"Co-IP, in vivo phosphorylation assay, T287A mutant expression, and centrosome counting","pmids":["19687009"],"confidence":"Medium","gaps":["Single lab; downstream effector of T287 phosphorylation initially unclear","Mechanism of centrosome reduplication suppression not detailed"]},{"year":2010,"claim":"Established a multi-kinase phospho-code: AMPK controls CLIP-170-dependent MT dynamics and directional migration, while Plk1 (S195) and CK2 (S1318) jointly govern dynactin binding and kinetochore-MT attachment timing.","evidence":"In vitro kinase assays, phospho-site mapping, phosphomimetic rescue, and migration/kinetochore-fiber assays","pmids":["20495555","20664522"],"confidence":"High","gaps":["How distinct phosphorylations are spatiotemporally integrated unclear","Phosphatases reversing these marks not identified"]},{"year":2011,"claim":"Connected CLIP-170 to neuronal morphogenesis and clarified the EB1-CLIP-170 cooperative mechanism on dynamics: mTOR-promoted CLIP-170/IQGAP1 complex shapes dendrites, and EB1+CLIP-170 deplete end-bound Pi to modify the GTP cap.","evidence":"Co-IP, RNAi, dendrite morphometry, and in vitro dynamics with SAXS/AUC/[γ-32P]GTP pulsing","pmids":["21430156","22424550"],"confidence":"High","gaps":["Dendrite study Medium confidence","Link between GTP-cap modification and rescue in cells not established"]},{"year":2013,"claim":"Identified a direct small-molecule regulator: pregnenolone binds the coiled-coil to switch CLIP-170 to an extended active conformation, increasing MT, dynactin, and LIS1 engagement — a non-kinase route to relieving autoinhibition.","evidence":"Photoaffinity capture, direct binding, conformational analysis, zebrafish epiboly, and migration assays","pmids":["23955365"],"confidence":"High","gaps":["Physiological pregnenolone concentrations and tissue relevance unclear","Binding site not residue-resolved"]},{"year":2014,"claim":"Defined the mitotic phospho-network in detail — CDK1-T287 enables PLK1 kinetochore recruitment, Plk1-S312 cyclically tunes MT-end binding, and LRRK1-T1384 promotes dynein-dynactin engagement for EGFR endosome transport.","evidence":"In vitro kinase/binding assays, site mapping, phosphomutant rescue, and kinetochore/transport assays","pmids":["24777477","24451569","25413345"],"confidence":"High","gaps":["Order of these phospho-events within mitosis not fully resolved","Cross-talk between LRRK1 and cell-cycle kinases unexplored"]},{"year":2015,"claim":"Demonstrated that CLIP-170 captures incoming herpesvirus particles in an EB1/DCTN1 +TIP complex to initiate retrograde transport, distinguishing CLIP-170-specific from general dynein function.","evidence":"RNAi, dominant-negative expression, live imaging, and quantitative infection assay in primary human cells","pmids":["26504169"],"confidence":"High","gaps":["Direct viral-capsid contact not biochemically defined","Whether all retrograde cargoes use the same capture mode unclear"]},{"year":2016,"claim":"Quantified how CLIP-170 phosphorylation and α-tubulin tyrosination jointly time and probabilistically gate initiation of dynein-driven retrograde transport in axons.","evidence":"Single-molecule reconstitution, neuronal transport assays, and computational simulation","pmids":["26972003"],"confidence":"High","gaps":["Which kinase sets the relevant phospho-state in the distal axon unspecified here","In vivo relevance to axonal cargoes broadly not tested"]},{"year":2017,"claim":"Showed CLIP-170 (with IQGAP1/Rac1) drives ninein redeployment to non-centrosomal MTOCs during epithelial differentiation, and identified TIRAP degradation as a mechanism for CLIP-170 negative regulation of TLR4 inflammation.","evidence":"RNAi, double-KO mouse tissue/organoids, immunofluorescence; and Co-IP, ubiquitination assay, cytokine ELISA, in vivo siRNA","pmids":["28179500","29222167"],"confidence":"High","gaps":["TLR4/TIRAP study Medium confidence","Mechanism by which CLIP-170 promotes TIRAP ubiquitination (E3 identity) unknown"]},{"year":2018,"claim":"Resolved the molecular basis of EB1 engagement and added immune cell function: multivalent CAP-Gly/SXIP-like modules strengthen EB1 binding, and AMPK-phosphorylated CLIP-170 is required for MTOC repositioning to the immune synapse.","evidence":"ITC, SEC, mutagenesis; and imaging with phosphomutant/dominant-negative AMPK plus dynein single-molecule tracking","pmids":["30455356","30487641"],"confidence":"High","gaps":["Immune-synapse study Medium confidence","How multivalency is regulated dynamically in cells unclear"]},{"year":2020,"claim":"Added JNK as a stress-activated regulator boosting CLIP-170 rescue activity, and established AMPK-S311 phosphorylation as a physiological controller of cardiomyocyte microtubule turnover.","evidence":"In vitro kinase/dynamics assays with phosphomutants; and S311A transgenic mice with cardiac imaging and pharmacology","pmids":["32491151","33251722"],"confidence":"High","gaps":["Relationship between S311 (AMPK) and other AMPK sites unclear","How rescue remnants are selected as future rescue sites unresolved"]},{"year":2021,"claim":"Expanded the CLIP-170 interactome and properties: direct mutually exclusive F-actin/MT binding, recycling Met-endosome transport, anti-inflammatory SOCS3 and TFPI2/TIRAP axes, DCTN1 competition restraining HIV-1 infection, and condensate-like phase behavior.","evidence":"Co-sedimentation/competition, Co-IP, live imaging, ubiquitination assays, infectivity assays, KO/KD models, and FRAP","pmids":["35283190","30537020","33372035","39617791","34686593","34890409"],"confidence":"High","gaps":["Several axes (Met, SOCS3, TFPI2, HIV-1, condensate) are Medium confidence single-lab","Physiological significance of CLIP-170 phase separation undefined"]},{"year":null,"claim":"How the multiple kinase inputs, conformational switching, EB1-dependent tracking, and competing C-terminal partners are integrated to dictate cargo specificity in a given cellular context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking phospho-state to choice of cargo or pathway","Phosphatases and the in vivo trigger relieving autoinhibition largely unidentified","Functional role of phase separation versus discrete complexes unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,3,15,47]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,9,14,24]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13,30,42]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,6,47]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[17,28,37]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,24]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[7,16]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[16,27,32,34,23]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[24,33,41,35]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[22,38,46]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,11,26]}],"complexes":["dynein-dynactin complex","EB1/CLIP-170 +TIP network","Rac1/Cdc42-IQGAP1-CLIP-170 complex"],"partners":["EB1","DCTN1","LIS1","IQGAP1","MDIA1","TIRAP","SOCS3","MTOR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P30622","full_name":"CAP-Gly domain-containing linker protein 1","aliases":["Cytoplasmic linker protein 1","Cytoplasmic linker protein 170 alpha-2","CLIP-170","Reed-Sternberg intermediate filament-associated protein","Restin"],"length_aa":1438,"mass_kda":162.2,"function":"Binds to the plus end of microtubules and regulates the dynamics of the microtubule cytoskeleton. Promotes microtubule growth and microtubule bundling. Links cytoplasmic vesicles to microtubules and thereby plays an important role in intracellular vesicle trafficking. Plays a role macropinocytosis and endosome trafficking","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton; Cytoplasmic vesicle membrane; Cell projection, ruffle","url":"https://www.uniprot.org/uniprotkb/P30622/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CLIP1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000130779","cell_line_id":"CID000624","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"cytoskeleton","grade":3},{"compartment":"membrane","grade":2}],"interactors":[{"gene":"PDE4DIP","stoichiometry":10.0},{"gene":"CLASP1","stoichiometry":4.0},{"gene":"DYNC1H1","stoichiometry":4.0},{"gene":"DYNC1I2","stoichiometry":4.0},{"gene":"BICD2","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CLASP2","stoichiometry":0.2},{"gene":"DCTN3","stoichiometry":0.2},{"gene":"LETM1","stoichiometry":0.2},{"gene":"CS","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000624","total_profiled":1310},"omim":[{"mim_id":"619413","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 144A; CCDC144A","url":"https://www.omim.org/entry/619413"},{"mim_id":"618146","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 251; CFAP251","url":"https://www.omim.org/entry/618146"},{"mim_id":"617870","title":"CENTROSOMAL PROTEIN 350; CEP350","url":"https://www.omim.org/entry/617870"},{"mim_id":"179838","title":"CAP-GLY DOMAIN-CONTAINING LINKER PROTEIN 1; CLIP1","url":"https://www.omim.org/entry/179838"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubule ends","reliability":"Approved"},{"location":"Mid piece","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":283.5}],"url":"https://www.proteinatlas.org/search/CLIP1"},"hgnc":{"alias_symbol":["CYLN1","CLIP170","CLIP","CLIP-170"],"prev_symbol":["RSN"]},"alphafold":{"accession":"P30622","domains":[{"cath_id":"2.30.30.190","chopping":"63-126","consensus_level":"high","plddt":93.828,"start":63,"end":126},{"cath_id":"2.30.30.190","chopping":"221-281","consensus_level":"high","plddt":93.457,"start":221,"end":281}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30622","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30622-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30622-F1-predicted_aligned_error_v6.png","plddt_mean":71.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CLIP1","jax_strain_url":"https://www.jax.org/strain/search?query=CLIP1"},"sequence":{"accession":"P30622","fasta_url":"https://rest.uniprot.org/uniprotkb/P30622.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30622/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30622"}},"corpus_meta":[{"pmid":"12110184","id":"PMC_12110184","title":"Rac1 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cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36172736","citation_count":6,"is_preprint":false},{"pmid":"26231764","id":"PMC_26231764","title":"CLIP-170 tethers kinetochores to microtubule plus ends against poleward force by dynein for stable kinetochore-microtubule attachment.","date":"2015","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/26231764","citation_count":6,"is_preprint":false},{"pmid":"39607512","id":"PMC_39607512","title":"CLIP170 enhancing FOSL1 expression via attenuating ubiquitin-mediated degradation of β-catenin drives renal cell carcinoma progression.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/39607512","citation_count":5,"is_preprint":false},{"pmid":"20498706","id":"PMC_20498706","title":"Tip1/CLIP-170 protein is required for correct chromosome poleward movement in fission yeast.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20498706","citation_count":5,"is_preprint":false},{"pmid":"35933602","id":"PMC_35933602","title":"Rsn-2-mediated directed foam enrichment of β-lactamase.","date":"2022","source":"Biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/35933602","citation_count":4,"is_preprint":false},{"pmid":"38705933","id":"PMC_38705933","title":"CLIP170 inhibits the metastasis and EMT of papillary thyroid cancer through the TGF-β pathway.","date":"2024","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38705933","citation_count":3,"is_preprint":false},{"pmid":"31071203","id":"PMC_31071203","title":"The concerted actions of Tip1/CLIP-170, Klp5/Kinesin-8, and Alp14/XMAP215 regulate microtubule catastrophe at the cell end.","date":"2019","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31071203","citation_count":3,"is_preprint":false},{"pmid":"10082970","id":"PMC_10082970","title":"Differential usage of two 5' splice sites in a complex exon generates additional protein sequence complexity in chicken CLIP-170 isoforms.","date":"1999","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10082970","citation_count":3,"is_preprint":false},{"pmid":"35283190","id":"PMC_35283190","title":"The CLIP-170 N-terminal domain binds directly to both F-actin and microtubules in a mutually exclusive manner.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35283190","citation_count":2,"is_preprint":false},{"pmid":"22613460","id":"PMC_22613460","title":"The cholangiocyte marker, BD. 1, forms a stable complex with CLIP170 and shares an identity with eIF3a, a multifunctional subunit of the eIF3 initiation complex.","date":"2012","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22613460","citation_count":2,"is_preprint":false},{"pmid":"38575808","id":"PMC_38575808","title":"LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/38575808","citation_count":1,"is_preprint":false},{"pmid":"12600181","id":"PMC_12600181","title":"[Expression of p16INK4a, p15INK4b, p21WAF1/Clip1 cell cycle inhibitors on blastic cells in patients with acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL) ].","date":"2002","source":"Polskie Archiwum Medycyny Wewnetrznej","url":"https://pubmed.ncbi.nlm.nih.gov/12600181","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47093,"output_tokens":11687,"usd":0.158292,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22749,"output_tokens":7580,"usd":0.151622,"stage2_stop_reason":"end_turn"},"total_usd":0.309914,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"CLIP-170 links endocytic carrier vesicles to microtubules in vitro; its N-terminal domain contains a novel tandem-repeat motif responsible for microtubule binding, and the protein forms a homodimer with a long central coiled-coil domain connecting the N-terminal microtubule-binding domain to the C-terminal organelle-interacting domain.\",\n      \"method\": \"cDNA cloning, in vitro vesicle-microtubule binding assay, domain analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of vesicle-MT binding, structural domain identification, founding paper replicated by subsequent work\",\n      \"pmids\": [\"1356075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The tandem repeat in the N-terminal domain of CLIP-170 is essential for microtubule binding in vivo; the C-terminal domain is required for anchoring microtubules to peripheral cytoplasmic structures (cargo-binding function), and overexpression of intact CLIP-170 causes microtubule bundling dependent on the C-terminal domain.\",\n      \"method\": \"Transient expression of intact and deletion/mutation mutants in HeLa and Vero cells, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mutagenesis in cells with clear phenotypic readouts, replicated across labs\",\n      \"pmids\": [\"7983157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CLIP-170 dynamically treadmills on growing microtubule plus ends in vivo at rates matching microtubule elongation (~0.15–0.4 µm/s), highlighting newly polymerized tubulin; microtubule-drug treatment rapidly abolishes this movement, indicating that plus-end association is coupled to active polymerization.\",\n      \"method\": \"GFP-CLIP-170 live-cell imaging, fluorescent speckle microscopy, pharmacological perturbation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative live imaging, drug perturbation, independently replicated\",\n      \"pmids\": [\"10052454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CLIP-170 plus-end targeting is closely linked to tubulin polymerization: the N-terminal microtubule-interacting domain alone localizes to plus ends; CLIP-170 associates with newly formed microtubules traced by biotinylated tubulin and cross-links/sediments with non-polymerized tubulin in vitro.\",\n      \"method\": \"Biotin-tubulin microinjection, in vitro co-sedimentation, cross-linking, transfection of domain fragments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple in vitro assays plus live-cell tracing, replicated concept\",\n      \"pmids\": [\"9885247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CLIP-170 recruits dynactin to microtubule plus ends via its C-terminal putative cargo-binding domain; overexpression of p150(Glued) and mutant CLIP-170 forms indicate that CLIP-170 is upstream of dynactin in endosomal cargo loading at microtubule ends.\",\n      \"method\": \"Colocalization immunofluorescence, overexpression of wild-type and mutant CLIP-170 and p150(Glued), endosomal trafficking assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression/localization studies in cells, single lab, two orthogonal approaches\",\n      \"pmids\": [\"10588646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Dynactin and CLIP-170 colocalize along distal segments of interphase microtubules; dynactin (Arp1 subunit) can be removed from microtubules by dynamitin overexpression without affecting CLIP-170, indicating they use partially distinct microtubule-association mechanisms.\",\n      \"method\": \"Multi-antibody immunofluorescence, dynamitin overexpression, temperature-shift experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-antibody approach, single lab, colocalization-based\",\n      \"pmids\": [\"10212138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CLIP-170 is a thin 135-nm homodimer with two kinks in its coiled-coil rod; the N-terminal domain binds microtubules with a stoichiometry of one dimeric head per four tubulin heterodimers; the rod and tail domains reduce microtubule-binding stoichiometry of the full-length protein.\",\n      \"method\": \"Purification of authentic CLIP-170, electron microscopy (glycerol spray/rotary shadowing), in vitro microtubule-binding stoichiometry assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — purified protein, EM structural characterization, quantitative in vitro binding assays\",\n      \"pmids\": [\"10464331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CLIP-170 transiently localizes to prometaphase kinetochores and codistributes with dynein and dynactin there; overexpression of the C-terminal domain displaces endogenous CLIP-170 from kinetochores and causes a prometaphase delay; dynamitin overexpression reduces CLIP-170 at kinetochores, suggesting dynein/dynactin-dependent kinetochore targeting of CLIP-170.\",\n      \"method\": \"Immunofluorescence, transient overexpression of C-terminal CLIP-170 fragment, dynamitin overexpression\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain overexpression with functional readout, single lab\",\n      \"pmids\": [\"9585405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IQGAP1 (an effector of Rac1/Cdc42) directly interacts with CLIP-170, and activated Rac1/Cdc42, IQGAP1, and CLIP-170 form a tripartite complex. Expression of C-terminal IQGAP1 fragment (containing the CLIP-170 binding region) delocalizes GFP-CLIP-170 from microtubule tips and alters microtubule arrays; IQGAP1 mutant defective in Rac1/Cdc42 binding induces multiple leading edges.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, GFP live imaging, dominant-negative overexpression in Vero cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional dominant-negative, live imaging, replicated concept\",\n      \"pmids\": [\"12110184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CLIP-170 directly interacts with LIS1 via the distal zinc finger motif of CLIP-170's C-terminal domain; LIS1 is required for CLIP-170 kinetochore recruitment, and LIS1 acts as a regulated adapter between CLIP-170 and cytoplasmic dynein. Overexpression of CLIP-170 causes zinc finger-dependent co-localization of phospho-LIS1 and dynactin on microtubule bundles.\",\n      \"method\": \"Co-immunoprecipitation, colocalization, domain mutant overexpression, indirect immunofluorescence\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction mapped to specific domain, functional consequence in cells, replicated by other labs\",\n      \"pmids\": [\"11940666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"LIS1 WD-repeat domain overexpression displaces CLIP-170 from kinetochores without affecting dynein/dynactin; LIS1 NH2-terminal overexpression displaces endogenous LIS1 with no effect on CLIP-170, dynein, or dynactin; dynamitin overexpression removes both CLIP-170 and LIS1. LIS1 interacts directly with dynein heavy chain (AAA1 domain) and intermediate chain, and with dynamitin.\",\n      \"method\": \"Co-expression/co-immunoprecipitation, two-hybrid assay, domain overexpression, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP + two-hybrid + domain dissection, replicated\",\n      \"pmids\": [\"11889140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"FRAP/mTOR interacts with CLIP-170 and phosphorylates it in vitro at rapamycin-sensitive sites; rapamycin inhibits CLIP-170 binding to microtubules in vivo, indicating that mTOR-mediated phosphorylation positively regulates CLIP-170 microtubule-binding activity.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, rapamycin treatment, microtubule-binding assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus cellular microtubule-binding assay, single lab with two orthogonal methods\",\n      \"pmids\": [\"12231510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CLIP-170 interacts with dynactin via the second metal-binding (zinc finger) motif of its C-terminal tail, and with EB1 via a mechanism requiring neither metal-binding motif; these interactions are separable, and CLIP-170 can target dynactin to microtubule plus ends independently of EB1.\",\n      \"method\": \"Site-directed mutagenesis, transfection/colocalization assay in mammalian cells\",\n      \"journal\": \"Cell motility and the cytoskeleton\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with localization readout, single lab\",\n      \"pmids\": [\"12789661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CLIP-170 N-terminal domain (H2) promotes microtubule rescues and stimulates nucleation in vitro; by cryo-EM, H2 induces tubulin ring formation in solution and curved oligomers at microtubule plus ends, suggesting CLIP-170 copolymerizes with tubulin and modulates dynamics through tubulin-oligomer intermediates.\",\n      \"method\": \"In vitro microtubule dynamics assay (pure tubulin + centrosomes), electron cryomicroscopy\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro dynamics assay plus cryo-EM structural data, single lab\",\n      \"pmids\": [\"15589150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CLIP-170 undergoes an intramolecular autoinhibitory interaction between its N-terminal microtubule-binding domain (first metal-binding motif) and its C-terminal domain, as shown by scanning force microscopy and FRET. This intramolecular folding reduces MT-binding. The NH2 terminus of p150(Glued) binds the CLIP-170 C-terminus (second metal-binding motif); p150(Glued) and LIS1 compete for binding to the CLIP-170 C-terminus. RNAi depletion of CLIP-170 strongly reduces dynactin accumulation at MT tips.\",\n      \"method\": \"Scanning force microscopy, FRET, RNAi knockdown, direct binding assays (GST pulldown/co-IP), immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — FRET + SFM structural evidence + RNAi functional assay + direct binding, single comprehensive study with multiple orthogonal methods\",\n      \"pmids\": [\"15381688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CLIP-170 has stronger affinity for tubulin dimer than polymer and can distinguish GTP- from GDP-tubulin; the second CAP-Gly domain with adjacent serine-rich region is the minimal plus-end tracking unit capable of both +TIP behavior in vivo and tubulin polymerization promotion in vitro, whereas the first CAP-Gly domain alone is incompetent for either activity.\",\n      \"method\": \"In vitro biochemistry (sedimentation, affinity assays), live-cell imaging of CLIP-170 CAP-Gly domain fragments\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemistry + live-cell domain mapping, single lab with two orthogonal methods\",\n      \"pmids\": [\"16120651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CLIP-170 localizes dynamically to the outermost part of unattached kinetochores and to growing microtubule ends; RNAi depletion of CLIP-170 causes defective chromosome congression and diminished kinetochore-microtubule attachments without detectably affecting microtubule dynamics or k-fiber stability.\",\n      \"method\": \"High-resolution immunofluorescence, RNAi depletion, live-cell imaging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with specific mitotic phenotype readout, single lab\",\n      \"pmids\": [\"16362039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CLIP-170 is essential for male fertility and spermatogenesis; in spermatids it associates with the manchette and centrosomes and transitions from a mobile plus-end tracking protein to a relatively immobile structural protein, indicating a structural role in spermatid differentiation and sperm head shaping.\",\n      \"method\": \"CLIP-170 knockout and GFP knock-in mice, live testis imaging, FRAP\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with specific fertility phenotype + GFP knock-in live imaging + FRAP in physiological tissue\",\n      \"pmids\": [\"16230537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EB1 is required for plus-end localization of CLIP-170, which in turn is required to localize p150(Glued) to plus ends; CLIP-170 depletion causes defects in microtubule dynamics and cell polarization after scratch wounding. However, removal of p150(Glued) from plus ends by EB1 or CLIP-170 depletion does not affect organelle distribution or membrane traffic, indicating that CLIP-170/p150(Glued) plus-end function is not required for general membrane trafficking.\",\n      \"method\": \"RNAi depletion (EB1, CLIP-170, p150Glued), immunofluorescence, membrane trafficking assays (transferrin uptake, ER-Golgi transport), live-cell imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi epistasis hierarchy established with multiple functional readouts, positive and negative findings\",\n      \"pmids\": [\"16772339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CLIP-170 requires EB1 for microtubule plus-end tracking; reconstituted in vitro at single-molecule resolution, EB1 autonomously tracks growing ends while CLIP-170 alone shows lattice diffusion and fails to selectively track ends. EB1 addition is both necessary and sufficient to mediate CLIP-170 plus-end tracking. GTP hydrolysis is required for end-specificity.\",\n      \"method\": \"In vitro reconstitution with TIRF single-molecule microscopy, pharmacological (GMPCPP) perturbation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — single-molecule reconstitution in vitro with orthogonal pharmacological control, replicated by Bieling et al. 2008\",\n      \"pmids\": [\"19126680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"EB1 autonomously recognizes specific binding sites at growing microtubule ends; CLIP-170 does not end-track by itself but requires EB1 and recognizes composite binding sites constituted by end-accumulated EB1 and tyrosinated α-tubulin; unlike fission yeast Tip1, mammalian CLIP-170 end-tracking does not require motor activity.\",\n      \"method\": \"In vitro reconstitution with purified proteins, TIRF microscopy, tubulin tyrosination manipulation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full reconstitution in vitro, multiple protein variants tested, orthogonal chemical/biochemical controls\",\n      \"pmids\": [\"19103809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GFP-CLIP-170 turns over rapidly on microtubule plus ends (rate-limited by diffusion); growing microtubule ends contain a surplus of relatively low-affinity CLIP-170 binding sites. The apparent comet fluorescence loss does not reflect single-molecule behavior but overall structural changes at the MT end.\",\n      \"method\": \"Quantitative fluorescence microscopy, FRAP, single-molecule analysis of GFP-CLIP-170 and GFP-EB3\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP + quantitative imaging, single lab\",\n      \"pmids\": [\"18283108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CLIP-170 is specifically required for efficient CR3/αMβ2-integrin-triggered phagocytosis in macrophages; it directly interacts with the formin homology 2 (FH2) domain of mDia1 via a direct protein-protein interaction, controls mDia1 recruitment to phagocytic cups, and thereby regulates actin polymerization essential for phagocytosis. This interaction is negatively regulated during αMβ2-mediated phagocytosis.\",\n      \"method\": \"RNAi knockdown, dominant-negative expression, direct binding assay, immunofluorescence, phagocytosis assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding confirmed, RNAi phenotype in primary macrophages, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"19114595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Dynein, Lis1, and CLIP-170 counteract Eg5-dependent centrosome separation during bipolar spindle assembly; CLIP-170 depletion allows spindle bipolarity with less Eg5 activity, a function mediated through CLIP-170's interaction with dynein (not shared by CLIP-115, which lacks the dynein-dynactin interaction domain).\",\n      \"method\": \"RNAi depletion in human cells, spindle bipolarity assay, Eg5 inhibitor (monastrol) titration\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi epistasis with paralog (CLIP-115) comparison, single lab\",\n      \"pmids\": [\"19020519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CLIP-170 initiates minus-end-directed transport of membrane organelles (melanosomes) in Xenopus melanophores by capturing organelles at growing microtubule plus ends; inhibition of MT dynamics or loss of CLIP-170 from MT tips dramatically inhibits pigment aggregation.\",\n      \"method\": \"Live-cell imaging in Xenopus melanophores, MT dynamics inhibition, CLIP-170 dominant-negative expression\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live-cell organelle transport assay with pharmacological and genetic perturbation, clear mechanistic readout\",\n      \"pmids\": [\"19758557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CLIP-170 binds to both α-tubulin and β-tubulin (not only the acidic C-terminal tails) including H12 helices of both tubulins, as shown by chemical cross-linking/mass spectrometry. CLIP-170 can use its multiple tubulin-binding sites to bind EB1 and microtubules simultaneously.\",\n      \"method\": \"Chemical cross-linking, mass spectrometry, in vitro binding assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chemical cross-linking MS reveals binding contacts, in vitro assays, single lab\",\n      \"pmids\": [\"19913027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AMPK directly phosphorylates CLIP-170; phosphorylation is required for proper microtubule dynamics and directional cell migration. Non-phosphorylatable CLIP-170 causes prolonged MT-tip accumulation and slower tubulin polymerization; these phenotypes are rescued by phosphomimetic CLIP-170. AMPK inhibition impairs MT stabilization and directional migration, also rescued by phosphomimetic CLIP-170.\",\n      \"method\": \"In vitro kinase assay, expression of phosphomimetic/non-phosphorylatable CLIP-170 mutants, live-cell microtubule imaging, cell migration assay (wound healing)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay + rescue with phosphomimetic in cells, multiple phenotypic readouts, replicated by subsequent work\",\n      \"pmids\": [\"20495555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Polo-like kinase 1 (Plk1) phosphorylates CLIP-170 at S195, and casein kinase 2 (CK2) phosphorylates it at S1318; Plk1 phosphorylation enhances CLIP-170 association with CK2; CK2 phosphorylation is required for CLIP-170 interaction with dynactin and kinetochore localization. Both phosphorylation events are required for timely formation of kinetochore-microtubule attachments.\",\n      \"method\": \"In vitro kinase assay, phospho-site mapping, co-immunoprecipitation, expression of phosphomutants, kinetochore-fiber assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay + site mapping + phosphomutant rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20664522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cdc2 (CDK1) phosphorylates CLIP-170 at Thr287 in vivo; expression of non-phosphorylatable T287A causes CLIP-170 mislocalization, accumulation of Plk1 and cyclin B, and G2/M block; depletion of CLIP-170 leads to centrosome reduplication, and Cdc2 phosphorylation of CLIP-170 is required to prevent it.\",\n      \"method\": \"Co-immunoprecipitation, in vivo phosphorylation assay, T287A phosphomutant expression, centrosome counting, cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo phosphorylation + mutant phenotype, single lab\",\n      \"pmids\": [\"19687009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CLIP-170 and IQGAP1 cooperatively regulate dendrite morphology in neurons; mTOR kinase interacts with CLIP-170 and is required for efficient formation of a CLIP-170/IQGAP1 complex; dynamic microtubules, CLIP-170, and IQGAP1 are required for proper dendritic arbor morphology and PI3K-mTOR-induced dendritic complexity.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, live-cell imaging of dendritic dynamics, morphometric analysis in rat neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + RNAi + morphometric analysis, single lab\",\n      \"pmids\": [\"21430156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EB1 and a minimal CLIP-170 fragment (ClipCG12 with two non-interacting CAP-Gly domains) cooperatively regulate microtubule dynamic instability; together at 250 nM they modulate dynamics and deplete stably bound Pi at microtubule ends, suggesting they modify the stabilizing GTP cap by cooperative action.\",\n      \"method\": \"In vitro microtubule dynamics assay, SAXS, analytical ultracentrifugation, [γ-32P]GTP pulsing\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with multiple biophysical methods (SAXS, AUC, dynamics assay, radioisotope), single lab\",\n      \"pmids\": [\"22424550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Pregnenolone (P5) directly binds CLIP-170 at its coiled-coil domain, changing it to an extended (active) conformation that increases CLIP-170 interactions with microtubules, dynactin p150(Glued), and LIS1, promoting CLIP-170-dependent microtubule polymerization and cell migration.\",\n      \"method\": \"Photoaffinity probe capture from embryonic extract, direct binding assay, conformational analysis, in vivo zebrafish epiboly assay, mammalian cell migration assay\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — photoaffinity capture + direct binding + conformational change + in vivo genetic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"23955365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CLIP-170 colocalizes with PLK1 at kinetochores during early mitosis; CLIP-170 depletion reduces PLK1 kinetochore recruitment, causing kinetochore-fiber instability and chromosome misalignment. CDK1-dependent phosphorylation at T287 is required: non-phosphorylatable T287A fails to restore PLK1 kinetochore localization or rescue chromosome alignment defects.\",\n      \"method\": \"RNAi depletion, immunofluorescence, phosphomutant (T287A) rescue assay, kinetochore-fiber stability assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi + phosphomutant rescue with multiple mitotic phenotypic readouts, single lab with orthogonal methods\",\n      \"pmids\": [\"24777477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LRRK1 phosphorylates CLIP-170 at Thr1384 in its C-terminal zinc knuckle motif; this promotes CLIP-170 association with dynein-dynactin complexes and causes accumulation of p150(Glued) at microtubule plus ends, thereby facilitating migration of EGFR-containing endosomes.\",\n      \"method\": \"In vitro kinase assay, phospho-site mapping, co-immunoprecipitation, live-cell EGFR trafficking assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay + site mapping + Co-IP + transport assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25413345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Plk1 phosphorylates CLIP-170 at Ser312 during mitosis; in vitro phosphorylation by Plk1 diminishes CLIP-170 binding to microtubule ends and lattice without affecting EB3 binding; proper Ser312 phosphorylation/dephosphorylation cycling is required for stable kinetochore-microtubule attachment and chromosome alignment.\",\n      \"method\": \"In vitro kinase/binding assay with purified CLIP-170 N-terminal fragment, phospho-site mapping, mitotic phenotype analysis with phosphomutants\",\n      \"journal\": \"Cell structure and function\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase + binding assay + phosphomutant phenotype, single lab with two orthogonal methods\",\n      \"pmids\": [\"24451569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CLIP-170 at microtubule plus ends is required to initiate retrograde transport of herpes simplex virus (HSV-1) particles in primary human cells; CLIP-170 functions in a +TIP complex with EB1 and DCTN1 to capture incoming virus particles. Depletion of CLIP-170 completely blocks long-range retrograde transport and suppresses infection ~5000-fold without affecting transferrin uptake or dynein-dependent organelle movement.\",\n      \"method\": \"RNAi depletion, dominant-negative expression, live-cell imaging, infection assay in primary human cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi + dominant-negative, quantitative infection assay, multiple controls distinguishing CLIP-170-specific vs. general dynein function\",\n      \"pmids\": [\"26504169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CLIP-170 phosphorylation and α-tubulin tyrosination cooperatively control initiation of dynein-driven retrograde transport in the distal axon; CLIP-170 primarily regulates the time to microtubule encounter, while tyrosination of the lattice regulates the probability of binding.\",\n      \"method\": \"In vitro single-molecule reconstitution, live-cell transport assay in primary neurons, computational simulation, pharmacological manipulation of tubulin PTMs\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — single-molecule reconstitution + neuronal transport assay + simulation, multiple orthogonal methods\",\n      \"pmids\": [\"26972003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CLIP-170 is required for redeployment of ninein from centrosomes to non-centrosomal microtubule organizing centres (n-MTOCs) during epithelial differentiation, thereby enabling apico-basal microtubule array formation; IQGAP1 and active Rac1 cooperate with CLIP-170 in this process. Confirmed using CLIP-170/CLIP-115 double KO intestinal tissue and organoids.\",\n      \"method\": \"RNAi depletion, KO mouse tissue (Clip1/Clip2 double KO), organoid culture, immunofluorescence\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO + RNAi in multiple model systems with defined organelle-redistribution phenotype\",\n      \"pmids\": [\"28179500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CLIP170 interacts with the TLR2/TLR4 adaptor TIRAP, induces its ubiquitination and subsequent proteasomal degradation, and thereby negatively regulates TLR4-mediated proinflammatory cytokine (IL-6, TNF-α) production in macrophages.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown (siRNA), ubiquitination assay, cytokine ELISA, in vivo siRNA delivery in mice\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + ubiquitination assay + in vivo knockdown, single lab\",\n      \"pmids\": [\"29222167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CLIP-170 contains multiple EB1-binding modules in its N-terminal region: two CAP-Gly domains (engaging EB1's C-terminal EEY motif only), a bridging SXIP motif, and an array of divergent SXIP-like motifs N-terminal to the first CAP-Gly domain. These modules act multivalently to strengthen the CLIP-170-EB1 interaction.\",\n      \"method\": \"Isothermal titration calorimetry, size-exclusion chromatography, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative biophysical binding measurements with mutational dissection, single lab\",\n      \"pmids\": [\"30455356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CLIP-170 phosphorylation (by AMPK) is essential for MTOC repositioning to the immunological synapse during T cell activation; T cell stimulation induces dynein co-localization with CLIP-170 and plus-end tracking, and phosphorylated CLIP-170 is required for dynein recruitment to plus-end tracking and subsequent dynein relocation to the contact surface.\",\n      \"method\": \"Fluorescence imaging, CLIP-170 phosphorylation inhibition (dominant-negative AMPK/phosphomutant), single-molecule tracking of dynein\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging + phosphomutant approach, single lab\",\n      \"pmids\": [\"30487641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CLIP-170 associates with MT plus ends to coordinate recycling and outward transport of Met RTK-containing endosomes (Rab4-positive); HGF stimulation induces GGA3 and CLIP-170 recruitment to an activated Met RTK complex, and CLIP-170 is required for net outward movement of Met-positive vesicles toward the cell cortex and lamellipodia.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging, dominant-negative CLIP-170, RNAi knockdown, endosome trafficking assay\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + live imaging + genetic perturbation, single lab\",\n      \"pmids\": [\"30537020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JNK directly phosphorylates CLIP-170 in its microtubule-binding domain upon cell stress, increasing CLIP-170's rescue-promoting activity; phosphomimetic CLIP-170 enhances rescue events in vitro and in cells, and increases CLIP-170 remnant occurrence on the microtubule lattice at potential future rescue sites.\",\n      \"method\": \"In vitro kinase assay, in vitro microtubule dynamics assay, phosphomimetic/non-phosphorylatable mutants, live-cell imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase + dynamics assay + cellular imaging with phosphomutants, single lab with multiple methods\",\n      \"pmids\": [\"32491151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AMPK-mediated phosphorylation of CLIP-170 at Ser311 regulates microtubule turnover at intercalated disks in cardiomyocytes; inhibition of this phosphorylation (S311A transgenic mice) causes MT accumulation at intercalated disks, cardiomyocyte elongation, and progressive decline in cardiac contraction.\",\n      \"method\": \"CLIP-170 S311A transgenic mouse, time-lapse imaging, pharmacological (MYK-461) modulation of AMPK localization\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic mouse model + live imaging + pharmacological perturbation with cardiac function readout\",\n      \"pmids\": [\"33251722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CLIP-170 directly interacts with TIRAP (TLR adaptor) and CLIP-170 induces TIRAP ubiquitination and degradation, negatively regulating TLR4 signaling; TFPI2 inhibits CLIP-170-mediated TIRAP ubiquitination by binding the CLIP-170 R24 residue of TFPI2's KD1 domain, and HOPE (hypothermic oxygenated perfusion) exerts anti-inflammatory effects by modulating the TFPI2/CLIP-170/TIRAP axis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, rat liver IRI model, Western blot\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + ubiquitination assay + in vivo model, single lab\",\n      \"pmids\": [\"39617791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DCTN1 (dynactin-1) competes with CLIP-170 for binding to incoming HIV-1 particles; outside its dynactin role, DCTN1 functions as a +TIP that sequesters CLIP-170 from viral cores, inhibiting early HIV-1 infection. Deletion of the zinc knuckle domain of CLIP-170 increases its binding to virus particles but does not promote infection, indicating this Zn domain mediates a critical proviral CLIP-170 function blocked by DCTN1.\",\n      \"method\": \"RNAi knockdown of DCTN1, CLIP-170 Zn-domain deletion mutant, virus particle co-immunoprecipitation, infectivity assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with viral particles + infectivity assay + domain mutant, single lab\",\n      \"pmids\": [\"34686593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SOCS3 interacts with CLIP-170 (and CLASP2) via its N-terminal domain; the SOCS3-CLIP-170/CLASP2 complex is essential for maximal anti-inflammatory SOCS3 effects in lung endothelium. Knockdown of CLIP-170 impairs SOCS3-JAK2 interaction and abolishes SOCS3's protective effects against IL-6 and bacterial pathogen-induced barrier dysfunction.\",\n      \"method\": \"Co-immunoprecipitation, endothelial cell KD, EC-specific SOCS3 KO mice, lung permeability/inflammation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + genetic KO + KD with functional barrier readout, single lab\",\n      \"pmids\": [\"33372035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The CLIP-170 N-terminal domain directly binds filamentous actin (F-actin) with relatively weak affinity; the F-actin-binding region overlaps with the microtubule-binding region; in vitro competition assays show that CLIP-170-F-actin and CLIP-170-MT interactions are mutually exclusive.\",\n      \"method\": \"High-speed co-sedimentation assays, CLIP-170 fragment/mutant analysis, in vitro competition assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with domain mapping and competition assay, single lab\",\n      \"pmids\": [\"35283190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Overexpression of CLIP-170 in cells induces large patch structures with hallmarks of biomolecular condensates (phase-separated liquid droplets): they contain CLIP-170 and other +TIP network proteins, are dynamic by FRAP, and exclude other known condensate markers; bioinformatic analysis confirms conserved intrinsically disordered regions in key +TIPs.\",\n      \"method\": \"Video microscopy, immunofluorescence, FRAP, bioinformatic disorder prediction\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP + imaging evidence for condensate properties, supported by bioinformatics, single lab\",\n      \"pmids\": [\"34890409\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CLIP-170 (CLIP1) is a homodimeric microtubule plus-end tracking protein (+TIP) that binds growing microtubule ends via its N-terminal CAP-Gly domains in an EB1-dependent manner (EB1 is necessary and sufficient for CLIP-170 end-tracking), uses its C-terminal zinc-finger/metal-binding motifs to recruit dynactin (p150Glued) and interact with LIS1 and dynein, and undergoes extensive phospho-regulation by multiple kinases (mTOR, AMPK, CDK1/Cdc2, Plk1, CK2, JNK, LRRK1) that control its microtubule affinity, conformation (autoinhibited closed vs. open extended state), and ability to link organelle capture at growing MT ends to minus-end-directed dynein transport, facilitate kinetochore-microtubule attachments in mitosis, coordinate microtubule-actin cross-talk via IQGAP1 and formins, and regulate TLR4 signaling by promoting TIRAP degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CLIP1 (CLIP-170) is a homodimeric microtubule plus-end tracking protein (+TIP) that links growing microtubule ends to organelle capture, minus-end-directed transport, and microtubule dynamics regulation [#0, #2, #24]. It is a thin 135-nm homodimer in which a long coiled-coil rod connects an N-terminal microtubule/tubulin-binding region — built from tandem CAP-Gly modules, with the second CAP-Gly domain and adjacent serine-rich region constituting the minimal plus-end tracking and polymerization-promoting unit — to a C-terminal cargo/metal-binding domain [#0, #6, #15]. Plus-end tracking is not autonomous: CLIP-170 alone diffuses on the lattice, and EB1 is necessary and sufficient to confer end-specificity, with CLIP-170 recognizing composite sites formed by end-accumulated EB1 and tyrosinated α-tubulin through multivalent CAP-Gly and SXIP-like modules [#19, #20, #39]. At the plus end CLIP-170 promotes microtubule rescue and nucleation via curved tubulin-oligomer intermediates and, with EB1, cooperatively tunes the stabilizing GTP cap [#13, #30]. Through its C-terminal zinc-finger motifs, CLIP-170 recruits dynactin (p150Glued) and binds LIS1, which together couple it to cytoplasmic dynein; p150Glued and LIS1 compete for the same C-terminal site, and an intramolecular fold between the N- and C-termini autoinhibits microtubule binding [#9, #12, #14]. This +TIP-to-dynein relay drives capture of membrane organelles at growing ends and initiation of retrograde transport — of melanosomes, EGFR- and Met-containing endosomes, and incoming herpesvirus particles — and positions CLIP-170 at unattached kinetochores where it supports chromosome congression, kinetochore-microtubule attachment, and PLK1 recruitment during mitosis [#16, #24, #33, #35, #41, #32]. CLIP-170 activity is extensively controlled by phosphorylation: mTOR, AMPK, JNK, CDK1, Plk1, CK2, and LRRK1 phosphorylate distinct sites to regulate its microtubule affinity, rescue activity, dynactin/dynein engagement, and kinetochore function, governing directional cell migration, cardiomyocyte microtubule turnover, and MTOC repositioning [#11, #26, #42, #27, #34, #33, #43]. CLIP-170 also coordinates microtubule-actin cross-talk through direct, mutually exclusive binding to F-actin and via IQGAP1 and the formin mDia1, supporting cell polarization, dendrite morphology, phagocytosis, and non-centrosomal MTOC assembly [#47, #8, #22, #29, #37], and negatively regulates TLR4 signaling by promoting ubiquitination and degradation of the adaptor TIRAP [#38]. Genetic knockout establishes that CLIP-170 is essential for spermatogenesis and male fertility [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established CLIP-170 as the founding molecular linker between membranous organelles and microtubules, defining the modular architecture that all later mechanism rests on.\",\n      \"evidence\": \"cDNA cloning, in vitro vesicle-microtubule binding assay, and domain analysis\",\n      \"pmids\": [\"1356075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how plus-end specificity arises\", \"C-terminal cargo partners not yet identified\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Mapped the division of labor between domains — N-terminal tandem repeat for microtubule binding and C-terminal domain for peripheral cargo anchoring — converting the structural model into a functional one.\",\n      \"evidence\": \"Domain/deletion mutant expression in HeLa and Vero cells with immunofluorescence\",\n      \"pmids\": [\"7983157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of end-tracking vs lattice binding unresolved\", \"No direct partner identification\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Discovered that CLIP-170 treadmills on growing plus ends coupled to active polymerization and biochemically characterized the homodimer and its tubulin/plus-end binding, establishing the +TIP behavior and its link to newly polymerized tubulin.\",\n      \"evidence\": \"GFP live-cell imaging, biotin-tubulin tracing, in vitro co-sedimentation/cross-linking, and EM of purified protein\",\n      \"pmids\": [\"10052454\", \"9885247\", \"10464331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether end-tracking is autonomous or requires partners unknown\", \"Binding stoichiometry to dimer vs polymer not fully resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Placed CLIP-170 upstream of dynactin at plus ends, linking +TIP behavior to the dynein transport machinery for endosomal cargo loading.\",\n      \"evidence\": \"Colocalization and overexpression of WT/mutant CLIP-170 and p150Glued with endosomal trafficking assays\",\n      \"pmids\": [\"10588646\", \"10212138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding site not yet mapped\", \"Overexpression-based; physiological requirement unestablished\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identified CLIP-170 at prometaphase kinetochores codistributing with dynein/dynactin, extending its role from interphase trafficking to mitotic chromosome segregation.\",\n      \"evidence\": \"Immunofluorescence, C-terminal fragment and dynamitin overexpression\",\n      \"pmids\": [\"9585405\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Targeting mechanism inferred from dynamitin, not directly demonstrated\", \"Functional contribution to attachment not yet tested by depletion\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapped the C-terminal zinc-finger to LIS1 and dynactin binding and connected CLIP-170 to Rac1/Cdc42-IQGAP1 signaling, defining how it couples to dynein and to actin-based polarity cues.\",\n      \"evidence\": \"Reciprocal Co-IP, two-hybrid, domain mutagenesis, and live imaging in cells\",\n      \"pmids\": [\"11940666\", \"11889140\", \"12110184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LIS1/dynactin binding is coordinated in time unclear\", \"Direct vs indirect IQGAP1 contact at residue level not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed mTOR directly phosphorylates CLIP-170 to positively regulate its microtubule binding, opening the theme of kinase control of +TIP activity.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, rapamycin treatment, and microtubule-binding assay\",\n      \"pmids\": [\"12231510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phospho-sites not mapped\", \"In vivo physiological context undefined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved how CLIP-170 modulates dynamics and how its own activity is gated — promoting rescue/nucleation via curved tubulin oligomers while an intramolecular fold autoinhibits microtubule binding and sets up p150Glued/LIS1 competition.\",\n      \"evidence\": \"In vitro dynamics assay, cryo-EM, scanning force microscopy, FRET, RNAi, and direct binding assays\",\n      \"pmids\": [\"15589150\", \"15381688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What relieves autoinhibition in vivo not established here\", \"Structural basis of oligomer induction at atomic resolution lacking\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the minimal plus-end tracking unit (second CAP-Gly + serine-rich region) and CLIP-170's preference for GTP-tubulin dimer, and demonstrated its functional requirement at kinetochores for chromosome congression.\",\n      \"evidence\": \"In vitro biochemistry, live-cell domain imaging, and RNAi with mitotic readouts\",\n      \"pmids\": [\"16120651\", \"16362039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetochore study Medium confidence, single lab\", \"How GTP-tubulin discrimination is achieved structurally unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated genetically that CLIP-170 is essential for male fertility and undergoes a +TIP-to-structural transition in spermatids, establishing an organismal, non-trafficking role.\",\n      \"evidence\": \"Knockout and GFP knock-in mice, live testis imaging, and FRAP\",\n      \"pmids\": [\"16230537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the mobility transition unknown\", \"Manchette/centrosome binding partners in spermatids unidentified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the long-standing question of plus-end specificity: in vitro single-molecule reconstitution showed EB1 is necessary and sufficient for CLIP-170 end-tracking, which depends on EB1 plus tyrosinated α-tubulin and GTP hydrolysis, not motor activity.\",\n      \"evidence\": \"TIRF single-molecule reconstitution with purified proteins and GMPCPP/tyrosination controls\",\n      \"pmids\": [\"19126680\", \"19103809\", \"18283108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EB1 dependence integrates with intrinsic tubulin affinity in cells unclear\", \"Stoichiometry of the composite binding site not fully defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended CLIP-170 function into innate immunity, spindle bipolarity, and actin regulation — direct mDia1 binding for phagocytosis, dynein-dependent counteraction of Eg5, and CR3-triggered actin polymerization.\",\n      \"evidence\": \"RNAi, dominant-negative expression, direct binding assays, and phagocytosis/spindle assays\",\n      \"pmids\": [\"19114595\", \"19020519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mDia1 binding interface not residue-mapped\", \"Eg5-counteraction study Medium confidence\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated CLIP-170 initiates minus-end-directed organelle transport by capturing cargo at growing plus ends, and that it contacts both α- and β-tubulin H12 helices, mechanistically linking +TIP capture to dynein transport.\",\n      \"evidence\": \"Live melanophore imaging with MT-dynamics inhibition, plus cross-linking/mass spectrometry of tubulin contacts\",\n      \"pmids\": [\"19758557\", \"19913027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Handoff step from CLIP-170 capture to dynein motility not directly visualized\", \"Tubulin contact study Medium confidence\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Initiated the cell-cycle kinase control theme by showing CDK1/Cdc2 phosphorylates CLIP-170 at Thr287 to control localization, mitotic progression, and prevention of centrosome reduplication.\",\n      \"evidence\": \"Co-IP, in vivo phosphorylation assay, T287A mutant expression, and centrosome counting\",\n      \"pmids\": [\"19687009\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; downstream effector of T287 phosphorylation initially unclear\", \"Mechanism of centrosome reduplication suppression not detailed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established a multi-kinase phospho-code: AMPK controls CLIP-170-dependent MT dynamics and directional migration, while Plk1 (S195) and CK2 (S1318) jointly govern dynactin binding and kinetochore-MT attachment timing.\",\n      \"evidence\": \"In vitro kinase assays, phospho-site mapping, phosphomimetic rescue, and migration/kinetochore-fiber assays\",\n      \"pmids\": [\"20495555\", \"20664522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How distinct phosphorylations are spatiotemporally integrated unclear\", \"Phosphatases reversing these marks not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected CLIP-170 to neuronal morphogenesis and clarified the EB1-CLIP-170 cooperative mechanism on dynamics: mTOR-promoted CLIP-170/IQGAP1 complex shapes dendrites, and EB1+CLIP-170 deplete end-bound Pi to modify the GTP cap.\",\n      \"evidence\": \"Co-IP, RNAi, dendrite morphometry, and in vitro dynamics with SAXS/AUC/[γ-32P]GTP pulsing\",\n      \"pmids\": [\"21430156\", \"22424550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dendrite study Medium confidence\", \"Link between GTP-cap modification and rescue in cells not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a direct small-molecule regulator: pregnenolone binds the coiled-coil to switch CLIP-170 to an extended active conformation, increasing MT, dynactin, and LIS1 engagement — a non-kinase route to relieving autoinhibition.\",\n      \"evidence\": \"Photoaffinity capture, direct binding, conformational analysis, zebrafish epiboly, and migration assays\",\n      \"pmids\": [\"23955365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological pregnenolone concentrations and tissue relevance unclear\", \"Binding site not residue-resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the mitotic phospho-network in detail — CDK1-T287 enables PLK1 kinetochore recruitment, Plk1-S312 cyclically tunes MT-end binding, and LRRK1-T1384 promotes dynein-dynactin engagement for EGFR endosome transport.\",\n      \"evidence\": \"In vitro kinase/binding assays, site mapping, phosphomutant rescue, and kinetochore/transport assays\",\n      \"pmids\": [\"24777477\", \"24451569\", \"25413345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of these phospho-events within mitosis not fully resolved\", \"Cross-talk between LRRK1 and cell-cycle kinases unexplored\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that CLIP-170 captures incoming herpesvirus particles in an EB1/DCTN1 +TIP complex to initiate retrograde transport, distinguishing CLIP-170-specific from general dynein function.\",\n      \"evidence\": \"RNAi, dominant-negative expression, live imaging, and quantitative infection assay in primary human cells\",\n      \"pmids\": [\"26504169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct viral-capsid contact not biochemically defined\", \"Whether all retrograde cargoes use the same capture mode unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Quantified how CLIP-170 phosphorylation and α-tubulin tyrosination jointly time and probabilistically gate initiation of dynein-driven retrograde transport in axons.\",\n      \"evidence\": \"Single-molecule reconstitution, neuronal transport assays, and computational simulation\",\n      \"pmids\": [\"26972003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which kinase sets the relevant phospho-state in the distal axon unspecified here\", \"In vivo relevance to axonal cargoes broadly not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed CLIP-170 (with IQGAP1/Rac1) drives ninein redeployment to non-centrosomal MTOCs during epithelial differentiation, and identified TIRAP degradation as a mechanism for CLIP-170 negative regulation of TLR4 inflammation.\",\n      \"evidence\": \"RNAi, double-KO mouse tissue/organoids, immunofluorescence; and Co-IP, ubiquitination assay, cytokine ELISA, in vivo siRNA\",\n      \"pmids\": [\"28179500\", \"29222167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TLR4/TIRAP study Medium confidence\", \"Mechanism by which CLIP-170 promotes TIRAP ubiquitination (E3 identity) unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the molecular basis of EB1 engagement and added immune cell function: multivalent CAP-Gly/SXIP-like modules strengthen EB1 binding, and AMPK-phosphorylated CLIP-170 is required for MTOC repositioning to the immune synapse.\",\n      \"evidence\": \"ITC, SEC, mutagenesis; and imaging with phosphomutant/dominant-negative AMPK plus dynein single-molecule tracking\",\n      \"pmids\": [\"30455356\", \"30487641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Immune-synapse study Medium confidence\", \"How multivalency is regulated dynamically in cells unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Added JNK as a stress-activated regulator boosting CLIP-170 rescue activity, and established AMPK-S311 phosphorylation as a physiological controller of cardiomyocyte microtubule turnover.\",\n      \"evidence\": \"In vitro kinase/dynamics assays with phosphomutants; and S311A transgenic mice with cardiac imaging and pharmacology\",\n      \"pmids\": [\"32491151\", \"33251722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between S311 (AMPK) and other AMPK sites unclear\", \"How rescue remnants are selected as future rescue sites unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded the CLIP-170 interactome and properties: direct mutually exclusive F-actin/MT binding, recycling Met-endosome transport, anti-inflammatory SOCS3 and TFPI2/TIRAP axes, DCTN1 competition restraining HIV-1 infection, and condensate-like phase behavior.\",\n      \"evidence\": \"Co-sedimentation/competition, Co-IP, live imaging, ubiquitination assays, infectivity assays, KO/KD models, and FRAP\",\n      \"pmids\": [\"35283190\", \"30537020\", \"33372035\", \"39617791\", \"34686593\", \"34890409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Several axes (Met, SOCS3, TFPI2, HIV-1, condensate) are Medium confidence single-lab\", \"Physiological significance of CLIP-170 phase separation undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple kinase inputs, conformational switching, EB1-dependent tracking, and competing C-terminal partners are integrated to dictate cargo specificity in a given cellular context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking phospho-state to choice of cargo or pathway\", \"Phosphatases and the in vivo trigger relieving autoinhibition largely unidentified\", \"Functional role of phase separation versus discrete complexes unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 3, 15, 47]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 9, 14, 24]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 30, 42]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 6, 47]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [17, 28, 37]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 24]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [7, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [16, 27, 32, 34, 23]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [24, 33, 41, 35]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [22, 38, 46]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 11, 26]}\n    ],\n    \"complexes\": [\"dynein-dynactin complex\", \"EB1/CLIP-170 +TIP network\", \"Rac1/Cdc42-IQGAP1-CLIP-170 complex\"],\n    \"partners\": [\"EB1\", \"DCTN1\", \"LIS1\", \"IQGAP1\", \"mDia1\", \"TIRAP\", \"SOCS3\", \"MTOR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":9,"faith_total":9,"faith_pct":100.0}}