{"gene":"HOOK2","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2006,"finding":"Hook2 localizes to the centrosome throughout all phases of the cell cycle via its C-terminal domain, which directly binds to centriolin/CEP110. Mislocalized wild-type or mutant Hook2 perturbs endogenous centrosomal and pericentrosomal proteins. Interference with Hook2 function results in loss of radial microtubule organization and defective microtubule regrowth after nocodazole-induced depolymerization.","method":"Direct binding assay (C-terminal domain of Hook2 and centriolin/CEP110), immunofluorescence localization through cell cycle, dominant-negative overexpression with centrosome/microtubule phenotype readout","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated, localization confirmed across cell cycle, loss-of-function with specific centrosomal/microtubule phenotypes, multiple orthogonal methods in single focused study","pmids":["17140400"],"is_preprint":false},{"year":2007,"finding":"Hook2 overexpression promotes accumulation of the cystic fibrosis transmembrane regulator (CFTR) in aggresomes without altering its biochemical properties or steady-state level. A dominant-negative form of Hook2 lacking the centriolin-binding C-terminal domain inhibits aggresome formation, indicating Hook2 contributes to pericentrosomal localization of aggresomes by promoting microtubule-based delivery of protein aggregates.","method":"Overexpression and dominant-negative expression of Hook2 with CFTR aggresome formation assay; immunofluorescence","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with specific phenotypic readout (aggresome formation), single lab but two complementary approaches","pmids":["17540036"],"is_preprint":false},{"year":2008,"finding":"Hook2 (along with Hook1 and Hook3) forms part of a multiprotein FTS-Hook-FHIP (FHF) complex. Hook proteins associate with a conserved C-terminal motif of FTS, form homo- and heterodimers, and the ~500-kDa FHF complex interacts with components of both class B and class C of the HOPS complex to promote vesicle trafficking and/or fusion. Hook2 can interact interchangeably with other Hook proteins within this complex.","method":"Proteomic analysis (mass spectrometry) of purified FTS complexes from HEK293T cells, yeast two-hybrid, co-immunoprecipitation, siRNA depletion with endosomal trafficking readout","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mass spectrometry, yeast two-hybrid, siRNA functional follow-up, replicated across orthogonal methods in single rigorous study","pmids":["18799622"],"is_preprint":false},{"year":2009,"finding":"MSUT-2 (the human ortholog of C. elegans SUT-2) binds specifically to HOOK2 among the three human HOOK paralogs (HOOK1, HOOK2, HOOK3), as demonstrated by yeast two-hybrid and in vitro protein binding assays, suggesting the SUT-2/HOOK interaction is conserved across animal phyla.","method":"Yeast two-hybrid screen, in vitro protein binding assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid confirmed by in vitro binding, two orthogonal methods but limited functional follow-up for HOOK2 specifically","pmids":["19273536"],"is_preprint":false},{"year":2009,"finding":"CENP-F binds Hook2 at the centrosome, as identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation. Ablation of CENP-F eliminates microtubule repolymerization from the centrosome after nocodazole treatment but not from the Golgi. Expression of a CENP-F truncation containing only the Hook2-binding domain recapitulates the centrosome-specific microtubule nucleation defect, indicating CENP-F acts through Hook2 at the centrosome.","method":"Yeast two-hybrid, co-immunoprecipitation with novel immunochemical reagents, CENP-F knockout cells with MT repolymerization assay, truncation expression","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, KO cells with specific phenotype, domain truncation confirms Hook2-mediated function, multiple orthogonal methods","pmids":["19793914"],"is_preprint":false},{"year":2011,"finding":"Hook2 localizes at the Golgi apparatus and centrosome/basal body in human retinal epithelial cells. Hook2 depletion disrupts ciliogenesis before formation of the ciliary vesicle at the distal tip of the mother centriole. Hook2 interacts with and stabilizes PCM1 (pericentriolar material protein 1), and co-immunoprecipitates with GFP::Rab8a and PCM1 in a complex. Overexpression of GFP::Rab8a can rescue the ciliogenesis defect caused by Hook2 depletion.","method":"siRNA depletion with ciliogenesis phenotype readout, yeast two-hybrid, co-immunoprecipitation, GFP::Rab8a rescue experiment, immunofluorescence localization","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — siRNA depletion with specific ciliogenesis phenotype, Co-IP confirming complex, rescue experiment establishing functional interaction, multiple orthogonal methods","pmids":["21998199"],"is_preprint":false},{"year":2015,"finding":"LRGUK-1 binds directly to HOOK2 via its GUK-like domain, as shown by yeast two-hybrid and co-immunoprecipitation. Both proteins co-localize to the manchette during spermatogenesis. Loss of LRGUK-1 causes defects in basal body attachment, axoneme extension, and manchette microtubule organization that may be mediated in part through its interaction with HOOK2.","method":"Yeast two-hybrid screen of adult testis library, co-immunoprecipitation/co-localization, domain mapping (GUK-like domain essential for HOOK2 binding), LRGUK-1 knockout mouse with spermatogenesis phenotype","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid confirmed by Co-IP and co-localization, domain mapping, but functional attribution specifically to HOOK2 is indirect","pmids":["25781171"],"is_preprint":false},{"year":2016,"finding":"LRGUK1 binds to HOOK2 (as well as HOOK1 and HOOK3) specifically through its GUK-like domain, confirmed by yeast two-hybrid and validated biochemically. All three HOOK proteins localize to the manchette, and LRGUK1 functions within a multiprotein complex (including HOOK proteins, RIMBP3, and KLC3) required for manchette-based microtubule dynamics in haploid male germ cells.","method":"Yeast two-hybrid screen, domain mapping (GUK-like domain required for HOOK2 binding), biochemical validation, co-localization studies","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid confirmed with domain mapping and biochemical validation, co-localization data; functional link to HOOK2 is within a larger complex context","pmids":["28003339"],"is_preprint":false},{"year":2016,"finding":"Hook2 interacts with PAR6α via its C-terminal domain binding to the aPKC-binding domain of PAR6α, localizing PAR6α to the centrosome during polarized cell migration. Hook2 depletion decreases PAR6α at the centrosome and disrupts Golgi reorientation toward the migration front. Overexpression of Hook2 induces aggresome formation with recruitment of PAR6α, aPKC, and PAR3.","method":"Co-immunoprecipitation, domain mapping, siRNA depletion with Golgi reorientation and PAR6α localization readout, overexpression phenotype analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with domain mapping, siRNA loss-of-function with specific polarization phenotype, overexpression gain-of-function; single lab","pmids":["27624926"],"is_preprint":false},{"year":2020,"finding":"The FHF complex interacts with the AP-4 adaptor protein complex via direct binding of the AP-4 μ4 subunit to coiled-coil domains in Hook1 and Hook2. Knockdown of FHF subunits (including Hook2) causes dispersal of AP-4 and its cargo ATG9A from the perinuclear region, consistent with FHF coupling organelles to dynein-dynactin for retrograde microtubule transport.","method":"Affinity purification-mass spectrometry, direct binding assay (μ4 subunit to Hook coiled-coil domains), siRNA knockdown with AP-4/ATG9A localization readout","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct binding established with AP-4 μ4 subunit, AP-MS identification, siRNA functional readout, multiple orthogonal methods in a single rigorous study","pmids":["32073997"],"is_preprint":false},{"year":2021,"finding":"FTS-FHIP2A-Hook2 complexes associate with Rab1A-tagged ER-to-Golgi cargos, and FHIP2A is involved in the motility of Rab1A tubules. These Hook2-containing FHF complexes move with dynein and dynactin in single-molecule in vitro reconstitution assays. This contrasts with FTS-FHIP1B-Hook1/Hook3 complexes that associate with Rab5-positive early endosomes, demonstrating cargo specificity through combinatorial FHF assembly.","method":"Proteomic interactome of each FHIP protein, live-cell imaging, single-molecule in vitro reconstitution with dynein/dynactin, siRNA knockdown of FHIP2A with Rab1A tubule motility readout","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of motility, proteomic interactome, live-cell imaging, siRNA functional readout; multiple orthogonal methods establishing cargo specificity of Hook2-containing complex","pmids":["34882091"],"is_preprint":false},{"year":2021,"finding":"Mitotic phosphorylation of LIC1-CTD (dynein light intermediate chain 1 C-terminal domain) at cdk1 sites engages the prolyl isomerase Pin1 predominantly to Hook2-dynein-Nde1-Lis1 complexes but not to dynein-spindly-dynactin complexes, indicating Hook2-containing dynein complexes are selectively regulated by mitotic phosphorylation and Pin1.","method":"Co-immunoprecipitation of endogenous complexes, phosphomutant analysis, cell biological phenotype readouts (kinetochore loading, chromosome congression, mitotic Golgi fragmentation)","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with phosphomutants distinguishing Hook2-dynein from spindly-dynactin, specific phenotypic readouts, single lab","pmids":["34709360"],"is_preprint":false},{"year":2013,"finding":"In the ovarian cancer cell line SKOV-3, exon 14 of HOOK2 on chromosome 19 is fused with exon 2 of ACTN3 from chromosome 11 in a der(19)t(11;19) translocation, producing a fusion protein. The breakpoint in HOOK2 introduces a frameshift in ACTN3 predicted to cause loss of ACTN3 function; the fusion protein was detected by 2D Western blotting at the calculated molecular mass.","method":"Array-based breakpoint mapping, PCR spanning breakpoints on genomic DNA and cDNA, sequencing, 2D Western blotting","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — breakpoint characterized at molecular level by sequencing and protein confirmed by 2D Western blot; single study, functional consequences of the HOOK2 portion not fully characterized","pmids":["23362175"],"is_preprint":false},{"year":2019,"finding":"Hook2 is present at the midbody and centrosome during cytokinesis in human epithelial cells. Knockdown of Hook2 causes disappearance of LSR, tricellulin, PAR3, and other molecules from the centrosome during cytokinesis, while the epithelial barrier is maintained, indicating Hook2 is required for recruitment of multiple proteins to the centrosome during cell division.","method":"Immunofluorescence localization, siRNA knockdown with centrosome protein localization readout during cytokinesis","journal":"The journal of histochemistry and cytochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization and siRNA knockdown with specific centrosomal protein recruitment phenotype; single lab, single study","pmids":["31662022"],"is_preprint":false},{"year":2025,"finding":"HOOK2 mRNA is significantly upregulated in second-trimester amniotic fluid from women who later develop preeclampsia, and its expression increases with higher shear stress in trophoblast cells. Knockdown of HOOK2 significantly increases trophoblast invasion while migration shows no significant change, suggesting HOOK2 negatively regulates trophoblast invasiveness under hemodynamic stress conditions.","method":"RNA sequencing of amniotic fluid, siRNA knockdown in HTR-8/SVneo cells with invasion and migration assays under shear stress conditions","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — siRNA knockdown with invasion phenotype, single lab, single study, no mechanistic pathway placement","pmids":["41226568"],"is_preprint":false}],"current_model":"HOOK2 is a centrosomal adaptor protein that directly binds centriolin/CEP110 via its C-terminal domain to maintain centrosomal structure and microtubule organization; it forms part of the FTS-Hook-FHIP (FHF) multiprotein complex that links cargo—specifically Rab1A-positive ER-to-Golgi vesicles—to cytoplasmic dynein-dynactin for retrograde microtubule transport; it interacts with PCM1 and Rab8a to regulate a limiting step in primary ciliogenesis; it recruits the aPKC/PAR6α polarity complex to the centrosome during cell migration; it promotes aggresome formation by facilitating microtubule-based delivery of misfolded proteins to the pericentriolar region; and it is selectively incorporated into Pin1-binding dynein complexes under mitotic CDK1-mediated phosphorylation of the dynein LIC1 subunit."},"narrative":{"mechanistic_narrative":"HOOK2 is a centrosomal adaptor protein that organizes microtubule-based architecture and links specific cargoes to the cytoplasmic dynein-dynactin retrograde transport machinery [PMID:17140400, PMID:34882091]. It localizes to the centrosome throughout the cell cycle via its C-terminal domain, which directly binds centriolin/CEP110, and loss of HOOK2 function abolishes radial microtubule organization and regrowth after depolymerization [PMID:17140400]; it acts at the centrosome downstream of CENP-F, whose Hook2-binding domain alone is sufficient to drive centrosome-specific microtubule nucleation [PMID:19793914]. As a subunit of the ~500-kDa FTS-Hook-FHIP (FHF) complex, HOOK2 forms homo- and heterodimers with other Hook paralogs and couples organelles to dynein-dynactin: in combination with FHIP2A it confers specificity for Rab1A-positive ER-to-Golgi cargo and moves processively with dynein and dynactin in single-molecule reconstitutions, while the complex also binds the AP-4 μ4 subunit to position AP-4/ATG9A cargo perinuclearly [PMID:18799622, PMID:32073997, PMID:34882091]. HOOK2 regulates a limiting step in primary ciliogenesis by stabilizing PCM1 and complexing with Rab8a, the overexpression of which rescues the HOOK2-depletion ciliary defect [PMID:21998199], and it recruits the PAR6α/aPKC/PAR3 polarity machinery to the centrosome to drive Golgi reorientation during directed cell migration [PMID:27624926]. It further promotes pericentrosomal aggresome formation by facilitating microtubule-based delivery of misfolded protein aggregates [PMID:17540036], and is selectively incorporated into Hook2-dynein-Nde1-Lis1 complexes that are engaged by Pin1 upon mitotic CDK1 phosphorylation of the dynein LIC1 C-terminus [PMID:34709360].","teleology":[{"year":2006,"claim":"Established HOOK2's foundational identity as a constitutive centrosomal protein required for radial microtubule organization, answering where it acts and through which binding partner.","evidence":"Direct binding assay of the Hook2 C-terminal domain to centriolin/CEP110, cell-cycle immunofluorescence, and dominant-negative microtubule-regrowth phenotypes","pmids":["17140400"],"confidence":"High","gaps":["Did not define how centriolin recruitment relates to dynein cargo transport","No structural basis for the C-terminal/centriolin interaction"]},{"year":2007,"claim":"Showed HOOK2 contributes to aggresome biogenesis, extending its centrosomal role to microtubule-based delivery of protein aggregates.","evidence":"Overexpression and C-terminal-deletion dominant-negative Hook2 with a CFTR aggresome formation assay","pmids":["17540036"],"confidence":"Medium","gaps":["Mechanism linking Hook2 to motor-driven aggregate transport not resolved","Whether endogenous Hook2 is rate-limiting for aggresome formation untested"]},{"year":2008,"claim":"Placed HOOK2 within the conserved FTS-Hook-FHIP multiprotein complex, reframing it from a standalone centrosomal protein to a trafficking adaptor.","evidence":"Mass spectrometry of purified FTS complexes, yeast two-hybrid, co-immunoprecipitation, and siRNA with endosomal trafficking readout in HEK293T cells","pmids":["18799622"],"confidence":"High","gaps":["Did not assign cargo specificity to the Hook2-containing complex versus other paralogs","Direct motor coupling not yet demonstrated"]},{"year":2009,"claim":"Identified CENP-F as a centrosomal partner acting through HOOK2, demonstrating HOOK2 transmits an upstream signal for centrosome-specific microtubule nucleation.","evidence":"Yeast two-hybrid, co-immunoprecipitation, CENP-F knockout microtubule repolymerization assay, and a Hook2-binding truncation rescue","pmids":["19793914"],"confidence":"High","gaps":["Molecular events downstream of the CENP-F/Hook2 interaction unresolved","Golgi-derived microtubule nucleation independent of this pathway"]},{"year":2009,"claim":"Demonstrated paralog-selective binding of MSUT-2 to HOOK2, indicating distinct partner repertoires among the three Hook proteins.","evidence":"Yeast two-hybrid and in vitro protein binding assays comparing HOOK1/2/3","pmids":["19273536"],"confidence":"Medium","gaps":["No functional consequence of the MSUT-2/HOOK2 interaction tested","Cellular context of the interaction unknown"]},{"year":2011,"claim":"Defined HOOK2 as a regulator of a limiting step in primary ciliogenesis via PCM1 stabilization and Rab8a complex formation.","evidence":"siRNA depletion with ciliogenesis readout, co-immunoprecipitation with PCM1 and GFP::Rab8a, and Rab8a overexpression rescue in retinal epithelial cells","pmids":["21998199"],"confidence":"High","gaps":["How Hook2 mechanistically stabilizes PCM1 not defined","Connection between ciliary role and FHF dynein coupling unexplored"]},{"year":2015,"claim":"Linked HOOK2 to manchette microtubule organization in spermatogenesis through direct binding of LRGUK-1.","evidence":"Yeast two-hybrid, co-immunoprecipitation/co-localization, GUK-like domain mapping, and LRGUK-1 knockout mouse phenotype","pmids":["25781171"],"confidence":"Medium","gaps":["Functional attribution to HOOK2 specifically is indirect","Whether HOOK2 loss alone replicates the manchette defect untested"]},{"year":2016,"claim":"Expanded the manchette model to a defined LRGUK1-Hook-RIMBP3-KLC3 complex, situating HOOK2 in germ-cell microtubule dynamics.","evidence":"Yeast two-hybrid, GUK-like domain mapping, biochemical validation, and co-localization in haploid male germ cells","pmids":["28003339"],"confidence":"Medium","gaps":["Specific contribution of HOOK2 versus HOOK1/HOOK3 not separated","Stoichiometry and assembly order of the complex unknown"]},{"year":2016,"claim":"Showed HOOK2 recruits the PAR6α/aPKC polarity complex to the centrosome to drive Golgi reorientation during directed migration, connecting it to cell polarity.","evidence":"Reciprocal co-immunoprecipitation, domain mapping, siRNA with Golgi-reorientation/PAR6α localization readout, and overexpression aggresome recruitment","pmids":["27624926"],"confidence":"Medium","gaps":["Whether dynein transport mediates PAR6α recruitment not tested","Single-lab phenotype lacking independent replication"]},{"year":2019,"claim":"Established HOOK2 as a general recruiter of multiple proteins to the centrosome during cytokinesis.","evidence":"Immunofluorescence and siRNA knockdown with LSR/tricellulin/PAR3 centrosome localization readout during cytokinesis","pmids":["31662022"],"confidence":"Medium","gaps":["Mechanism of multi-protein recruitment unresolved","Functional consequence for cytokinesis completion not defined"]},{"year":2020,"claim":"Demonstrated direct coupling of the FHF complex to the AP-4 adaptor via Hook coiled-coil domains, mechanistically linking HOOK2 to retrograde transport of AP-4/ATG9A cargo.","evidence":"Affinity purification-mass spectrometry, direct binding of AP-4 μ4 to Hook coiled-coil domains, and siRNA with AP-4/ATG9A localization readout","pmids":["32073997"],"confidence":"High","gaps":["Whether HOOK2 versus HOOK1 dominates AP-4 binding in vivo not separated","Dynein motor engagement inferred rather than reconstituted here"]},{"year":2021,"claim":"Resolved cargo specificity by showing FTS-FHIP2A-Hook2 complexes select Rab1A ER-to-Golgi cargo and move processively with dynein-dynactin, distinct from Hook1/Hook3 endosomal complexes.","evidence":"FHIP interactome proteomics, live-cell imaging, single-molecule in vitro reconstitution with dynein/dynactin, and FHIP2A siRNA Rab1A tubule motility readout","pmids":["34882091"],"confidence":"High","gaps":["Structural basis of combinatorial FHIP/Hook cargo selection unresolved","Regulation of switching between cargo-specific complexes unknown"]},{"year":2021,"claim":"Showed mitotic CDK1 phosphorylation of dynein LIC1 selectively engages Pin1 to Hook2-dynein-Nde1-Lis1 complexes, revealing cell-cycle-specific regulation of Hook2 motor complexes.","evidence":"Co-immunoprecipitation of endogenous complexes, phosphomutant analysis, and mitotic phenotype readouts (kinetochore loading, chromosome congression, Golgi fragmentation)","pmids":["34709360"],"confidence":"Medium","gaps":["Functional output of Pin1 isomerization on Hook2 complexes not fully defined","Single-lab study without orthogonal structural confirmation"]},{"year":2013,"claim":"Documented a HOOK2-ACTN3 fusion from a t(11;19) translocation in an ovarian cancer line, a structural genomic event involving HOOK2.","evidence":"Array breakpoint mapping, PCR/sequencing across genomic and cDNA breakpoints, and 2D Western blot detection of the fusion protein in SKOV-3 cells","pmids":["23362175"],"confidence":"Medium","gaps":["Functional consequence of the HOOK2 portion of the fusion uncharacterized","Not shown to be recurrent or oncogenic"]},{"year":2025,"claim":"Associated HOOK2 with trophoblast invasiveness under hemodynamic stress in the context of preeclampsia.","evidence":"RNA sequencing of amniotic fluid and siRNA knockdown in HTR-8/SVneo trophoblast cells with invasion/migration assays under shear stress","pmids":["41226568"],"confidence":"Low","gaps":["No mechanistic pathway placement connecting HOOK2 to invasion","Single study, not independently confirmed","Link to known centrosomal/transport functions unestablished"]},{"year":null,"claim":"How HOOK2-specific FHF complexes structurally discriminate their cargoes and how its centrosomal scaffolding and cargo-transport roles are mechanistically integrated remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of a HOOK2-containing FHF-dynein complex","Regulatory inputs that switch HOOK2 between ciliary, polarity, aggresome, and transport functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,9,10]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,4,5,13]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[5,8]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,6,7]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,9,10]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[11,13]}],"complexes":["FTS-Hook-FHIP (FHF) complex","Hook2-dynein-Nde1-Lis1 complex","LRGUK1-Hook-RIMBP3-KLC3 manchette complex"],"partners":["CEP110","CENP-F","PCM1","RAB8A","PARD6A","LRGUK1","FTS","FHIP2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96ED9","full_name":"Protein Hook homolog 2","aliases":[],"length_aa":719,"mass_kda":83.2,"function":"Component of the FTS/Hook/FHIP complex (FHF complex). The FHF complex may function to promote vesicle trafficking and/or fusion via the homotypic vesicular protein sorting complex (the HOPS complex). Contributes to the establishment and maintenance of centrosome function. May function in the positioning or formation of aggresomes, which are pericentriolar accumulations of misfolded proteins, proteasomes and chaperones. FHF complex promotes the distribution of AP-4 complex to the perinuclear area of the cell (PubMed:32073997)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm; Cytoplasm, cytoskeleton; Golgi apparatus, trans-Golgi network","url":"https://www.uniprot.org/uniprotkb/Q96ED9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HOOK2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"IPO13","stoichiometry":0.2},{"gene":"POLR3E","stoichiometry":0.2},{"gene":"TMA16","stoichiometry":0.2},{"gene":"TOMM20A","stoichiometry":0.2},{"gene":"VDAC1","stoichiometry":0.2},{"gene":"VDAC3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HOOK2","total_profiled":1310},"omim":[{"mim_id":"620891","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 181; CCDC181","url":"https://www.omim.org/entry/620891"},{"mim_id":"620230","title":"FHF COMPLEX SUBUNIT HOOK-INTERACTING PROTEIN 2B; FHIP2B","url":"https://www.omim.org/entry/620230"},{"mim_id":"620229","title":"FHF COMPLEX SUBUNIT HOOK-INTERACTING PROTEIN 1B; FHIP1B","url":"https://www.omim.org/entry/620229"},{"mim_id":"617312","title":"FHF COMPLEX SUBUNIT HOOK-INTERACTING PROTEIN 2A; FHIP2A","url":"https://www.omim.org/entry/617312"},{"mim_id":"616478","title":"LEUCINE-RICH REPEATS- AND GUANYLATE KINASE DOMAIN-CONTAINING PROTEIN; LRGUK","url":"https://www.omim.org/entry/616478"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HOOK2"},"hgnc":{"alias_symbol":["HK2"],"prev_symbol":[]},"alphafold":{"accession":"Q96ED9","domains":[{"cath_id":"1.10.418.10","chopping":"6-139","consensus_level":"high","plddt":88.8419,"start":6,"end":139}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96ED9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96ED9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96ED9-F1-predicted_aligned_error_v6.png","plddt_mean":82.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HOOK2","jax_strain_url":"https://www.jax.org/strain/search?query=HOOK2"},"sequence":{"accession":"Q96ED9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96ED9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96ED9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96ED9"}},"corpus_meta":[{"pmid":"19273536","id":"PMC_19273536","title":"SUT-2 potentiates tau-induced neurotoxicity in Caenorhabditis elegans.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19273536","citation_count":95,"is_preprint":false},{"pmid":"18799622","id":"PMC_18799622","title":"An FTS/Hook/p107(FHIP) complex interacts with and promotes endosomal clustering by the homotypic vacuolar protein sorting complex.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18799622","citation_count":95,"is_preprint":false},{"pmid":"26540294","id":"PMC_26540294","title":"Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.","date":"2015","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26540294","citation_count":77,"is_preprint":false},{"pmid":"25781171","id":"PMC_25781171","title":"LRGUK-1 is required for basal body and manchette function during spermatogenesis and male fertility.","date":"2015","source":"PLoS 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\"Hook2 localizes to the centrosome throughout all phases of the cell cycle via its C-terminal domain, which directly binds to centriolin/CEP110. Mislocalized wild-type or mutant Hook2 perturbs endogenous centrosomal and pericentrosomal proteins. Interference with Hook2 function results in loss of radial microtubule organization and defective microtubule regrowth after nocodazole-induced depolymerization.\",\n      \"method\": \"Direct binding assay (C-terminal domain of Hook2 and centriolin/CEP110), immunofluorescence localization through cell cycle, dominant-negative overexpression with centrosome/microtubule phenotype readout\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated, localization confirmed across cell cycle, loss-of-function with specific centrosomal/microtubule phenotypes, multiple orthogonal methods in single focused study\",\n      \"pmids\": [\"17140400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Hook2 overexpression promotes accumulation of the cystic fibrosis transmembrane regulator (CFTR) in aggresomes without altering its biochemical properties or steady-state level. A dominant-negative form of Hook2 lacking the centriolin-binding C-terminal domain inhibits aggresome formation, indicating Hook2 contributes to pericentrosomal localization of aggresomes by promoting microtubule-based delivery of protein aggregates.\",\n      \"method\": \"Overexpression and dominant-negative expression of Hook2 with CFTR aggresome formation assay; immunofluorescence\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with specific phenotypic readout (aggresome formation), single lab but two complementary approaches\",\n      \"pmids\": [\"17540036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Hook2 (along with Hook1 and Hook3) forms part of a multiprotein FTS-Hook-FHIP (FHF) complex. Hook proteins associate with a conserved C-terminal motif of FTS, form homo- and heterodimers, and the ~500-kDa FHF complex interacts with components of both class B and class C of the HOPS complex to promote vesicle trafficking and/or fusion. Hook2 can interact interchangeably with other Hook proteins within this complex.\",\n      \"method\": \"Proteomic analysis (mass spectrometry) of purified FTS complexes from HEK293T cells, yeast two-hybrid, co-immunoprecipitation, siRNA depletion with endosomal trafficking readout\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mass spectrometry, yeast two-hybrid, siRNA functional follow-up, replicated across orthogonal methods in single rigorous study\",\n      \"pmids\": [\"18799622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MSUT-2 (the human ortholog of C. elegans SUT-2) binds specifically to HOOK2 among the three human HOOK paralogs (HOOK1, HOOK2, HOOK3), as demonstrated by yeast two-hybrid and in vitro protein binding assays, suggesting the SUT-2/HOOK interaction is conserved across animal phyla.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro protein binding assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid confirmed by in vitro binding, two orthogonal methods but limited functional follow-up for HOOK2 specifically\",\n      \"pmids\": [\"19273536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CENP-F binds Hook2 at the centrosome, as identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation. Ablation of CENP-F eliminates microtubule repolymerization from the centrosome after nocodazole treatment but not from the Golgi. Expression of a CENP-F truncation containing only the Hook2-binding domain recapitulates the centrosome-specific microtubule nucleation defect, indicating CENP-F acts through Hook2 at the centrosome.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation with novel immunochemical reagents, CENP-F knockout cells with MT repolymerization assay, truncation expression\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, KO cells with specific phenotype, domain truncation confirms Hook2-mediated function, multiple orthogonal methods\",\n      \"pmids\": [\"19793914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Hook2 localizes at the Golgi apparatus and centrosome/basal body in human retinal epithelial cells. Hook2 depletion disrupts ciliogenesis before formation of the ciliary vesicle at the distal tip of the mother centriole. Hook2 interacts with and stabilizes PCM1 (pericentriolar material protein 1), and co-immunoprecipitates with GFP::Rab8a and PCM1 in a complex. Overexpression of GFP::Rab8a can rescue the ciliogenesis defect caused by Hook2 depletion.\",\n      \"method\": \"siRNA depletion with ciliogenesis phenotype readout, yeast two-hybrid, co-immunoprecipitation, GFP::Rab8a rescue experiment, immunofluorescence localization\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA depletion with specific ciliogenesis phenotype, Co-IP confirming complex, rescue experiment establishing functional interaction, multiple orthogonal methods\",\n      \"pmids\": [\"21998199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LRGUK-1 binds directly to HOOK2 via its GUK-like domain, as shown by yeast two-hybrid and co-immunoprecipitation. Both proteins co-localize to the manchette during spermatogenesis. Loss of LRGUK-1 causes defects in basal body attachment, axoneme extension, and manchette microtubule organization that may be mediated in part through its interaction with HOOK2.\",\n      \"method\": \"Yeast two-hybrid screen of adult testis library, co-immunoprecipitation/co-localization, domain mapping (GUK-like domain essential for HOOK2 binding), LRGUK-1 knockout mouse with spermatogenesis phenotype\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid confirmed by Co-IP and co-localization, domain mapping, but functional attribution specifically to HOOK2 is indirect\",\n      \"pmids\": [\"25781171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LRGUK1 binds to HOOK2 (as well as HOOK1 and HOOK3) specifically through its GUK-like domain, confirmed by yeast two-hybrid and validated biochemically. All three HOOK proteins localize to the manchette, and LRGUK1 functions within a multiprotein complex (including HOOK proteins, RIMBP3, and KLC3) required for manchette-based microtubule dynamics in haploid male germ cells.\",\n      \"method\": \"Yeast two-hybrid screen, domain mapping (GUK-like domain required for HOOK2 binding), biochemical validation, co-localization studies\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid confirmed with domain mapping and biochemical validation, co-localization data; functional link to HOOK2 is within a larger complex context\",\n      \"pmids\": [\"28003339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Hook2 interacts with PAR6α via its C-terminal domain binding to the aPKC-binding domain of PAR6α, localizing PAR6α to the centrosome during polarized cell migration. Hook2 depletion decreases PAR6α at the centrosome and disrupts Golgi reorientation toward the migration front. Overexpression of Hook2 induces aggresome formation with recruitment of PAR6α, aPKC, and PAR3.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, siRNA depletion with Golgi reorientation and PAR6α localization readout, overexpression phenotype analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with domain mapping, siRNA loss-of-function with specific polarization phenotype, overexpression gain-of-function; single lab\",\n      \"pmids\": [\"27624926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The FHF complex interacts with the AP-4 adaptor protein complex via direct binding of the AP-4 μ4 subunit to coiled-coil domains in Hook1 and Hook2. Knockdown of FHF subunits (including Hook2) causes dispersal of AP-4 and its cargo ATG9A from the perinuclear region, consistent with FHF coupling organelles to dynein-dynactin for retrograde microtubule transport.\",\n      \"method\": \"Affinity purification-mass spectrometry, direct binding assay (μ4 subunit to Hook coiled-coil domains), siRNA knockdown with AP-4/ATG9A localization readout\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding established with AP-4 μ4 subunit, AP-MS identification, siRNA functional readout, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"32073997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FTS-FHIP2A-Hook2 complexes associate with Rab1A-tagged ER-to-Golgi cargos, and FHIP2A is involved in the motility of Rab1A tubules. These Hook2-containing FHF complexes move with dynein and dynactin in single-molecule in vitro reconstitution assays. This contrasts with FTS-FHIP1B-Hook1/Hook3 complexes that associate with Rab5-positive early endosomes, demonstrating cargo specificity through combinatorial FHF assembly.\",\n      \"method\": \"Proteomic interactome of each FHIP protein, live-cell imaging, single-molecule in vitro reconstitution with dynein/dynactin, siRNA knockdown of FHIP2A with Rab1A tubule motility readout\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of motility, proteomic interactome, live-cell imaging, siRNA functional readout; multiple orthogonal methods establishing cargo specificity of Hook2-containing complex\",\n      \"pmids\": [\"34882091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mitotic phosphorylation of LIC1-CTD (dynein light intermediate chain 1 C-terminal domain) at cdk1 sites engages the prolyl isomerase Pin1 predominantly to Hook2-dynein-Nde1-Lis1 complexes but not to dynein-spindly-dynactin complexes, indicating Hook2-containing dynein complexes are selectively regulated by mitotic phosphorylation and Pin1.\",\n      \"method\": \"Co-immunoprecipitation of endogenous complexes, phosphomutant analysis, cell biological phenotype readouts (kinetochore loading, chromosome congression, mitotic Golgi fragmentation)\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with phosphomutants distinguishing Hook2-dynein from spindly-dynactin, specific phenotypic readouts, single lab\",\n      \"pmids\": [\"34709360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In the ovarian cancer cell line SKOV-3, exon 14 of HOOK2 on chromosome 19 is fused with exon 2 of ACTN3 from chromosome 11 in a der(19)t(11;19) translocation, producing a fusion protein. The breakpoint in HOOK2 introduces a frameshift in ACTN3 predicted to cause loss of ACTN3 function; the fusion protein was detected by 2D Western blotting at the calculated molecular mass.\",\n      \"method\": \"Array-based breakpoint mapping, PCR spanning breakpoints on genomic DNA and cDNA, sequencing, 2D Western blotting\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — breakpoint characterized at molecular level by sequencing and protein confirmed by 2D Western blot; single study, functional consequences of the HOOK2 portion not fully characterized\",\n      \"pmids\": [\"23362175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Hook2 is present at the midbody and centrosome during cytokinesis in human epithelial cells. Knockdown of Hook2 causes disappearance of LSR, tricellulin, PAR3, and other molecules from the centrosome during cytokinesis, while the epithelial barrier is maintained, indicating Hook2 is required for recruitment of multiple proteins to the centrosome during cell division.\",\n      \"method\": \"Immunofluorescence localization, siRNA knockdown with centrosome protein localization readout during cytokinesis\",\n      \"journal\": \"The journal of histochemistry and cytochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization and siRNA knockdown with specific centrosomal protein recruitment phenotype; single lab, single study\",\n      \"pmids\": [\"31662022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HOOK2 mRNA is significantly upregulated in second-trimester amniotic fluid from women who later develop preeclampsia, and its expression increases with higher shear stress in trophoblast cells. Knockdown of HOOK2 significantly increases trophoblast invasion while migration shows no significant change, suggesting HOOK2 negatively regulates trophoblast invasiveness under hemodynamic stress conditions.\",\n      \"method\": \"RNA sequencing of amniotic fluid, siRNA knockdown in HTR-8/SVneo cells with invasion and migration assays under shear stress conditions\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — siRNA knockdown with invasion phenotype, single lab, single study, no mechanistic pathway placement\",\n      \"pmids\": [\"41226568\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HOOK2 is a centrosomal adaptor protein that directly binds centriolin/CEP110 via its C-terminal domain to maintain centrosomal structure and microtubule organization; it forms part of the FTS-Hook-FHIP (FHF) multiprotein complex that links cargo—specifically Rab1A-positive ER-to-Golgi vesicles—to cytoplasmic dynein-dynactin for retrograde microtubule transport; it interacts with PCM1 and Rab8a to regulate a limiting step in primary ciliogenesis; it recruits the aPKC/PAR6α polarity complex to the centrosome during cell migration; it promotes aggresome formation by facilitating microtubule-based delivery of misfolded proteins to the pericentriolar region; and it is selectively incorporated into Pin1-binding dynein complexes under mitotic CDK1-mediated phosphorylation of the dynein LIC1 subunit.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HOOK2 is a centrosomal adaptor protein that organizes microtubule-based architecture and links specific cargoes to the cytoplasmic dynein-dynactin retrograde transport machinery [#0, #10]. It localizes to the centrosome throughout the cell cycle via its C-terminal domain, which directly binds centriolin/CEP110, and loss of HOOK2 function abolishes radial microtubule organization and regrowth after depolymerization [#0]; it acts at the centrosome downstream of CENP-F, whose Hook2-binding domain alone is sufficient to drive centrosome-specific microtubule nucleation [#4]. As a subunit of the ~500-kDa FTS-Hook-FHIP (FHF) complex, HOOK2 forms homo- and heterodimers with other Hook paralogs and couples organelles to dynein-dynactin: in combination with FHIP2A it confers specificity for Rab1A-positive ER-to-Golgi cargo and moves processively with dynein and dynactin in single-molecule reconstitutions, while the complex also binds the AP-4 \\u03bc4 subunit to position AP-4/ATG9A cargo perinuclearly [#2, #9, #10]. HOOK2 regulates a limiting step in primary ciliogenesis by stabilizing PCM1 and complexing with Rab8a, the overexpression of which rescues the HOOK2-depletion ciliary defect [#5], and it recruits the PAR6\\u03b1/aPKC/PAR3 polarity machinery to the centrosome to drive Golgi reorientation during directed cell migration [#8]. It further promotes pericentrosomal aggresome formation by facilitating microtubule-based delivery of misfolded protein aggregates [#1], and is selectively incorporated into Hook2-dynein-Nde1-Lis1 complexes that are engaged by Pin1 upon mitotic CDK1 phosphorylation of the dynein LIC1 C-terminus [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established HOOK2's foundational identity as a constitutive centrosomal protein required for radial microtubule organization, answering where it acts and through which binding partner.\",\n      \"evidence\": \"Direct binding assay of the Hook2 C-terminal domain to centriolin/CEP110, cell-cycle immunofluorescence, and dominant-negative microtubule-regrowth phenotypes\",\n      \"pmids\": [\"17140400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how centriolin recruitment relates to dynein cargo transport\", \"No structural basis for the C-terminal/centriolin interaction\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed HOOK2 contributes to aggresome biogenesis, extending its centrosomal role to microtubule-based delivery of protein aggregates.\",\n      \"evidence\": \"Overexpression and C-terminal-deletion dominant-negative Hook2 with a CFTR aggresome formation assay\",\n      \"pmids\": [\"17540036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking Hook2 to motor-driven aggregate transport not resolved\", \"Whether endogenous Hook2 is rate-limiting for aggresome formation untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed HOOK2 within the conserved FTS-Hook-FHIP multiprotein complex, reframing it from a standalone centrosomal protein to a trafficking adaptor.\",\n      \"evidence\": \"Mass spectrometry of purified FTS complexes, yeast two-hybrid, co-immunoprecipitation, and siRNA with endosomal trafficking readout in HEK293T cells\",\n      \"pmids\": [\"18799622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not assign cargo specificity to the Hook2-containing complex versus other paralogs\", \"Direct motor coupling not yet demonstrated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified CENP-F as a centrosomal partner acting through HOOK2, demonstrating HOOK2 transmits an upstream signal for centrosome-specific microtubule nucleation.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, CENP-F knockout microtubule repolymerization assay, and a Hook2-binding truncation rescue\",\n      \"pmids\": [\"19793914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular events downstream of the CENP-F/Hook2 interaction unresolved\", \"Golgi-derived microtubule nucleation independent of this pathway\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated paralog-selective binding of MSUT-2 to HOOK2, indicating distinct partner repertoires among the three Hook proteins.\",\n      \"evidence\": \"Yeast two-hybrid and in vitro protein binding assays comparing HOOK1/2/3\",\n      \"pmids\": [\"19273536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of the MSUT-2/HOOK2 interaction tested\", \"Cellular context of the interaction unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined HOOK2 as a regulator of a limiting step in primary ciliogenesis via PCM1 stabilization and Rab8a complex formation.\",\n      \"evidence\": \"siRNA depletion with ciliogenesis readout, co-immunoprecipitation with PCM1 and GFP::Rab8a, and Rab8a overexpression rescue in retinal epithelial cells\",\n      \"pmids\": [\"21998199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Hook2 mechanistically stabilizes PCM1 not defined\", \"Connection between ciliary role and FHF dynein coupling unexplored\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked HOOK2 to manchette microtubule organization in spermatogenesis through direct binding of LRGUK-1.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation/co-localization, GUK-like domain mapping, and LRGUK-1 knockout mouse phenotype\",\n      \"pmids\": [\"25781171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional attribution to HOOK2 specifically is indirect\", \"Whether HOOK2 loss alone replicates the manchette defect untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Expanded the manchette model to a defined LRGUK1-Hook-RIMBP3-KLC3 complex, situating HOOK2 in germ-cell microtubule dynamics.\",\n      \"evidence\": \"Yeast two-hybrid, GUK-like domain mapping, biochemical validation, and co-localization in haploid male germ cells\",\n      \"pmids\": [\"28003339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific contribution of HOOK2 versus HOOK1/HOOK3 not separated\", \"Stoichiometry and assembly order of the complex unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed HOOK2 recruits the PAR6\\u03b1/aPKC polarity complex to the centrosome to drive Golgi reorientation during directed migration, connecting it to cell polarity.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, domain mapping, siRNA with Golgi-reorientation/PAR6\\u03b1 localization readout, and overexpression aggresome recruitment\",\n      \"pmids\": [\"27624926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether dynein transport mediates PAR6\\u03b1 recruitment not tested\", \"Single-lab phenotype lacking independent replication\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established HOOK2 as a general recruiter of multiple proteins to the centrosome during cytokinesis.\",\n      \"evidence\": \"Immunofluorescence and siRNA knockdown with LSR/tricellulin/PAR3 centrosome localization readout during cytokinesis\",\n      \"pmids\": [\"31662022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of multi-protein recruitment unresolved\", \"Functional consequence for cytokinesis completion not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated direct coupling of the FHF complex to the AP-4 adaptor via Hook coiled-coil domains, mechanistically linking HOOK2 to retrograde transport of AP-4/ATG9A cargo.\",\n      \"evidence\": \"Affinity purification-mass spectrometry, direct binding of AP-4 \\u03bc4 to Hook coiled-coil domains, and siRNA with AP-4/ATG9A localization readout\",\n      \"pmids\": [\"32073997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HOOK2 versus HOOK1 dominates AP-4 binding in vivo not separated\", \"Dynein motor engagement inferred rather than reconstituted here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved cargo specificity by showing FTS-FHIP2A-Hook2 complexes select Rab1A ER-to-Golgi cargo and move processively with dynein-dynactin, distinct from Hook1/Hook3 endosomal complexes.\",\n      \"evidence\": \"FHIP interactome proteomics, live-cell imaging, single-molecule in vitro reconstitution with dynein/dynactin, and FHIP2A siRNA Rab1A tubule motility readout\",\n      \"pmids\": [\"34882091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of combinatorial FHIP/Hook cargo selection unresolved\", \"Regulation of switching between cargo-specific complexes unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed mitotic CDK1 phosphorylation of dynein LIC1 selectively engages Pin1 to Hook2-dynein-Nde1-Lis1 complexes, revealing cell-cycle-specific regulation of Hook2 motor complexes.\",\n      \"evidence\": \"Co-immunoprecipitation of endogenous complexes, phosphomutant analysis, and mitotic phenotype readouts (kinetochore loading, chromosome congression, Golgi fragmentation)\",\n      \"pmids\": [\"34709360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional output of Pin1 isomerization on Hook2 complexes not fully defined\", \"Single-lab study without orthogonal structural confirmation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Documented a HOOK2-ACTN3 fusion from a t(11;19) translocation in an ovarian cancer line, a structural genomic event involving HOOK2.\",\n      \"evidence\": \"Array breakpoint mapping, PCR/sequencing across genomic and cDNA breakpoints, and 2D Western blot detection of the fusion protein in SKOV-3 cells\",\n      \"pmids\": [\"23362175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the HOOK2 portion of the fusion uncharacterized\", \"Not shown to be recurrent or oncogenic\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Associated HOOK2 with trophoblast invasiveness under hemodynamic stress in the context of preeclampsia.\",\n      \"evidence\": \"RNA sequencing of amniotic fluid and siRNA knockdown in HTR-8/SVneo trophoblast cells with invasion/migration assays under shear stress\",\n      \"pmids\": [\"41226568\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanistic pathway placement connecting HOOK2 to invasion\", \"Single study, not independently confirmed\", \"Link to known centrosomal/transport functions unestablished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HOOK2-specific FHF complexes structurally discriminate their cargoes and how its centrosomal scaffolding and cargo-transport roles are mechanistically integrated remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of a HOOK2-containing FHF-dynein complex\", \"Regulatory inputs that switch HOOK2 between ciliary, polarity, aggresome, and transport functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 9, 10]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 4, 5, 13]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 9, 10]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [11, 13]}\n    ],\n    \"complexes\": [\n      \"FTS-Hook-FHIP (FHF) complex\",\n      \"Hook2-dynein-Nde1-Lis1 complex\",\n      \"LRGUK1-Hook-RIMBP3-KLC3 manchette complex\"\n    ],\n    \"partners\": [\n      \"CEP110\",\n      \"CENP-F\",\n      \"PCM1\",\n      \"RAB8A\",\n      \"PARD6A\",\n      \"LRGUK1\",\n      \"FTS\",\n      \"FHIP2A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}