{"gene":"SPAG5","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2001,"finding":"hMAP126 (SPAG5) was identified as a novel mitotic spindle-associated protein that interacts with p29 in a yeast two-hybrid assay, localizes to the mitotic spindle, and is phosphorylated by p34(cdc2) kinase in vitro, indicating post-translational regulation during mitosis.","method":"Yeast two-hybrid, subcellular localization by immunofluorescence, in vitro kinase assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (Y2H, localization, in vitro kinase assay) in a single study; not independently replicated","pmids":["11549262"],"is_preprint":false},{"year":2001,"finding":"Spag5 encodes a ~200 kDa testicular protein that binds the major outer dense fiber protein Odf1 via a leucine zipper motif located in the C-terminal region; it shares 73% similarity with the mitotic spindle protein Deepest.","method":"Yeast two-hybrid, leucine zipper domain mapping","journal":"Molecular reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 — interaction mapped to specific domain by Y2H; single lab","pmids":["11468777"],"is_preprint":false},{"year":2002,"finding":"Targeted disruption of Spag5 in mice (Spag5-null) showed no detectable spermatogenesis or fertility defect, indicating that Spag5 is dispensable for these processes in vivo, likely due to functional compensation.","method":"Homologous recombination knockout, spermatogenesis and fertility analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — clean genetic knockout with defined phenotypic readout; well-controlled study","pmids":["11884588"],"is_preprint":false},{"year":2006,"finding":"Rat Spag5 localizes to the endoplasmic reticulum and microtubules in somatic cells, confirmed by in vivo localization and in vitro microtubule-binding assays; in contrast, in elongated spermatids and epididymal sperm, a 58 kDa Spag5 form associates with outer dense fibers (ODF) but not axonemal microtubules, demonstrating cell-type-dependent localization and function.","method":"Immunofluorescence, in vitro microtubule-binding assay, immunoelectron microscopy, Western blot","journal":"Molecular reproduction and development","confidence":"High","confidence_rationale":"Tier 1-2 — orthogonal methods (in vivo/in vitro MT binding, immuno-EM) with functional context","pmids":["16211599"],"is_preprint":false},{"year":2006,"finding":"A 25 bp duplication insertion in exon 6 of Spag5/astrin in hypogonadic (hgn/hgn) rats produces a truncated Spag5 protein lacking the C-terminal spindle-targeting domain, resulting in defective mitotic spindle organization and apoptotic death of proliferating Sertoli cells, establishing SPAG5 as essential for Sertoli cell proliferation and testis development.","method":"Positional cloning, mutant characterization, immunohistochemistry, domain analysis","journal":"Reproduction (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — natural loss-of-function mutation mapped to specific domain with defined cellular phenotype","pmids":["16816335"],"is_preprint":false},{"year":2012,"finding":"SPAG5/Astrin was identified in the retina and found to interact with USH2AisoB interaction partner NINLisoB; SPAG5, USH2AisoB, and NINLisoB colocalize at the basal bodies of photoreceptor cells, connecting SPAG5 to the Usher protein network and suggesting a postmitotic role in microtubule-based ciliary trafficking.","method":"Co-localization by immunofluorescence, in situ hybridization, qPCR, protein interaction analysis","journal":"Cilia","confidence":"Medium","confidence_rationale":"Tier 3 — localization with functional hypothesis but no direct functional assay; single lab","pmids":["23351521"],"is_preprint":false},{"year":2014,"finding":"ORP8 (OSBP-related protein 8) was identified as a binding partner of SPAG5/Astrin by yeast two-hybrid, confirmed by pull-down and co-immunoprecipitation; ORP8 overexpression recruits SPAG5 to ER membranes in interphase cells, and SPAG5 knockdown significantly reduces the G2/M cell cycle arrest induced by both ORP8 overexpression and 25-hydroxycholesterol treatment, placing SPAG5 downstream of ORP8 in oxysterol-mediated cell cycle regulation.","method":"Yeast two-hybrid, pull-down, co-IP, cell cycle analysis by flow cytometry, siRNA knockdown","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding confirmed by pull-down + co-IP, epistasis established by knockdown with defined cell cycle phenotype","pmids":["24424245"],"is_preprint":false},{"year":2018,"finding":"SPAG5 interacts with the centrosomal protein CEP55, and this interaction triggers phosphorylation of AKT at Ser473, activating the PI3K/AKT signaling pathway to promote tumor growth and metastasis in hepatocellular carcinoma; inhibition of PI3K/AKT signaling markedly attenuated SPAG5-mediated cell growth.","method":"Co-immunoprecipitation, phosphorylation assay, in vitro and in vivo functional assays, PI3K/AKT inhibitor treatment","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus functional rescue, single lab","pmids":["30089483"],"is_preprint":false},{"year":2018,"finding":"SPAG5 promotes hepatocellular carcinoma progression by downregulating SCARA5 through modulation of β-catenin degradation, thereby activating β-catenin/TCF4 signaling; SPAG5 and SCARA5 expression are inversely correlated in HCC tissues.","method":"shRNA knockdown, overexpression, in vitro/in vivo functional assays, Western blot, co-expression analysis","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 3 — functional assays with pathway placement but mechanism of β-catenin degradation modulation not biochemically reconstituted","pmids":["30249289"],"is_preprint":false},{"year":2019,"finding":"SPAG5 interacts with c-MYC binding protein (MYCBP) in triple-negative breast cancer, increasing MYCBP protein levels and thereby enhancing c-MYC transcriptional activity, which drives expression of c-MYC target genes including CDC20, CDC25C, BRCA1, BRCA2, and RAD51; knockdown of MYCBP or c-MYC abolished SPAG5-induced cell-cycle progression and proliferation.","method":"Co-immunoprecipitation, overexpression, knockdown, c-MYC transcriptional activity assay, in vitro and in vivo functional assays","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus epistasis via knockdown rescue; single lab","pmids":["30736840"],"is_preprint":false},{"year":2019,"finding":"SPAG5 promotes gastric cancer cell progression by activating the Wnt/β-catenin/Survivin axis; SPAG5 knockdown inhibited proliferation in vivo and in vitro, and SPAG5-mediated effects required Survivin expression downstream of β-catenin.","method":"shRNA knockdown, overexpression, Western blot, in vivo xenograft, epistasis rescue assay","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 — functional knockdown with pathway correlation but mechanism upstream of β-catenin not biochemically defined","pmids":["30904482"],"is_preprint":false},{"year":2019,"finding":"p53-p21 axis transcriptionally suppresses SPAG5 expression in lung adenocarcinoma; restoration of p53 via MDM2 inhibitor Nutlin-3a reduced SPAG5 levels only in wild-type p53 cells, and knockdown of p53 or p21 attenuated Nutlin-3a-induced SPAG5 repression.","method":"MDM2 inhibitor treatment, p53/p21 knockdown, RT-PCR, Western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with pharmacological and siRNA approaches; single lab","pmids":["30955859"],"is_preprint":false},{"year":2020,"finding":"SPAG5 is a direct transcriptional target of YAP/TAZ/TEAD (Hippo pathway effectors) in breast cancer; depletion of YAP, TAZ, or TEAD strongly reduced SPAG5 expression, pharmacological targeting of YAP/TAZ reduced SPAG5, and SPAG5 depletion impaired cancer cell cycle progression, proliferation, and migration. Additionally, SPAG5 is directly targeted at the post-transcriptional level by miR-10b-3p.","method":"ChIP, siRNA knockdown, pharmacological inhibition, luciferase reporter assay, cell functional assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirms direct transcriptional regulation; multiple orthogonal methods; single lab","pmids":["33230261"],"is_preprint":false},{"year":2020,"finding":"SPAG5-AS1 (lncRNA) interacts with ubiquitin-specific peptidase USP14, leading to de-ubiquitination and stabilization of SPAG5 protein; additionally, SPAG5-AS1 acts as a ceRNA sponging miR-769-5p to regulate YY1, which transcriptionally upregulates both SPAG5-AS1 and SPAG5; elevated SPAG5 inhibits autophagy and promotes apoptosis in podocytes via the AKT/mTOR pathway.","method":"Pulldown, RIP, co-IP, ChIP, luciferase reporter assay, flow cytometry, Western blot","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple orthogonal interaction assays; single lab; USP14-mediated stabilization mechanistically supported","pmids":["31957155"],"is_preprint":false},{"year":2020,"finding":"SPAG5 promotes breast cancer cell proliferation and invasion by upregulating Wnt3 expression and increasing β-catenin/TCF4 transcriptional activity; inhibition of Wnt3 or β-catenin reversed SPAG5-mediated oncogenic effects.","method":"siRNA knockdown, overexpression, luciferase reporter assay, functional cell assays","journal":"Clinical and experimental pharmacology & physiology","confidence":"Low","confidence_rationale":"Tier 3 — functional assays with pathway placement; mechanism of Wnt3 upregulation not biochemically defined; single lab","pmids":["30854682"],"is_preprint":false},{"year":2020,"finding":"SPAG5 promotes osteosarcoma metastasis via the SPAG5-FOXM1-MMP2 axis; SPAG5 stabilizes FOXM1 protein by inhibiting its degradation, thereby increasing FOXM1-driven MMP2 expression and promoting EMT and lung metastasis in vivo.","method":"siRNA knockdown, overexpression, in vivo metastasis model, Western blot, functional invasion assays","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 3 — functional epistasis chain established with in vivo validation; protein stability mechanism inferred but not directly reconstituted","pmids":["32668328"],"is_preprint":false},{"year":2022,"finding":"CLUH interacts stably and RNA-independently with SPAG5 in cytosolic granular structures, identified by co-IP and BioID proximity labeling in mammalian cells.","method":"Co-immunoprecipitation, BioID proximity labeling, fluorescence imaging","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 — two orthogonal interaction methods (co-IP + BioID) confirm CLUH-SPAG5 interaction; single lab","pmids":["35012549"],"is_preprint":false},{"year":2022,"finding":"Splicing factor SF3B4 promotes SPAG5 expression by enabling proper pre-mRNA splicing; SF3B4 knockdown leads to retained introns and reduced SPAG5 mRNA maturation, and SPAG5 deficiency impairs the oncogenic effects of SF3B4 overexpression in cervical cancer cells.","method":"RNA-seq, alternative splicing analysis, knockdown/overexpression, in vitro and in vivo functional assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-seq-based mechanistic epistasis linking SF3B4 splicing activity to SPAG5 maturation; single lab","pmids":["35853859"],"is_preprint":false},{"year":2024,"finding":"SPAG5 knockdown activates autophagy in HUVECs and in ApoE-/- mouse aorta by inhibiting the PI3K/Akt/mTOR signaling pathway, resulting in reduced atherosclerotic plaque formation; autophagy inhibitor 3-MA reversed the protective effects of SPAG5 silencing, establishing SPAG5 as an upstream regulator of autophagy via PI3K/Akt/mTOR.","method":"siRNA knockdown, mouse AS model, Western blot, flow cytometry, GFP-LC3 imaging, autophagy inhibitor rescue","journal":"BMC cardiovascular disorders","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo + in vitro with pharmacological rescue; single lab","pmids":["38807081"],"is_preprint":false},{"year":2024,"finding":"In TNBC, high SPAG5 expression is regulated by coordinated activity of YAP, mutant p53, and MYC; depletion of YAP or mutant p53 reduced SPAG5 expression and MYC recruitment to the SPAG5 promoter, and MYC targeting reduced SPAG5 expression and TNBC tumorigenicity in a SPAG5-expression-dependent manner.","method":"ChIP, siRNA knockdown, promoter analysis, in vitro/in vivo functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP for MYC on SPAG5 promoter plus functional epistasis; single lab","pmids":["39164278"],"is_preprint":false}],"current_model":"SPAG5 (Sperm-Associated Antigen 5/Astrin/hMAP126) is a mitotic spindle-associated protein that localizes to spindle microtubules in somatic cells and to outer dense fibers in spermatozoa; it is phosphorylated by CDK1 (p34cdc2), interacts with ODF1 via leucine zippers, binds CEP55 to activate PI3K/AKT (Ser473 phosphorylation), associates with MYCBP to enhance c-MYC transcriptional activity, is stabilized by USP14-mediated de-ubiquitination, is transcriptionally driven by YAP/TAZ/TEAD and repressed by the p53-p21 axis, stabilizes FOXM1 to upregulate MMP2, and regulates autophagy via the PI3K/Akt/mTOR pathway; loss of its C-terminal spindle-targeting domain causes mitotic defects and Sertoli cell apoptosis in rats, while complete knockout in mice is tolerated due to compensation."},"narrative":{"teleology":[{"year":2001,"claim":"Identification of SPAG5 as a novel mitotic spindle protein that interacts with p29 and is phosphorylated by CDK1 established its basic identity as a cell-cycle-regulated microtubule-associated factor, while parallel discovery of its Odf1-binding leucine zipper domain connected it to sperm outer dense fiber biology.","evidence":"Yeast two-hybrid, immunofluorescence localization, in vitro CDK1 kinase assay, and leucine zipper domain mapping in two independent studies","pmids":["11549262","11468777"],"confidence":"Medium","gaps":["CDK1 phosphorylation sites not mapped","in vivo significance of p29 interaction unknown","Odf1 interaction not confirmed by co-IP"]},{"year":2002,"claim":"Genetic knockout of Spag5 in mice revealed no spermatogenesis or fertility defect, demonstrating functional redundancy and raising the question of which processes genuinely require SPAG5.","evidence":"Homologous recombination knockout in mice with systematic fertility and spermatogenesis analysis","pmids":["11884588"],"confidence":"High","gaps":["Compensating gene(s) not identified","mitotic phenotype in somatic tissues of knockout mice not examined"]},{"year":2006,"claim":"Demonstration that SPAG5 binds microtubules in somatic cells but associates with outer dense fibers (not axonemal microtubules) in spermatids established its cell-type-dependent function, while a natural truncating mutation in rats proved the C-terminal spindle-targeting domain is essential for Sertoli cell mitosis.","evidence":"Immunoelectron microscopy, in vitro microtubule-binding assay, positional cloning of hgn rat mutation, immunohistochemistry of mutant testes","pmids":["16211599","16816335"],"confidence":"High","gaps":["Structural basis of C-terminal spindle targeting not resolved","whether human SPAG5 mutations cause male infertility not tested"]},{"year":2012,"claim":"Localization of SPAG5 to photoreceptor basal bodies with Usher syndrome proteins NINLisoB and USH2AisoB suggested a postmitotic ciliary trafficking role beyond its known mitotic function.","evidence":"Immunofluorescence co-localization and protein interaction analysis in retinal tissue","pmids":["23351521"],"confidence":"Medium","gaps":["No functional assay for SPAG5 in ciliary trafficking performed","interaction with USH2A not confirmed by reciprocal co-IP","relevance to Usher syndrome pathogenesis not established"]},{"year":2014,"claim":"Discovery that ORP8 recruits SPAG5 to ER membranes and that SPAG5 is required for ORP8- and oxysterol-mediated G2/M arrest placed SPAG5 as an effector in lipid-sensing cell cycle control.","evidence":"Yeast two-hybrid confirmed by pull-down and co-IP, siRNA knockdown with flow cytometry cell cycle analysis","pmids":["24424245"],"confidence":"High","gaps":["Direct mechanism by which SPAG5 enforces G2/M arrest downstream of ORP8 unknown","oxysterol-SPAG5 axis not validated in vivo"]},{"year":2018,"claim":"Identification of CEP55 as a SPAG5 binding partner that triggers AKT Ser473 phosphorylation, and demonstration that SPAG5 modulates β-catenin degradation to activate TCF4 signaling, revealed two distinct oncogenic signaling axes through which SPAG5 promotes cancer cell growth.","evidence":"Co-IP, phosphorylation assays, PI3K inhibitor rescue in HCC cells; shRNA knockdown with β-catenin/SCARA5 epistasis in HCC","pmids":["30089483","30249289"],"confidence":"Medium","gaps":["How SPAG5-CEP55 interaction activates PI3K not biochemically defined","mechanism of β-catenin stabilization by SPAG5 not reconstituted"]},{"year":2019,"claim":"SPAG5 was shown to bind MYCBP to enhance c-MYC transcriptional activity driving cell cycle genes, while the p53-p21 axis was identified as a transcriptional repressor of SPAG5, together defining a regulatory circuit linking tumor suppressors and oncogenes to SPAG5 expression and function.","evidence":"Co-IP and epistasis via MYCBP/c-MYC knockdown in TNBC; MDM2 inhibitor treatment with p53/p21 knockdown in lung adenocarcinoma","pmids":["30736840","30955859"],"confidence":"Medium","gaps":["Whether SPAG5 directly stabilizes MYCBP protein or acts transcriptionally not resolved","p53-p21 repression mechanism (direct binding vs indirect) not defined"]},{"year":2020,"claim":"Multiple studies converged to show that SPAG5 transcription is directly driven by YAP/TAZ/TEAD (confirmed by ChIP), that USP14 stabilizes SPAG5 protein via de-ubiquitination, and that SPAG5 stabilizes FOXM1 to upregulate MMP2 and promote metastasis, together defining the transcriptional, post-translational, and downstream effector logic of SPAG5 in cancer.","evidence":"ChIP for YAP/TAZ/TEAD on SPAG5 promoter, USP14 pulldown/co-IP/de-ubiquitination assay, FOXM1 stability assays with in vivo metastasis models","pmids":["33230261","31957155","32668328"],"confidence":"Medium","gaps":["USP14-mediated de-ubiquitination site(s) on SPAG5 not mapped","mechanism by which SPAG5 inhibits FOXM1 degradation not biochemically reconstituted","relative contributions of YAP vs MYC vs p53 to SPAG5 transcription not quantified"]},{"year":2022,"claim":"Identification of CLUH as a stable, RNA-independent interactor and SF3B4 as a splicing factor required for proper SPAG5 mRNA maturation expanded the regulatory network controlling SPAG5 protein levels beyond transcription and ubiquitin-mediated turnover.","evidence":"Co-IP and BioID proximity labeling for CLUH; RNA-seq alternative splicing analysis and epistasis for SF3B4","pmids":["35012549","35853859"],"confidence":"Medium","gaps":["Functional consequence of CLUH-SPAG5 interaction unknown","whether SF3B4-mediated splicing regulation of SPAG5 occurs in normal tissues not tested"]},{"year":2024,"claim":"SPAG5 was established as an upstream suppressor of autophagy via PI3K/Akt/mTOR, with in vivo relevance in atherosclerosis, while coordinated transcriptional regulation by YAP, mutant p53, and MYC was demonstrated at the SPAG5 promoter in TNBC.","evidence":"siRNA knockdown in HUVECs and ApoE-/- mice with autophagy inhibitor rescue; ChIP showing MYC recruitment to SPAG5 promoter dependent on YAP and mutant p53","pmids":["38807081","39164278"],"confidence":"Medium","gaps":["Direct molecular target through which SPAG5 activates PI3K in the autophagy context not identified","whether SPAG5 autophagy regulation is cell-type specific not determined"]},{"year":null,"claim":"The direct biochemical mechanism by which SPAG5 activates PI3K/AKT signaling, the structural basis of its spindle-targeting domain, and the identity of compensating factors in Spag5-knockout mice remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of SPAG5 or its domain-specific interactions exists","PI3K activation mechanism by SPAG5-CEP55 not reconstituted biochemically","compensating gene(s) in Spag5-null mice not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,9,15,18]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,4,6,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8,10,13,18]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[13,18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4]}],"complexes":[],"partners":["CEP55","MYCBP","ODF1","ORP8","CLUH","FOXM1","USP14","NINL"],"other_free_text":[]},"mechanistic_narrative":"SPAG5 (Astrin/hMAP126) is a microtubule-associated protein essential for mitotic spindle organization and cell cycle progression, with additional roles in spermatogenesis-related outer dense fiber assembly, autophagy regulation, and multiple oncogenic signaling pathways. SPAG5 localizes to spindle microtubules during mitosis and is phosphorylated by CDK1 (p34cdc2); its C-terminal domain is required for spindle targeting, and truncation causes defective spindle organization and Sertoli cell apoptosis in rats [PMID:11549262, PMID:16816335, PMID:16211599]. Transcriptionally, SPAG5 is driven by YAP/TAZ/TEAD and MYC while being repressed by the p53-p21 axis, and its protein is stabilized by USP14-mediated de-ubiquitination [PMID:33230261, PMID:39164278, PMID:30955859, PMID:31957155]. SPAG5 activates PI3K/AKT signaling through interaction with CEP55, stabilizes FOXM1 to drive MMP2 expression, enhances c-MYC transcriptional activity via MYCBP binding, modulates β-catenin signaling, and suppresses autophagy through the PI3K/Akt/mTOR pathway [PMID:30089483, PMID:32668328, PMID:30736840, PMID:30249289, PMID:38807081]."},"prefetch_data":{"uniprot":{"accession":"Q96R06","full_name":"Sperm-associated antigen 5","aliases":["Astrin","Deepest","Mitotic spindle-associated protein p126","MAP126"],"length_aa":1193,"mass_kda":134.4,"function":"Essential component of the mitotic spindle required for normal chromosome segregation and progression into anaphase (PubMed:11724960, PubMed:12356910, PubMed:27462074). Required for chromosome alignment, normal timing of sister chromatid segregation, and maintenance of spindle pole architecture (PubMed:17664331, PubMed:27462074). In complex with SKAP, promotes stable microtubule-kinetochore attachments. May contribute to the regulation of separase activity. May regulate AURKA localization to mitotic spindle, but not to centrosomes and CCNB1 localization to both mitotic spindle and centrosomes (PubMed:18361916, PubMed:21402792). Involved in centriole duplication. Required for CDK5RAP2, CEP152, WDR62 and CEP63 centrosomal localization and promotes the centrosomal localization of CDK2 (PubMed:26297806). In non-mitotic cells, upon stress induction, inhibits mammalian target of rapamycin complex 1 (mTORC1) association and recruits the mTORC1 component RPTOR to stress granules (SGs), thereby preventing mTORC1 hyperactivation-induced apoptosis (PubMed:23953116). May enhance GSK3B-mediated phosphorylation of other substrates, such as MAPT/TAU (PubMed:18055457)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, spindle; Cytoplasm, cytoskeleton, spindle pole; Chromosome, centromere, kinetochore; Midbody; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasmic granule; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite","url":"https://www.uniprot.org/uniprotkb/Q96R06/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SPAG5","classification":"Common Essential","n_dependent_lines":477,"n_total_lines":1208,"dependency_fraction":0.39486754966887416},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"MAP4","stoichiometry":0.2},{"gene":"OSBP","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SPAG5","total_profiled":1310},"omim":[{"mim_id":"620335","title":"CELL DIVISION CYCLE 20B; CDC20B","url":"https://www.omim.org/entry/620335"},{"mim_id":"615562","title":"SPERM-ASSOCIATED ANTIGEN 5; SPAG5","url":"https://www.omim.org/entry/615562"},{"mim_id":"614718","title":"KINETOCHORE-LOCALIZED ASTRIN/SPAG5-BINDING PROTEIN; KNSTRN","url":"https://www.omim.org/entry/614718"},{"mim_id":"613328","title":"ROIFMAN-CHITAYAT SYNDROME; ROCHIS","url":"https://www.omim.org/entry/613328"},{"mim_id":"605004","title":"GLYCOGEN SYNTHASE KINASE 3-BETA; GSK3B","url":"https://www.omim.org/entry/605004"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Mitotic spindle","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":35.7},{"tissue":"kidney","ntpm":37.6},{"tissue":"testis","ntpm":72.1}],"url":"https://www.proteinatlas.org/search/SPAG5"},"hgnc":{"alias_symbol":["DEEPEST","MAP126","hMAP126"],"prev_symbol":[]},"alphafold":{"accession":"Q96R06","domains":[{"cath_id":"-","chopping":"490-782","consensus_level":"medium","plddt":91.7363,"start":490,"end":782},{"cath_id":"1.20.5","chopping":"1126-1193","consensus_level":"medium","plddt":89.2037,"start":1126,"end":1193}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96R06","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96R06-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96R06-F1-predicted_aligned_error_v6.png","plddt_mean":62.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPAG5","jax_strain_url":"https://www.jax.org/strain/search?query=SPAG5"},"sequence":{"accession":"Q96R06","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96R06.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96R06/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96R06"}},"corpus_meta":[{"pmid":"11719903","id":"PMC_11719903","title":"Ethiopians 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Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/12832785","citation_count":4,"is_preprint":false},{"pmid":"38248982","id":"PMC_38248982","title":"Fungal Abundance and Diversity in the Mariana Trench, the Deepest Ecosystem on Earth.","date":"2024","source":"Journal of fungi (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38248982","citation_count":3,"is_preprint":false},{"pmid":"38807081","id":"PMC_38807081","title":"SPAG5 deficiency activates autophagy to reduce atherosclerotic plaque formation in ApoE-/- mice.","date":"2024","source":"BMC cardiovascular disorders","url":"https://pubmed.ncbi.nlm.nih.gov/38807081","citation_count":3,"is_preprint":false},{"pmid":"38875410","id":"PMC_38875410","title":"SPAG5 and ASPM play important roles in gastric cancer: An observational study.","date":"2024","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38875410","citation_count":3,"is_preprint":false},{"pmid":"39762615","id":"PMC_39762615","title":"Application of a high-throughput swarm-based deep neural network Algorithm reveals SPAG5 downregulation as a potential therapeutic target in adult AML.","date":"2025","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/39762615","citation_count":3,"is_preprint":false},{"pmid":"36346578","id":"PMC_36346578","title":"Long Non-coding RNA SPAG5-AS1 Attenuates Diabetic Retinal Vascular Dysfunction by Inhibiting Human Retinal Microvascular Endothelial Cell Proliferation, Migration, and Tube Formation by Regulating the MicroRNA-1224-5p/IRS-1 Axis.","date":"2022","source":"Molecular biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/36346578","citation_count":3,"is_preprint":false},{"pmid":"38940525","id":"PMC_38940525","title":"Distinct microbial nitrogen cycling processes in the deepest part of the ocean.","date":"2024","source":"mSystems","url":"https://pubmed.ncbi.nlm.nih.gov/38940525","citation_count":2,"is_preprint":false},{"pmid":"39276045","id":"PMC_39276045","title":"[Biological role of SPAG5 in the malignant proliferation of gastric cancer cells].","date":"2024","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/39276045","citation_count":1,"is_preprint":false},{"pmid":"38468949","id":"PMC_38468949","title":"Deep sea treasures - Insights from museum archives shed light on coral microbial diversity within deepest ocean ecosystems.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38468949","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50070,"output_tokens":4704,"usd":0.110385},"stage2":{"model":"claude-opus-4-6","input_tokens":8223,"output_tokens":3071,"usd":0.176835},"total_usd":0.28722,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"hMAP126 (SPAG5) was identified as a novel mitotic spindle-associated protein that interacts with p29 in a yeast two-hybrid assay, localizes to the mitotic spindle, and is phosphorylated by p34(cdc2) kinase in vitro, indicating post-translational regulation during mitosis.\",\n      \"method\": \"Yeast two-hybrid, subcellular localization by immunofluorescence, in vitro kinase assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (Y2H, localization, in vitro kinase assay) in a single study; not independently replicated\",\n      \"pmids\": [\"11549262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Spag5 encodes a ~200 kDa testicular protein that binds the major outer dense fiber protein Odf1 via a leucine zipper motif located in the C-terminal region; it shares 73% similarity with the mitotic spindle protein Deepest.\",\n      \"method\": \"Yeast two-hybrid, leucine zipper domain mapping\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — interaction mapped to specific domain by Y2H; single lab\",\n      \"pmids\": [\"11468777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Targeted disruption of Spag5 in mice (Spag5-null) showed no detectable spermatogenesis or fertility defect, indicating that Spag5 is dispensable for these processes in vivo, likely due to functional compensation.\",\n      \"method\": \"Homologous recombination knockout, spermatogenesis and fertility analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — clean genetic knockout with defined phenotypic readout; well-controlled study\",\n      \"pmids\": [\"11884588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Rat Spag5 localizes to the endoplasmic reticulum and microtubules in somatic cells, confirmed by in vivo localization and in vitro microtubule-binding assays; in contrast, in elongated spermatids and epididymal sperm, a 58 kDa Spag5 form associates with outer dense fibers (ODF) but not axonemal microtubules, demonstrating cell-type-dependent localization and function.\",\n      \"method\": \"Immunofluorescence, in vitro microtubule-binding assay, immunoelectron microscopy, Western blot\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — orthogonal methods (in vivo/in vitro MT binding, immuno-EM) with functional context\",\n      \"pmids\": [\"16211599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A 25 bp duplication insertion in exon 6 of Spag5/astrin in hypogonadic (hgn/hgn) rats produces a truncated Spag5 protein lacking the C-terminal spindle-targeting domain, resulting in defective mitotic spindle organization and apoptotic death of proliferating Sertoli cells, establishing SPAG5 as essential for Sertoli cell proliferation and testis development.\",\n      \"method\": \"Positional cloning, mutant characterization, immunohistochemistry, domain analysis\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — natural loss-of-function mutation mapped to specific domain with defined cellular phenotype\",\n      \"pmids\": [\"16816335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SPAG5/Astrin was identified in the retina and found to interact with USH2AisoB interaction partner NINLisoB; SPAG5, USH2AisoB, and NINLisoB colocalize at the basal bodies of photoreceptor cells, connecting SPAG5 to the Usher protein network and suggesting a postmitotic role in microtubule-based ciliary trafficking.\",\n      \"method\": \"Co-localization by immunofluorescence, in situ hybridization, qPCR, protein interaction analysis\",\n      \"journal\": \"Cilia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization with functional hypothesis but no direct functional assay; single lab\",\n      \"pmids\": [\"23351521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ORP8 (OSBP-related protein 8) was identified as a binding partner of SPAG5/Astrin by yeast two-hybrid, confirmed by pull-down and co-immunoprecipitation; ORP8 overexpression recruits SPAG5 to ER membranes in interphase cells, and SPAG5 knockdown significantly reduces the G2/M cell cycle arrest induced by both ORP8 overexpression and 25-hydroxycholesterol treatment, placing SPAG5 downstream of ORP8 in oxysterol-mediated cell cycle regulation.\",\n      \"method\": \"Yeast two-hybrid, pull-down, co-IP, cell cycle analysis by flow cytometry, siRNA knockdown\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding confirmed by pull-down + co-IP, epistasis established by knockdown with defined cell cycle phenotype\",\n      \"pmids\": [\"24424245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SPAG5 interacts with the centrosomal protein CEP55, and this interaction triggers phosphorylation of AKT at Ser473, activating the PI3K/AKT signaling pathway to promote tumor growth and metastasis in hepatocellular carcinoma; inhibition of PI3K/AKT signaling markedly attenuated SPAG5-mediated cell growth.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, in vitro and in vivo functional assays, PI3K/AKT inhibitor treatment\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus functional rescue, single lab\",\n      \"pmids\": [\"30089483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SPAG5 promotes hepatocellular carcinoma progression by downregulating SCARA5 through modulation of β-catenin degradation, thereby activating β-catenin/TCF4 signaling; SPAG5 and SCARA5 expression are inversely correlated in HCC tissues.\",\n      \"method\": \"shRNA knockdown, overexpression, in vitro/in vivo functional assays, Western blot, co-expression analysis\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional assays with pathway placement but mechanism of β-catenin degradation modulation not biochemically reconstituted\",\n      \"pmids\": [\"30249289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SPAG5 interacts with c-MYC binding protein (MYCBP) in triple-negative breast cancer, increasing MYCBP protein levels and thereby enhancing c-MYC transcriptional activity, which drives expression of c-MYC target genes including CDC20, CDC25C, BRCA1, BRCA2, and RAD51; knockdown of MYCBP or c-MYC abolished SPAG5-induced cell-cycle progression and proliferation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, knockdown, c-MYC transcriptional activity assay, in vitro and in vivo functional assays\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus epistasis via knockdown rescue; single lab\",\n      \"pmids\": [\"30736840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SPAG5 promotes gastric cancer cell progression by activating the Wnt/β-catenin/Survivin axis; SPAG5 knockdown inhibited proliferation in vivo and in vitro, and SPAG5-mediated effects required Survivin expression downstream of β-catenin.\",\n      \"method\": \"shRNA knockdown, overexpression, Western blot, in vivo xenograft, epistasis rescue assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — functional knockdown with pathway correlation but mechanism upstream of β-catenin not biochemically defined\",\n      \"pmids\": [\"30904482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p53-p21 axis transcriptionally suppresses SPAG5 expression in lung adenocarcinoma; restoration of p53 via MDM2 inhibitor Nutlin-3a reduced SPAG5 levels only in wild-type p53 cells, and knockdown of p53 or p21 attenuated Nutlin-3a-induced SPAG5 repression.\",\n      \"method\": \"MDM2 inhibitor treatment, p53/p21 knockdown, RT-PCR, Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with pharmacological and siRNA approaches; single lab\",\n      \"pmids\": [\"30955859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SPAG5 is a direct transcriptional target of YAP/TAZ/TEAD (Hippo pathway effectors) in breast cancer; depletion of YAP, TAZ, or TEAD strongly reduced SPAG5 expression, pharmacological targeting of YAP/TAZ reduced SPAG5, and SPAG5 depletion impaired cancer cell cycle progression, proliferation, and migration. Additionally, SPAG5 is directly targeted at the post-transcriptional level by miR-10b-3p.\",\n      \"method\": \"ChIP, siRNA knockdown, pharmacological inhibition, luciferase reporter assay, cell functional assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms direct transcriptional regulation; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"33230261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SPAG5-AS1 (lncRNA) interacts with ubiquitin-specific peptidase USP14, leading to de-ubiquitination and stabilization of SPAG5 protein; additionally, SPAG5-AS1 acts as a ceRNA sponging miR-769-5p to regulate YY1, which transcriptionally upregulates both SPAG5-AS1 and SPAG5; elevated SPAG5 inhibits autophagy and promotes apoptosis in podocytes via the AKT/mTOR pathway.\",\n      \"method\": \"Pulldown, RIP, co-IP, ChIP, luciferase reporter assay, flow cytometry, Western blot\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple orthogonal interaction assays; single lab; USP14-mediated stabilization mechanistically supported\",\n      \"pmids\": [\"31957155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SPAG5 promotes breast cancer cell proliferation and invasion by upregulating Wnt3 expression and increasing β-catenin/TCF4 transcriptional activity; inhibition of Wnt3 or β-catenin reversed SPAG5-mediated oncogenic effects.\",\n      \"method\": \"siRNA knockdown, overexpression, luciferase reporter assay, functional cell assays\",\n      \"journal\": \"Clinical and experimental pharmacology & physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — functional assays with pathway placement; mechanism of Wnt3 upregulation not biochemically defined; single lab\",\n      \"pmids\": [\"30854682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SPAG5 promotes osteosarcoma metastasis via the SPAG5-FOXM1-MMP2 axis; SPAG5 stabilizes FOXM1 protein by inhibiting its degradation, thereby increasing FOXM1-driven MMP2 expression and promoting EMT and lung metastasis in vivo.\",\n      \"method\": \"siRNA knockdown, overexpression, in vivo metastasis model, Western blot, functional invasion assays\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional epistasis chain established with in vivo validation; protein stability mechanism inferred but not directly reconstituted\",\n      \"pmids\": [\"32668328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CLUH interacts stably and RNA-independently with SPAG5 in cytosolic granular structures, identified by co-IP and BioID proximity labeling in mammalian cells.\",\n      \"method\": \"Co-immunoprecipitation, BioID proximity labeling, fluorescence imaging\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two orthogonal interaction methods (co-IP + BioID) confirm CLUH-SPAG5 interaction; single lab\",\n      \"pmids\": [\"35012549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Splicing factor SF3B4 promotes SPAG5 expression by enabling proper pre-mRNA splicing; SF3B4 knockdown leads to retained introns and reduced SPAG5 mRNA maturation, and SPAG5 deficiency impairs the oncogenic effects of SF3B4 overexpression in cervical cancer cells.\",\n      \"method\": \"RNA-seq, alternative splicing analysis, knockdown/overexpression, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-seq-based mechanistic epistasis linking SF3B4 splicing activity to SPAG5 maturation; single lab\",\n      \"pmids\": [\"35853859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPAG5 knockdown activates autophagy in HUVECs and in ApoE-/- mouse aorta by inhibiting the PI3K/Akt/mTOR signaling pathway, resulting in reduced atherosclerotic plaque formation; autophagy inhibitor 3-MA reversed the protective effects of SPAG5 silencing, establishing SPAG5 as an upstream regulator of autophagy via PI3K/Akt/mTOR.\",\n      \"method\": \"siRNA knockdown, mouse AS model, Western blot, flow cytometry, GFP-LC3 imaging, autophagy inhibitor rescue\",\n      \"journal\": \"BMC cardiovascular disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo + in vitro with pharmacological rescue; single lab\",\n      \"pmids\": [\"38807081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In TNBC, high SPAG5 expression is regulated by coordinated activity of YAP, mutant p53, and MYC; depletion of YAP or mutant p53 reduced SPAG5 expression and MYC recruitment to the SPAG5 promoter, and MYC targeting reduced SPAG5 expression and TNBC tumorigenicity in a SPAG5-expression-dependent manner.\",\n      \"method\": \"ChIP, siRNA knockdown, promoter analysis, in vitro/in vivo functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for MYC on SPAG5 promoter plus functional epistasis; single lab\",\n      \"pmids\": [\"39164278\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPAG5 (Sperm-Associated Antigen 5/Astrin/hMAP126) is a mitotic spindle-associated protein that localizes to spindle microtubules in somatic cells and to outer dense fibers in spermatozoa; it is phosphorylated by CDK1 (p34cdc2), interacts with ODF1 via leucine zippers, binds CEP55 to activate PI3K/AKT (Ser473 phosphorylation), associates with MYCBP to enhance c-MYC transcriptional activity, is stabilized by USP14-mediated de-ubiquitination, is transcriptionally driven by YAP/TAZ/TEAD and repressed by the p53-p21 axis, stabilizes FOXM1 to upregulate MMP2, and regulates autophagy via the PI3K/Akt/mTOR pathway; loss of its C-terminal spindle-targeting domain causes mitotic defects and Sertoli cell apoptosis in rats, while complete knockout in mice is tolerated due to compensation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SPAG5 (Astrin/hMAP126) is a microtubule-associated protein essential for mitotic spindle organization and cell cycle progression, with additional roles in spermatogenesis-related outer dense fiber assembly, autophagy regulation, and multiple oncogenic signaling pathways. SPAG5 localizes to spindle microtubules during mitosis and is phosphorylated by CDK1 (p34cdc2); its C-terminal domain is required for spindle targeting, and truncation causes defective spindle organization and Sertoli cell apoptosis in rats [PMID:11549262, PMID:16816335, PMID:16211599]. Transcriptionally, SPAG5 is driven by YAP/TAZ/TEAD and MYC while being repressed by the p53-p21 axis, and its protein is stabilized by USP14-mediated de-ubiquitination [PMID:33230261, PMID:39164278, PMID:30955859, PMID:31957155]. SPAG5 activates PI3K/AKT signaling through interaction with CEP55, stabilizes FOXM1 to drive MMP2 expression, enhances c-MYC transcriptional activity via MYCBP binding, modulates β-catenin signaling, and suppresses autophagy through the PI3K/Akt/mTOR pathway [PMID:30089483, PMID:32668328, PMID:30736840, PMID:30249289, PMID:38807081].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of SPAG5 as a novel mitotic spindle protein that interacts with p29 and is phosphorylated by CDK1 established its basic identity as a cell-cycle-regulated microtubule-associated factor, while parallel discovery of its Odf1-binding leucine zipper domain connected it to sperm outer dense fiber biology.\",\n      \"evidence\": \"Yeast two-hybrid, immunofluorescence localization, in vitro CDK1 kinase assay, and leucine zipper domain mapping in two independent studies\",\n      \"pmids\": [\"11549262\", \"11468777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CDK1 phosphorylation sites not mapped\", \"in vivo significance of p29 interaction unknown\", \"Odf1 interaction not confirmed by co-IP\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Genetic knockout of Spag5 in mice revealed no spermatogenesis or fertility defect, demonstrating functional redundancy and raising the question of which processes genuinely require SPAG5.\",\n      \"evidence\": \"Homologous recombination knockout in mice with systematic fertility and spermatogenesis analysis\",\n      \"pmids\": [\"11884588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compensating gene(s) not identified\", \"mitotic phenotype in somatic tissues of knockout mice not examined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstration that SPAG5 binds microtubules in somatic cells but associates with outer dense fibers (not axonemal microtubules) in spermatids established its cell-type-dependent function, while a natural truncating mutation in rats proved the C-terminal spindle-targeting domain is essential for Sertoli cell mitosis.\",\n      \"evidence\": \"Immunoelectron microscopy, in vitro microtubule-binding assay, positional cloning of hgn rat mutation, immunohistochemistry of mutant testes\",\n      \"pmids\": [\"16211599\", \"16816335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of C-terminal spindle targeting not resolved\", \"whether human SPAG5 mutations cause male infertility not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Localization of SPAG5 to photoreceptor basal bodies with Usher syndrome proteins NINLisoB and USH2AisoB suggested a postmitotic ciliary trafficking role beyond its known mitotic function.\",\n      \"evidence\": \"Immunofluorescence co-localization and protein interaction analysis in retinal tissue\",\n      \"pmids\": [\"23351521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional assay for SPAG5 in ciliary trafficking performed\", \"interaction with USH2A not confirmed by reciprocal co-IP\", \"relevance to Usher syndrome pathogenesis not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that ORP8 recruits SPAG5 to ER membranes and that SPAG5 is required for ORP8- and oxysterol-mediated G2/M arrest placed SPAG5 as an effector in lipid-sensing cell cycle control.\",\n      \"evidence\": \"Yeast two-hybrid confirmed by pull-down and co-IP, siRNA knockdown with flow cytometry cell cycle analysis\",\n      \"pmids\": [\"24424245\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism by which SPAG5 enforces G2/M arrest downstream of ORP8 unknown\", \"oxysterol-SPAG5 axis not validated in vivo\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of CEP55 as a SPAG5 binding partner that triggers AKT Ser473 phosphorylation, and demonstration that SPAG5 modulates β-catenin degradation to activate TCF4 signaling, revealed two distinct oncogenic signaling axes through which SPAG5 promotes cancer cell growth.\",\n      \"evidence\": \"Co-IP, phosphorylation assays, PI3K inhibitor rescue in HCC cells; shRNA knockdown with β-catenin/SCARA5 epistasis in HCC\",\n      \"pmids\": [\"30089483\", \"30249289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How SPAG5-CEP55 interaction activates PI3K not biochemically defined\", \"mechanism of β-catenin stabilization by SPAG5 not reconstituted\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"SPAG5 was shown to bind MYCBP to enhance c-MYC transcriptional activity driving cell cycle genes, while the p53-p21 axis was identified as a transcriptional repressor of SPAG5, together defining a regulatory circuit linking tumor suppressors and oncogenes to SPAG5 expression and function.\",\n      \"evidence\": \"Co-IP and epistasis via MYCBP/c-MYC knockdown in TNBC; MDM2 inhibitor treatment with p53/p21 knockdown in lung adenocarcinoma\",\n      \"pmids\": [\"30736840\", \"30955859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SPAG5 directly stabilizes MYCBP protein or acts transcriptionally not resolved\", \"p53-p21 repression mechanism (direct binding vs indirect) not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple studies converged to show that SPAG5 transcription is directly driven by YAP/TAZ/TEAD (confirmed by ChIP), that USP14 stabilizes SPAG5 protein via de-ubiquitination, and that SPAG5 stabilizes FOXM1 to upregulate MMP2 and promote metastasis, together defining the transcriptional, post-translational, and downstream effector logic of SPAG5 in cancer.\",\n      \"evidence\": \"ChIP for YAP/TAZ/TEAD on SPAG5 promoter, USP14 pulldown/co-IP/de-ubiquitination assay, FOXM1 stability assays with in vivo metastasis models\",\n      \"pmids\": [\"33230261\", \"31957155\", \"32668328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"USP14-mediated de-ubiquitination site(s) on SPAG5 not mapped\", \"mechanism by which SPAG5 inhibits FOXM1 degradation not biochemically reconstituted\", \"relative contributions of YAP vs MYC vs p53 to SPAG5 transcription not quantified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of CLUH as a stable, RNA-independent interactor and SF3B4 as a splicing factor required for proper SPAG5 mRNA maturation expanded the regulatory network controlling SPAG5 protein levels beyond transcription and ubiquitin-mediated turnover.\",\n      \"evidence\": \"Co-IP and BioID proximity labeling for CLUH; RNA-seq alternative splicing analysis and epistasis for SF3B4\",\n      \"pmids\": [\"35012549\", \"35853859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of CLUH-SPAG5 interaction unknown\", \"whether SF3B4-mediated splicing regulation of SPAG5 occurs in normal tissues not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"SPAG5 was established as an upstream suppressor of autophagy via PI3K/Akt/mTOR, with in vivo relevance in atherosclerosis, while coordinated transcriptional regulation by YAP, mutant p53, and MYC was demonstrated at the SPAG5 promoter in TNBC.\",\n      \"evidence\": \"siRNA knockdown in HUVECs and ApoE-/- mice with autophagy inhibitor rescue; ChIP showing MYC recruitment to SPAG5 promoter dependent on YAP and mutant p53\",\n      \"pmids\": [\"38807081\", \"39164278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target through which SPAG5 activates PI3K in the autophagy context not identified\", \"whether SPAG5 autophagy regulation is cell-type specific not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct biochemical mechanism by which SPAG5 activates PI3K/AKT signaling, the structural basis of its spindle-targeting domain, and the identity of compensating factors in Spag5-knockout mice remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of SPAG5 or its domain-specific interactions exists\", \"PI3K activation mechanism by SPAG5-CEP55 not reconstituted biochemically\", \"compensating gene(s) in Spag5-null mice not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 9, 15, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 4, 6, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8, 10, 13, 18]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CEP55\", \"MYCBP\", \"ODF1\", \"ORP8\", \"CLUH\", \"FOXM1\", \"USP14\", \"NINL\"],\n    \"other_free_text\": []\n  }\n}\n```"}