{"gene":"SACK1D","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2008,"finding":"CHICA (FAM83D) localizes to the mitotic spindle, is upregulated and phosphorylated during mitosis, and is required for proper metaphase plate organization and polar ejection forces. CHICA co-immunoprecipitates with the chromokinesin Kid and is required for Kid's spindle localization (but not its chromosome association). Depletion of CHICA or Kid (or both) causes chromosomes to collapse onto poles of monastrol-induced monopolar spindles.","method":"Co-immunoprecipitation, siRNA depletion, live-cell imaging, monopolar spindle assay","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus multiple orthogonal functional assays (siRNA, epistasis double-depletion, monastrol assay) in a single focused study","pmids":["18485706"],"is_preprint":false},{"year":2015,"finding":"The LC8 dynein light chain binds to a 69-residue intrinsically disordered region of CHICA (FAM83D) that contains four tandem TQT motifs. Crystal structures show that the first TQT motif dominates LC8 recruitment with rigidly fixed TQT-LC8 contacts, while non-TQT interactions are flexible. This defines an 'anchored flexibility' model for LC8 motif recognition.","method":"NMR (secondary chemical shifts, relaxation), isothermal titration calorimetry, X-ray crystallography of LC8–peptide complexes","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures plus NMR and calorimetry, multiple orthogonal methods in one rigorous study","pmids":["26652654"],"is_preprint":false},{"year":2013,"finding":"FAM83D physically interacts with FBXW7, downregulates FBXW7 expression, and thereby elevates levels of FBXW7 oncogenic substrates including mTOR. Inhibition of mTOR by rapamycin suppresses FAM83D-induced cell migration and invasion.","method":"Co-immunoprecipitation, ectopic overexpression and siRNA knockdown, rapamycin inhibitor treatment, migration/invasion assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional rescue with pharmacological inhibitor, single lab","pmids":["24344117"],"is_preprint":false},{"year":2019,"finding":"FAM83D recruits CK1α to the mitotic spindle. Cells lacking FAM83D, or bearing CK1α-binding-deficient FAM83D(F283A) knockin mutations, display pronounced spindle positioning defects and prolonged mitosis. Restoring FAM83D at the endogenous locus or artificially delivering CK1α to the spindle rescues these defects, establishing FAM83D as the spindle-targeting adaptor for CK1α during mitosis.","method":"CRISPR/Cas9 knockin (F283A mutation), FAM83D knockout rescue, artificial spindle targeting of CK1α, live-cell imaging, spindle positioning assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — endogenous knockin mutagenesis plus knockout rescue plus artificial retargeting constitutes multiple orthogonal lines of evidence","pmids":["31338967"],"is_preprint":false},{"year":2019,"finding":"FAM83D activates the PI3K/AKT/mTOR pathway in ovarian cancer cells; overexpression promotes proliferation and invasion while inhibiting autophagy, and these effects are suppressed by the mTOR inhibitor Torin1.","method":"siRNA knockdown and ectopic overexpression, Western blot (PI3K, AKT, mTOR, P62), Torin1 inhibitor rescue, xenograft mouse model","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue plus in vivo model, single lab","pmids":["30939187"],"is_preprint":false},{"year":2017,"finding":"FAM83D knockdown in colorectal cancer cells upregulates FBXW7 protein and reduces Notch1 protein. FBXW7 siRNA reverses suppression of Notch1 by FAM83D knockdown, and Notch1 overexpression reverses the anti-proliferative and anti-migratory effects of FAM83D knockdown, placing FAM83D upstream of the FBXW7/Notch1 axis.","method":"siRNA knockdown, epistasis rescue with FBXW7 siRNA and Notch1 overexpression, Western blot, migration/invasion assays","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiments with double-knockdown and overexpression rescue, single lab","pmids":["28407575"],"is_preprint":false},{"year":2015,"finding":"FAM83D activates the MEK/ERK signaling pathway and promotes S-phase entry in hepatocellular carcinoma cells; forced FAM83D expression enhances proliferation while knockdown has the opposite effect.","method":"Ectopic overexpression, siRNA knockdown, Western blot (p-MEK, p-ERK), cell cycle analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal functional manipulations with pathway readout, single lab","pmids":["25646692"],"is_preprint":false},{"year":2017,"finding":"FAM83D co-immunoprecipitates with HMMR, TPX2, and AURKA in gastric cancer cells, and FAM83D knockdown inhibits microtubule regrowth after nocodazole washout, supporting its role as a microtubule-associated protein involved in mitosis.","method":"Co-immunoprecipitation, microtubule regrowth assay after nocodazole washout, siRNA knockdown","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with multiple partners plus functional microtubule assay, single lab","pmids":["29088801"],"is_preprint":false},{"year":2016,"finding":"FAM83D inhibition in lung adenocarcinoma cells causes G1-phase arrest with downregulation of cyclin D1 (CCND1) and cyclin E1 (CCNE1), indicating that FAM83D promotes G1/S cell-cycle progression.","method":"siRNA knockdown, flow cytometry cell cycle analysis, Western blot (cyclin D1, cyclin E1), xenograft model","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with defined molecular and cell-cycle phenotype, in vivo validation, single lab","pmids":["27904773"],"is_preprint":false},{"year":2020,"finding":"FAM83D overexpression in NSCLC cells activates the AKT/mTOR pathway to promote EMT, invasion, and cisplatin resistance; pharmacological inhibition of AKT or mTOR reverts FAM83D-induced tumorigenic phenotypes.","method":"Retroviral/lentiviral stable overexpression and knockdown, Western blot, AKT/mTOR inhibitor treatment, xenograft model","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable genetic manipulation plus pharmacological rescue with in vivo validation, single lab","pmids":["32006253"],"is_preprint":false},{"year":2020,"finding":"In skeletal muscle cells, Fam83d overexpression represses myosin heavy chain and myogenin expression and suppresses phosphorylated ERK and AKT. The putative PLD-like domain of Fam83d is required for destabilizing CK1α and inhibiting ERK phosphorylation. Fam83d is induced during neurogenic muscle atrophy and localizes in a punctate cytoplasmic pattern in C2C12 cells.","method":"GFP-fusion localization, ectopic overexpression, domain-deletion analysis (PLD-like domain), Western blot (p-ERK, p-AKT, myogenin, MyHC), 26S proteasome inhibition","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis plus multiple pathway readouts, single lab","pmids":["32092437"],"is_preprint":false},{"year":2021,"finding":"Fam83D knockdown in pancreatic cancer cells reduces nuclear β-catenin, c-Myc, and LDHA levels and suppresses aerobic glycolysis; a Wnt/β-catenin inhibitor abolishes the effects of Fam83D overexpression, placing Fam83D upstream of the Wnt/β-catenin pathway.","method":"siRNA knockdown and overexpression, Wnt/β-catenin inhibitor rescue, Western blot (β-catenin, c-Myc, LDHA), Seahorse metabolic assay, xenograft model","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway rescue plus metabolic assay and in vivo model, single lab","pmids":["33571515"],"is_preprint":false},{"year":2022,"finding":"YTHDF2, an m6A reader, negatively regulates FAM83D protein expression in lung adenocarcinoma. YTHDF2 knockdown promotes migration and invasion through upregulation of FAM83D and consequent activation of the TGFβ1-SMAD2/3 pathway.","method":"Proteomic analysis of YTHDF2 KD cells, Western blot, migration and invasion assays, pathway rescue","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-lab proteomics screen with partial follow-up, mechanism assigned to FAM83D indirectly","pmids":["35186724"],"is_preprint":false},{"year":2023,"finding":"METTL3 physically interacts with FAM83D and mediates m6A modification of FAM83D mRNA, positively regulating FAM83D protein expression. METTL3 knockdown decreases FAM83D expression and inhibits Wnt/β-catenin pathway activation in triple-negative breast cancer.","method":"Co-immunoprecipitation (METTL3-FAM83D), m6A modification assay, Western blot, overexpression rescue experiments, xenograft model","journal":"Toxicology in vitro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus m6A modification assay and rescue, single lab","pmids":["38043628"],"is_preprint":false},{"year":2024,"finding":"Systematic mutational analysis mapped FBXW7-binding sites on FAM83D. Mutations at these sites abolish FAM83D's ability to promote FBXW7 ubiquitination and proteasomal degradation, and eliminate FAM83D-driven cell proliferation, migration, invasion, and tumor growth, establishing these sites as essential for FAM83D's oncogenic function.","method":"Comprehensive mutational analysis, co-immunoprecipitation, ubiquitination assays, in vitro functional assays, xenograft model","journal":"Breast cancer research : BCR","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — systematic mutagenesis combined with ubiquitination assay, Co-IP, and in vivo rescue, multiple orthogonal methods","pmids":["38454442"],"is_preprint":false},{"year":2022,"finding":"FAM83D silencing in glioblastoma cells decreases phosphorylated AKT and phosphorylated mTOR levels; AKT inhibitor MK2206 abolishes FAM83D overexpression-driven proliferation, and β-catenin re-expression reverses FAM83D-knockdown-induced anti-tumor effects, placing FAM83D upstream of the AKT/Wnt/β-catenin pathway.","method":"siRNA knockdown, MK2206 AKT inhibitor rescue, β-catenin re-expression rescue, Western blot, xenograft model","journal":"Environmental toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic rescue with inhibitor and re-expression, single lab","pmids":["35150198"],"is_preprint":false},{"year":2022,"finding":"FAM83D promotes hepatocellular carcinoma cell proliferation and migration by inhibiting FBXW7-mediated degradation of MCL1. FBXW7 siRNA or MCL1 overexpression reverse the effects of FAM83D knockdown on proliferation and apoptosis, and FBXW7 expression is inversely correlated with both FAM83D and MCL1 in patient data.","method":"siRNA knockdown and overexpression, epistasis with FBXW7 siRNA and MCL1 overexpression, Western blot, apoptosis assay","journal":"Translational cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double knockdown/overexpression epistasis with defined molecular phenotype, single lab","pmids":["36388033"],"is_preprint":false},{"year":2025,"finding":"HMMR binds to the C-terminal α-helix of SACK1D/FAM83D, co-localizes with the SACK1D-CK1α complex throughout mitosis, and is required for SACK1D-CK1α complex formation at the spindle and for correct spindle alignment. HMMR binding stabilizes SACK1D. Mitotic hyperphosphorylation of SACK1D signals its destruction upon mitotic exit, a process that also requires the C-terminal α-helix, suggesting hyperphosphorylation exposes a C-terminal degron.","method":"Co-immunoprecipitation, domain mapping (C-terminal helix deletion), phosphosite mapping, live-cell imaging, spindle alignment assay, protein stability assay","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, domain mapping, phosphosite mapping, functional imaging) in a single focused study","pmids":["41550726"],"is_preprint":false},{"year":2025,"finding":"HMMR interacts with FAM83D (via co-immunoprecipitation and mass spectrometry) and stabilizes FAM83D by inhibiting its ubiquitination. This HMMR-FAM83D interaction modulates β-catenin levels, driving NPC progression through Wnt/β-catenin signaling.","method":"Co-immunoprecipitation, mass spectrometry, Western blot, ubiquitination assay, RNA-seq, xenograft model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with MS validation plus ubiquitination assay, single lab","pmids":["41083782"],"is_preprint":false},{"year":2025,"finding":"FoxM1 directly transcriptionally activates FAM83D in cervical adenocarcinoma (validated by ChIP-seq, qPCR, and luciferase reporter assay). FoxM1 governs cell cycle progression and proliferation via FAM83D-dependent pathways. Additionally, FoxM1 physically interacts with KPNA2 (co-immunoprecipitation).","method":"ChIP-seq, luciferase reporter assay, qPCR, co-immunoprecipitation","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus luciferase reporter validation for transcriptional regulation, single lab","pmids":["40345484"],"is_preprint":false},{"year":2025,"finding":"FAM83D directly interacts with GSK3β (co-immunoprecipitation), promotes GSK3β Ser9 phosphorylation (inactivation), and thereby stabilizes Snail to drive EMT and metastasis in cervical cancer. AKT and PKA are upstream kinases in FAM83D-mediated GSK3β inactivation. GSK3β inhibition reverses the anti-metastatic effects of FAM83D knockdown.","method":"Co-immunoprecipitation, Western blot (pSer9-GSK3β, Snail), siRNA knockdown, GSK3β inhibitor rescue, in vivo lung/liver metastasis model","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus pharmacological epistasis and in vivo metastasis model, single lab","pmids":["41882663"],"is_preprint":false},{"year":2025,"finding":"In the context of targeted protein degradation, lenalidomide-derived molecular glue degraders DEG-77 and SJ3149 co-degrade SACK1D/FAM83D along with CK1α via the CUL4A-CRBN E3 ligase complex and the proteasome. This co-degradation requires direct CK1α-SACK1D interaction, as the CK1α-binding-deficient SACK1D/FAM83D is not co-degraded in cells from palmoplantar keratoderma patients.","method":"Molecular glue degrader treatment, proteasome inhibitor rescue, CRBN/CUL4A validation, patient-derived cell lines with R265P SACK1G mutation as negative control","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological degrader assay with multiple genetic controls including patient cells and proteasome inhibitor rescue, preprint","pmids":["bio_10.1101_2025.06.17.660125"],"is_preprint":true},{"year":2026,"finding":"Knockdown of FAM83D in glioma causes abnormal cell division leading to accumulation of cytoplasmic double-stranded DNA, which activates the cGAS-STING signaling pathway to induce tumor cell senescence. FAM83D-depleted cells also produce a SASP that promotes senescence in neighboring cells and drives macrophage polarization toward an M1 state via ANXA1-FPR1/2 ligand-receptor signaling.","method":"siRNA knockdown, cGAS-STING pathway Western blot/reporter, single-cell transcriptome sequencing, cell co-culture model, in situ allograft mouse model, cytoplasmic dsDNA detection","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (scRNA-seq, co-culture, in vivo) in a single lab study","pmids":["41742219"],"is_preprint":false}],"current_model":"SACK1D/FAM83D is a mitotic spindle adaptor protein that recruits CK1α to the spindle (via its C-terminal helix, stabilized by HMMR) to ensure proper spindle positioning and timely cell division; it also scaffolds the chromokinesin Kid at the spindle for polar ejection forces and chromosome congression; binds LC8 dynein light chain through tandem TQT motifs; undergoes mitotic hyperphosphorylation that signals its proteasomal destruction upon mitotic exit; and in cancer contexts activates oncogenic signaling (AKT/mTOR, MEK/ERK, Wnt/β-catenin) at least in part by physically binding and promoting degradation of the tumor suppressor FBXW7."},"narrative":{"mechanistic_narrative":"SACK1D/FAM83D is a mitotic spindle adaptor protein that scaffolds kinases and motor machinery onto the spindle to ensure correct chromosome behavior and spindle positioning during cell division [PMID:18485706, PMID:31338967]. It localizes to the mitotic spindle, where it recruits the chromokinesin Kid to generate polar ejection forces and organize the metaphase plate; loss of FAM83D or Kid causes chromosomes to collapse onto monopolar spindle poles [PMID:18485706]. Through its C-terminal α-helix it targets CK1α to the spindle, and a CK1α-binding-deficient mutant (F283A) produces spindle positioning defects and prolonged mitosis that are rescued by artificially retargeting CK1α to the spindle [PMID:31338967]. HMMR binds this same C-terminal helix, is required for assembly of the FAM83D-CK1α complex at the spindle and for correct spindle alignment, and stabilizes FAM83D against ubiquitination; mitotic hyperphosphorylation of FAM83D, also dependent on the C-terminal helix, signals its proteasomal destruction at mitotic exit, consistent with a phosphorylation-exposed C-terminal degron [PMID:41550726]. A separate intrinsically disordered region containing four tandem TQT motifs binds the LC8 dynein light chain, with the first TQT dominating recruitment in an \"anchored flexibility\" mode [PMID:26652654]. In cancer contexts FAM83D acts as an oncogenic driver: it physically binds FBXW7 and promotes its ubiquitination and degradation, stabilizing FBXW7 substrates and activating downstream signaling, and FBXW7-binding-site mutations abolish FAM83D-driven proliferation, invasion, and tumor growth [PMID:24344117, PMID:38454442]. Targeting CK1α and FAM83D for co-degradation through the CUL4A-CRBN E3 ligase is achievable with lenalidomide-derived molecular glues, dependent on the direct CK1α-FAM83D interaction [PMID:bio_10.1101_2025.06.17.660125].","teleology":[{"year":2008,"claim":"Established FAM83D (CHICA) as a mitotic spindle protein that physically recruits the chromokinesin Kid to drive polar ejection forces and metaphase plate organization, defining its first concrete mitotic function.","evidence":"Reciprocal Co-IP, siRNA depletion, double-depletion epistasis, and monastrol monopolar spindle assay with live-cell imaging","pmids":["18485706"],"confidence":"High","gaps":["Did not identify the spindle-targeting determinant within FAM83D","Phosphorylation observed during mitosis but kinases and sites not mapped"]},{"year":2013,"claim":"Identified the FAM83D-FBXW7 physical interaction as the route by which FAM83D elevates FBXW7 oncogenic substrates (mTOR), linking the spindle protein to oncogenic signaling.","evidence":"Co-IP, overexpression/knockdown, rapamycin rescue, migration/invasion assays","pmids":["24344117"],"confidence":"Medium","gaps":["FBXW7-binding region on FAM83D not mapped","Mechanism of FBXW7 downregulation (degradation vs transcription) not resolved here"]},{"year":2015,"claim":"Structurally resolved how an intrinsically disordered FAM83D region engages the LC8 dynein light chain, defining the molecular grammar of its TQT-motif recognition.","evidence":"NMR, ITC, and X-ray crystallography of LC8-peptide complexes","pmids":["26652654"],"confidence":"High","gaps":["Functional consequence of LC8 binding for FAM83D mitotic activity not tested","Whether LC8 binding is regulated by mitotic phosphorylation unknown"]},{"year":2017,"claim":"Connected FAM83D physically to the HMMR/TPX2/AURKA spindle module and showed it is required for microtubule regrowth, reinforcing its role as a microtubule-associated mitotic factor.","evidence":"Co-IP with HMMR, TPX2, AURKA and microtubule regrowth assay after nocodazole washout","pmids":["29088801"],"confidence":"Medium","gaps":["Direct vs indirect nature of each interaction not distinguished","No structural or domain mapping of the HMMR interaction at this stage"]},{"year":2019,"claim":"Defined FAM83D as the spindle-targeting adaptor for CK1α via its C-terminal residue F283, establishing a kinase-recruitment mechanism for spindle positioning and timely mitosis.","evidence":"CRISPR knockin of F283A, knockout rescue, artificial CK1α spindle retargeting, live-cell spindle positioning assay","pmids":["31338967"],"confidence":"High","gaps":["Spindle substrates of recruited CK1α not identified","Did not address what stabilizes the FAM83D-CK1α complex at the spindle"]},{"year":2020,"claim":"Generalized FAM83D's CK1α-destabilizing activity to a non-mitotic, differentiation context, implicating a putative PLD-like domain in regulating CK1α and ERK signaling.","evidence":"GFP localization, domain-deletion (PLD-like) analysis, Western blots of differentiation and signaling markers, proteasome inhibition in muscle cells","pmids":["32092437"],"confidence":"Medium","gaps":["PLD-like domain catalytic activity not biochemically demonstrated","Single-lab muscle model, generality unclear"]},{"year":2024,"claim":"Mapped the FBXW7-binding sites on FAM83D and showed they are essential for FAM83D-promoted FBXW7 ubiquitination/degradation and for its full oncogenic phenotype, cementing the FBXW7 axis as a core driver function.","evidence":"Systematic mutagenesis, Co-IP, ubiquitination assays, in vitro functional assays, xenograft model","pmids":["38454442"],"confidence":"High","gaps":["How FAM83D promotes FBXW7 ubiquitination mechanistically (recruited E3, autoubiquitination) not defined","Relationship between spindle and oncogenic FBXW7 functions of the same protein unresolved"]},{"year":2025,"claim":"Identified HMMR as a binding partner of the FAM83D C-terminal α-helix that is required for FAM83D-CK1α complex formation and spindle alignment and that stabilizes FAM83D, while linking mitotic hyperphosphorylation to a C-terminal degron controlling mitotic-exit destruction.","evidence":"Co-IP, C-terminal helix deletion mapping, phosphosite mapping, live-cell spindle alignment and protein stability assays","pmids":["41550726"],"confidence":"High","gaps":["The E3 ligase and degron recognition machinery acting at mitotic exit not identified","Which mitotic kinase hyperphosphorylates FAM83D not established"]},{"year":2025,"claim":"Demonstrated FAM83D and CK1α can be co-degraded by CRBN-based molecular glues in a manner dependent on their direct interaction, validating the FAM83D-CK1α complex as a pharmacological handle.","evidence":"Molecular glue degrader treatment, proteasome inhibitor rescue, CRBN/CUL4A validation, patient-derived cells carrying a CK1α-binding-deficient mutant as control (preprint)","pmids":["bio_10.1101_2025.06.17.660125"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Whether co-degradation has therapeutic consequences in cancer not tested"]},{"year":null,"claim":"How FAM83D's mitotic spindle/CK1α-adaptor role mechanistically connects to its oncogenic FBXW7-degrading activity, and what substrates the spindle-recruited CK1α phosphorylates, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking spindle adaptor and FBXW7-degradation functions","Spindle CK1α substrates unidentified","E3 ligase mediating mitotic-exit destruction of FAM83D unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,17]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,14]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,3,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,14,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[14,17]}],"complexes":["FAM83D-CK1α spindle complex"],"partners":["CSNK1A1","HMMR","FBXW7","KIF22","DYNLL1","TPX2","AURKA","GSK3B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"FAM83D","url":"https://depmap.org/portal/gene/FAM83D","classification":"Not Classified","n_dependent_lines":39,"n_total_lines":1208,"dependency_fraction":0.03228476821192053},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CSNK1A1","stoichiometry":0.2},{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"MAP4","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SACK1D","total_profiled":1310},"omim":[{"mim_id":"618380","title":"SCAFFOLDING CK1-ANCHORING PROTEIN D; SACK1D","url":"https://www.omim.org/entry/618380"}],"hpa":{"profiled":true,"resolved_as":"FAM83D","reliability":"Supported","locations":[{"location":"Mitotic spindle","reliability":"Supported"},{"location":"Microtubules","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":81.8},{"tissue":"intestine","ntpm":76.6},{"tissue":"smooth muscle","ntpm":88.9}],"url":"https://www.proteinatlas.org/search/FAM83D"},"hgnc":{"alias_symbol":["dJ616B8.3","CHICA"],"prev_symbol":["C20orf129","FAM83D"]},"alphafold":{},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SACK1D","jax_strain_url":"https://www.jax.org/strain/search?query=SACK1D"},"sequence":{}},"corpus_meta":[{"pmid":"26089666","id":"PMC_26089666","title":"Chitosan-tripolyphosphate nanoparticles as Arrabidaea chica standardized extract carrier: synthesis, characterization, biocompatibility, and antiulcerogenic activity.","date":"2015","source":"International journal of nanomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/26089666","citation_count":69,"is_preprint":false},{"pmid":"24344117","id":"PMC_24344117","title":"FAM83D promotes cell proliferation and motility by downregulating tumor suppressor gene 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CHICA co-immunoprecipitates with the chromokinesin Kid and is required for Kid's spindle localization (but not its chromosome association). Depletion of CHICA or Kid (or both) causes chromosomes to collapse onto poles of monastrol-induced monopolar spindles.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, live-cell imaging, monopolar spindle assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus multiple orthogonal functional assays (siRNA, epistasis double-depletion, monastrol assay) in a single focused study\",\n      \"pmids\": [\"18485706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The LC8 dynein light chain binds to a 69-residue intrinsically disordered region of CHICA (FAM83D) that contains four tandem TQT motifs. Crystal structures show that the first TQT motif dominates LC8 recruitment with rigidly fixed TQT-LC8 contacts, while non-TQT interactions are flexible. This defines an 'anchored flexibility' model for LC8 motif recognition.\",\n      \"method\": \"NMR (secondary chemical shifts, relaxation), isothermal titration calorimetry, X-ray crystallography of LC8–peptide complexes\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures plus NMR and calorimetry, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"26652654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FAM83D physically interacts with FBXW7, downregulates FBXW7 expression, and thereby elevates levels of FBXW7 oncogenic substrates including mTOR. Inhibition of mTOR by rapamycin suppresses FAM83D-induced cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ectopic overexpression and siRNA knockdown, rapamycin inhibitor treatment, migration/invasion assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional rescue with pharmacological inhibitor, single lab\",\n      \"pmids\": [\"24344117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAM83D recruits CK1α to the mitotic spindle. Cells lacking FAM83D, or bearing CK1α-binding-deficient FAM83D(F283A) knockin mutations, display pronounced spindle positioning defects and prolonged mitosis. Restoring FAM83D at the endogenous locus or artificially delivering CK1α to the spindle rescues these defects, establishing FAM83D as the spindle-targeting adaptor for CK1α during mitosis.\",\n      \"method\": \"CRISPR/Cas9 knockin (F283A mutation), FAM83D knockout rescue, artificial spindle targeting of CK1α, live-cell imaging, spindle positioning assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — endogenous knockin mutagenesis plus knockout rescue plus artificial retargeting constitutes multiple orthogonal lines of evidence\",\n      \"pmids\": [\"31338967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAM83D activates the PI3K/AKT/mTOR pathway in ovarian cancer cells; overexpression promotes proliferation and invasion while inhibiting autophagy, and these effects are suppressed by the mTOR inhibitor Torin1.\",\n      \"method\": \"siRNA knockdown and ectopic overexpression, Western blot (PI3K, AKT, mTOR, P62), Torin1 inhibitor rescue, xenograft mouse model\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue plus in vivo model, single lab\",\n      \"pmids\": [\"30939187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FAM83D knockdown in colorectal cancer cells upregulates FBXW7 protein and reduces Notch1 protein. FBXW7 siRNA reverses suppression of Notch1 by FAM83D knockdown, and Notch1 overexpression reverses the anti-proliferative and anti-migratory effects of FAM83D knockdown, placing FAM83D upstream of the FBXW7/Notch1 axis.\",\n      \"method\": \"siRNA knockdown, epistasis rescue with FBXW7 siRNA and Notch1 overexpression, Western blot, migration/invasion assays\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiments with double-knockdown and overexpression rescue, single lab\",\n      \"pmids\": [\"28407575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FAM83D activates the MEK/ERK signaling pathway and promotes S-phase entry in hepatocellular carcinoma cells; forced FAM83D expression enhances proliferation while knockdown has the opposite effect.\",\n      \"method\": \"Ectopic overexpression, siRNA knockdown, Western blot (p-MEK, p-ERK), cell cycle analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal functional manipulations with pathway readout, single lab\",\n      \"pmids\": [\"25646692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FAM83D co-immunoprecipitates with HMMR, TPX2, and AURKA in gastric cancer cells, and FAM83D knockdown inhibits microtubule regrowth after nocodazole washout, supporting its role as a microtubule-associated protein involved in mitosis.\",\n      \"method\": \"Co-immunoprecipitation, microtubule regrowth assay after nocodazole washout, siRNA knockdown\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with multiple partners plus functional microtubule assay, single lab\",\n      \"pmids\": [\"29088801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FAM83D inhibition in lung adenocarcinoma cells causes G1-phase arrest with downregulation of cyclin D1 (CCND1) and cyclin E1 (CCNE1), indicating that FAM83D promotes G1/S cell-cycle progression.\",\n      \"method\": \"siRNA knockdown, flow cytometry cell cycle analysis, Western blot (cyclin D1, cyclin E1), xenograft model\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with defined molecular and cell-cycle phenotype, in vivo validation, single lab\",\n      \"pmids\": [\"27904773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM83D overexpression in NSCLC cells activates the AKT/mTOR pathway to promote EMT, invasion, and cisplatin resistance; pharmacological inhibition of AKT or mTOR reverts FAM83D-induced tumorigenic phenotypes.\",\n      \"method\": \"Retroviral/lentiviral stable overexpression and knockdown, Western blot, AKT/mTOR inhibitor treatment, xenograft model\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable genetic manipulation plus pharmacological rescue with in vivo validation, single lab\",\n      \"pmids\": [\"32006253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In skeletal muscle cells, Fam83d overexpression represses myosin heavy chain and myogenin expression and suppresses phosphorylated ERK and AKT. The putative PLD-like domain of Fam83d is required for destabilizing CK1α and inhibiting ERK phosphorylation. Fam83d is induced during neurogenic muscle atrophy and localizes in a punctate cytoplasmic pattern in C2C12 cells.\",\n      \"method\": \"GFP-fusion localization, ectopic overexpression, domain-deletion analysis (PLD-like domain), Western blot (p-ERK, p-AKT, myogenin, MyHC), 26S proteasome inhibition\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis plus multiple pathway readouts, single lab\",\n      \"pmids\": [\"32092437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Fam83D knockdown in pancreatic cancer cells reduces nuclear β-catenin, c-Myc, and LDHA levels and suppresses aerobic glycolysis; a Wnt/β-catenin inhibitor abolishes the effects of Fam83D overexpression, placing Fam83D upstream of the Wnt/β-catenin pathway.\",\n      \"method\": \"siRNA knockdown and overexpression, Wnt/β-catenin inhibitor rescue, Western blot (β-catenin, c-Myc, LDHA), Seahorse metabolic assay, xenograft model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway rescue plus metabolic assay and in vivo model, single lab\",\n      \"pmids\": [\"33571515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDF2, an m6A reader, negatively regulates FAM83D protein expression in lung adenocarcinoma. YTHDF2 knockdown promotes migration and invasion through upregulation of FAM83D and consequent activation of the TGFβ1-SMAD2/3 pathway.\",\n      \"method\": \"Proteomic analysis of YTHDF2 KD cells, Western blot, migration and invasion assays, pathway rescue\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-lab proteomics screen with partial follow-up, mechanism assigned to FAM83D indirectly\",\n      \"pmids\": [\"35186724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL3 physically interacts with FAM83D and mediates m6A modification of FAM83D mRNA, positively regulating FAM83D protein expression. METTL3 knockdown decreases FAM83D expression and inhibits Wnt/β-catenin pathway activation in triple-negative breast cancer.\",\n      \"method\": \"Co-immunoprecipitation (METTL3-FAM83D), m6A modification assay, Western blot, overexpression rescue experiments, xenograft model\",\n      \"journal\": \"Toxicology in vitro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus m6A modification assay and rescue, single lab\",\n      \"pmids\": [\"38043628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Systematic mutational analysis mapped FBXW7-binding sites on FAM83D. Mutations at these sites abolish FAM83D's ability to promote FBXW7 ubiquitination and proteasomal degradation, and eliminate FAM83D-driven cell proliferation, migration, invasion, and tumor growth, establishing these sites as essential for FAM83D's oncogenic function.\",\n      \"method\": \"Comprehensive mutational analysis, co-immunoprecipitation, ubiquitination assays, in vitro functional assays, xenograft model\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — systematic mutagenesis combined with ubiquitination assay, Co-IP, and in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"38454442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FAM83D silencing in glioblastoma cells decreases phosphorylated AKT and phosphorylated mTOR levels; AKT inhibitor MK2206 abolishes FAM83D overexpression-driven proliferation, and β-catenin re-expression reverses FAM83D-knockdown-induced anti-tumor effects, placing FAM83D upstream of the AKT/Wnt/β-catenin pathway.\",\n      \"method\": \"siRNA knockdown, MK2206 AKT inhibitor rescue, β-catenin re-expression rescue, Western blot, xenograft model\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic rescue with inhibitor and re-expression, single lab\",\n      \"pmids\": [\"35150198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FAM83D promotes hepatocellular carcinoma cell proliferation and migration by inhibiting FBXW7-mediated degradation of MCL1. FBXW7 siRNA or MCL1 overexpression reverse the effects of FAM83D knockdown on proliferation and apoptosis, and FBXW7 expression is inversely correlated with both FAM83D and MCL1 in patient data.\",\n      \"method\": \"siRNA knockdown and overexpression, epistasis with FBXW7 siRNA and MCL1 overexpression, Western blot, apoptosis assay\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double knockdown/overexpression epistasis with defined molecular phenotype, single lab\",\n      \"pmids\": [\"36388033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HMMR binds to the C-terminal α-helix of SACK1D/FAM83D, co-localizes with the SACK1D-CK1α complex throughout mitosis, and is required for SACK1D-CK1α complex formation at the spindle and for correct spindle alignment. HMMR binding stabilizes SACK1D. Mitotic hyperphosphorylation of SACK1D signals its destruction upon mitotic exit, a process that also requires the C-terminal α-helix, suggesting hyperphosphorylation exposes a C-terminal degron.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (C-terminal helix deletion), phosphosite mapping, live-cell imaging, spindle alignment assay, protein stability assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, domain mapping, phosphosite mapping, functional imaging) in a single focused study\",\n      \"pmids\": [\"41550726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HMMR interacts with FAM83D (via co-immunoprecipitation and mass spectrometry) and stabilizes FAM83D by inhibiting its ubiquitination. This HMMR-FAM83D interaction modulates β-catenin levels, driving NPC progression through Wnt/β-catenin signaling.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, Western blot, ubiquitination assay, RNA-seq, xenograft model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with MS validation plus ubiquitination assay, single lab\",\n      \"pmids\": [\"41083782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FoxM1 directly transcriptionally activates FAM83D in cervical adenocarcinoma (validated by ChIP-seq, qPCR, and luciferase reporter assay). FoxM1 governs cell cycle progression and proliferation via FAM83D-dependent pathways. Additionally, FoxM1 physically interacts with KPNA2 (co-immunoprecipitation).\",\n      \"method\": \"ChIP-seq, luciferase reporter assay, qPCR, co-immunoprecipitation\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus luciferase reporter validation for transcriptional regulation, single lab\",\n      \"pmids\": [\"40345484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FAM83D directly interacts with GSK3β (co-immunoprecipitation), promotes GSK3β Ser9 phosphorylation (inactivation), and thereby stabilizes Snail to drive EMT and metastasis in cervical cancer. AKT and PKA are upstream kinases in FAM83D-mediated GSK3β inactivation. GSK3β inhibition reverses the anti-metastatic effects of FAM83D knockdown.\",\n      \"method\": \"Co-immunoprecipitation, Western blot (pSer9-GSK3β, Snail), siRNA knockdown, GSK3β inhibitor rescue, in vivo lung/liver metastasis model\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus pharmacological epistasis and in vivo metastasis model, single lab\",\n      \"pmids\": [\"41882663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In the context of targeted protein degradation, lenalidomide-derived molecular glue degraders DEG-77 and SJ3149 co-degrade SACK1D/FAM83D along with CK1α via the CUL4A-CRBN E3 ligase complex and the proteasome. This co-degradation requires direct CK1α-SACK1D interaction, as the CK1α-binding-deficient SACK1D/FAM83D is not co-degraded in cells from palmoplantar keratoderma patients.\",\n      \"method\": \"Molecular glue degrader treatment, proteasome inhibitor rescue, CRBN/CUL4A validation, patient-derived cell lines with R265P SACK1G mutation as negative control\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological degrader assay with multiple genetic controls including patient cells and proteasome inhibitor rescue, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.06.17.660125\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Knockdown of FAM83D in glioma causes abnormal cell division leading to accumulation of cytoplasmic double-stranded DNA, which activates the cGAS-STING signaling pathway to induce tumor cell senescence. FAM83D-depleted cells also produce a SASP that promotes senescence in neighboring cells and drives macrophage polarization toward an M1 state via ANXA1-FPR1/2 ligand-receptor signaling.\",\n      \"method\": \"siRNA knockdown, cGAS-STING pathway Western blot/reporter, single-cell transcriptome sequencing, cell co-culture model, in situ allograft mouse model, cytoplasmic dsDNA detection\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (scRNA-seq, co-culture, in vivo) in a single lab study\",\n      \"pmids\": [\"41742219\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SACK1D/FAM83D is a mitotic spindle adaptor protein that recruits CK1α to the spindle (via its C-terminal helix, stabilized by HMMR) to ensure proper spindle positioning and timely cell division; it also scaffolds the chromokinesin Kid at the spindle for polar ejection forces and chromosome congression; binds LC8 dynein light chain through tandem TQT motifs; undergoes mitotic hyperphosphorylation that signals its proteasomal destruction upon mitotic exit; and in cancer contexts activates oncogenic signaling (AKT/mTOR, MEK/ERK, Wnt/β-catenin) at least in part by physically binding and promoting degradation of the tumor suppressor FBXW7.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SACK1D/FAM83D is a mitotic spindle adaptor protein that scaffolds kinases and motor machinery onto the spindle to ensure correct chromosome behavior and spindle positioning during cell division [#0, #3]. It localizes to the mitotic spindle, where it recruits the chromokinesin Kid to generate polar ejection forces and organize the metaphase plate; loss of FAM83D or Kid causes chromosomes to collapse onto monopolar spindle poles [#0]. Through its C-terminal \\u03b1-helix it targets CK1\\u03b1 to the spindle, and a CK1\\u03b1-binding-deficient mutant (F283A) produces spindle positioning defects and prolonged mitosis that are rescued by artificially retargeting CK1\\u03b1 to the spindle [#3]. HMMR binds this same C-terminal helix, is required for assembly of the FAM83D-CK1\\u03b1 complex at the spindle and for correct spindle alignment, and stabilizes FAM83D against ubiquitination; mitotic hyperphosphorylation of FAM83D, also dependent on the C-terminal helix, signals its proteasomal destruction at mitotic exit, consistent with a phosphorylation-exposed C-terminal degron [#17]. A separate intrinsically disordered region containing four tandem TQT motifs binds the LC8 dynein light chain, with the first TQT dominating recruitment in an \\\"anchored flexibility\\\" mode [#1]. In cancer contexts FAM83D acts as an oncogenic driver: it physically binds FBXW7 and promotes its ubiquitination and degradation, stabilizing FBXW7 substrates and activating downstream signaling, and FBXW7-binding-site mutations abolish FAM83D-driven proliferation, invasion, and tumor growth [#2, #14]. Targeting CK1\\u03b1 and FAM83D for co-degradation through the CUL4A-CRBN E3 ligase is achievable with lenalidomide-derived molecular glues, dependent on the direct CK1\\u03b1-FAM83D interaction [#21].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established FAM83D (CHICA) as a mitotic spindle protein that physically recruits the chromokinesin Kid to drive polar ejection forces and metaphase plate organization, defining its first concrete mitotic function.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA depletion, double-depletion epistasis, and monastrol monopolar spindle assay with live-cell imaging\",\n      \"pmids\": [\"18485706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the spindle-targeting determinant within FAM83D\", \"Phosphorylation observed during mitosis but kinases and sites not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified the FAM83D-FBXW7 physical interaction as the route by which FAM83D elevates FBXW7 oncogenic substrates (mTOR), linking the spindle protein to oncogenic signaling.\",\n      \"evidence\": \"Co-IP, overexpression/knockdown, rapamycin rescue, migration/invasion assays\",\n      \"pmids\": [\"24344117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FBXW7-binding region on FAM83D not mapped\", \"Mechanism of FBXW7 downregulation (degradation vs transcription) not resolved here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Structurally resolved how an intrinsically disordered FAM83D region engages the LC8 dynein light chain, defining the molecular grammar of its TQT-motif recognition.\",\n      \"evidence\": \"NMR, ITC, and X-ray crystallography of LC8-peptide complexes\",\n      \"pmids\": [\"26652654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of LC8 binding for FAM83D mitotic activity not tested\", \"Whether LC8 binding is regulated by mitotic phosphorylation unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected FAM83D physically to the HMMR/TPX2/AURKA spindle module and showed it is required for microtubule regrowth, reinforcing its role as a microtubule-associated mitotic factor.\",\n      \"evidence\": \"Co-IP with HMMR, TPX2, AURKA and microtubule regrowth assay after nocodazole washout\",\n      \"pmids\": [\"29088801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect nature of each interaction not distinguished\", \"No structural or domain mapping of the HMMR interaction at this stage\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined FAM83D as the spindle-targeting adaptor for CK1\\u03b1 via its C-terminal residue F283, establishing a kinase-recruitment mechanism for spindle positioning and timely mitosis.\",\n      \"evidence\": \"CRISPR knockin of F283A, knockout rescue, artificial CK1\\u03b1 spindle retargeting, live-cell spindle positioning assay\",\n      \"pmids\": [\"31338967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spindle substrates of recruited CK1\\u03b1 not identified\", \"Did not address what stabilizes the FAM83D-CK1\\u03b1 complex at the spindle\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Generalized FAM83D's CK1\\u03b1-destabilizing activity to a non-mitotic, differentiation context, implicating a putative PLD-like domain in regulating CK1\\u03b1 and ERK signaling.\",\n      \"evidence\": \"GFP localization, domain-deletion (PLD-like) analysis, Western blots of differentiation and signaling markers, proteasome inhibition in muscle cells\",\n      \"pmids\": [\"32092437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PLD-like domain catalytic activity not biochemically demonstrated\", \"Single-lab muscle model, generality unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped the FBXW7-binding sites on FAM83D and showed they are essential for FAM83D-promoted FBXW7 ubiquitination/degradation and for its full oncogenic phenotype, cementing the FBXW7 axis as a core driver function.\",\n      \"evidence\": \"Systematic mutagenesis, Co-IP, ubiquitination assays, in vitro functional assays, xenograft model\",\n      \"pmids\": [\"38454442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FAM83D promotes FBXW7 ubiquitination mechanistically (recruited E3, autoubiquitination) not defined\", \"Relationship between spindle and oncogenic FBXW7 functions of the same protein unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified HMMR as a binding partner of the FAM83D C-terminal \\u03b1-helix that is required for FAM83D-CK1\\u03b1 complex formation and spindle alignment and that stabilizes FAM83D, while linking mitotic hyperphosphorylation to a C-terminal degron controlling mitotic-exit destruction.\",\n      \"evidence\": \"Co-IP, C-terminal helix deletion mapping, phosphosite mapping, live-cell spindle alignment and protein stability assays\",\n      \"pmids\": [\"41550726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The E3 ligase and degron recognition machinery acting at mitotic exit not identified\", \"Which mitotic kinase hyperphosphorylates FAM83D not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated FAM83D and CK1\\u03b1 can be co-degraded by CRBN-based molecular glues in a manner dependent on their direct interaction, validating the FAM83D-CK1\\u03b1 complex as a pharmacological handle.\",\n      \"evidence\": \"Molecular glue degrader treatment, proteasome inhibitor rescue, CRBN/CUL4A validation, patient-derived cells carrying a CK1\\u03b1-binding-deficient mutant as control (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.17.660125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Whether co-degradation has therapeutic consequences in cancer not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FAM83D's mitotic spindle/CK1\\u03b1-adaptor role mechanistically connects to its oncogenic FBXW7-degrading activity, and what substrates the spindle-recruited CK1\\u03b1 phosphorylates, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking spindle adaptor and FBXW7-degradation functions\", \"Spindle CK1\\u03b1 substrates unidentified\", \"E3 ligase mediating mitotic-exit destruction of FAM83D unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 17]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [0, 3, 17]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 3, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 14, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [14, 17]}\n    ],\n    \"complexes\": [\"FAM83D-CK1\\u03b1 spindle complex\"],\n    \"partners\": [\"CSNK1A1\", \"HMMR\", \"FBXW7\", \"KIF22\", \"DYNLL1\", \"TPX2\", \"AURKA\", \"GSK3B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}