| Claim/Function | Molecular mechanism | Key partners/substrates | Evidence type (biochemical/cell/animal/genetics/review) | Key quantitative data | Primary sources (include DOI URLs and year) |
|---|---|---|---|---|---|
| Human CAND2/TIP120B is the validated mammalian homolog/paralog of CAND1 and belongs to the cullin-associated, NEDD8-dissociated protein family | Foundational work identified CAND2/TIP120B as a highly related mammalian homolog of CAND1; CAND proteins are large HEAT-repeat cullin-binding factors associated with deneddylated cullins | CUL1 and other cullins; CAND family | Biochemical, review | CAND1/CAND2 share 63% sequence identity; human CAND proteins contain 25 HEAT motifs | Liu et al., 2002, https://doi.org/10.1016/S1097-2765(02)00783-9; Wang et al., 2025, https://doi.org/10.1038/s41467-025-57065-5 (pqac-00000009, pqac-00000008) |
| CAND2 binds cullins, especially CUL1, and associates with SCF complexes in muscle cells | TIP120B/CAND2 physically associates with CUL1 under overexpression and endogenous conditions; both N- and C-terminal regions are required for efficient CUL1 association; this cullin binding underlies its regulatory effect on SCF | CUL1, SCF complex, SKP1 | Biochemical, cell | C-terminal truncation largely abolishes CUL1 binding; qualitative co-localization shows ubiquitous distribution with slight nuclear concentration | Shiraishi et al., 2007, https://doi.org/10.1074/jbc.M611513200 (pqac-00000010, pqac-00000011) |
| CAND2 inhibits SCF-dependent ubiquitination of myogenin and stabilizes myogenin during myogenic differentiation | By binding CUL1, CAND2 disrupts or breaks down the SCF-myogenin complex, reducing SCF-dependent ubiquitination and proteasomal degradation of myogenin, thereby accelerating differentiation | Myogenin, CUL1, SCF | Biochemical, cell, review | MyoD half-life cited as ~60 min for context; direct quantitative half-life for myogenin not provided in extracted text | Shiraishi et al., 2007, https://doi.org/10.1074/jbc.M611513200; Diaz et al., 2022, https://doi.org/10.3390/biom12030416 (pqac-00000010, pqac-00000011, pqac-00000003) |
| CAND2 is muscle-enriched/muscle-specific in expression | Primary and review sources describe CAND2/TIP120B as a muscle-specific isoform/paralog, distinguishing it from ubiquitously expressed CAND1 | Striated muscle tissues; skeletal/cardiac muscle | Biochemical, review | No absolute expression value in extracted text; described as muscle-specific and detected in striated muscle/testis in review summary | Liu et al., 2002, https://doi.org/10.1016/S1097-2765(02)00783-9; Shiraishi et al., 2007, https://doi.org/10.1074/jbc.M611513200; Diaz et al., 2022, https://doi.org/10.3390/biom12030416 (pqac-00000009, pqac-00000010, pqac-00000003) |
| Subcellular localization of CAND2 includes cytosol and nucleus/nuclear bodies | In C2C12 cells, GFP-TIP120B is observed throughout the cell with slight nuclear enrichment and co-localizes with CUL1; recent summary cites Human Protein Atlas localization to cytosol and nuclear bodies | CUL1; nuclear bodies; cytosol | Cell, database-backed summary | Qualitative localization only in C2C12 assays; no percentages reported | Shiraishi et al., 2007, https://doi.org/10.1074/jbc.M611513200; Wang et al., 2025, https://doi.org/10.1038/s41467-025-57065-5 (pqac-00000011, pqac-00000000) |
| Current mechanistic understanding: CAND2 can promote SCF dynamics as an F-box protein exchange factor in human cells, but is less efficient than CAND1 | CAND2 binds the CUL1·RBX1 core similarly to CAND1 and promotes SCF-mediated protein degradation by catalyzing exchange/disassembly of SKP1·F-box modules; higher KM indicates lower exchange efficiency, potentially allowing longer retention of F-box proteins on CUL1 | CUL1, RBX1, SKP1·FBP modules, SCF | Biochemical, cell | CAND2 koff = 4.4 s^-1 and KM = 648 nM vs CAND1 koff = 2.5 s^-1 and KM = 355 nM (n = 5); weaker activity attributed to higher KM | Wang et al., 2025, https://doi.org/10.1038/s41467-025-57065-5 (pqac-00000000, pqac-00000001, pqac-00000008) |
| CAND2 can support SCF activity in cells and partially overlaps functionally with CAND1 | In CAND1/CAND2 double-knockout cells, ectopic CAND2 restores degradation of an SCF substrate, indicating that CAND2 is competent to promote SCF function in vivo, although CAND1 dominates some pathways | SCFβ-TrCP, phospho-IκBα | Cell | p-IκBα degradation rescued by CAND2HA in DKO cells; no defect in CAND2 single-KO for this pathway | Wang et al., 2025, https://doi.org/10.1038/s41467-025-57065-5 (pqac-00000001, pqac-00000008) |
| Both CAND1 and CAND2 are required for optimal activity of at least some SCF ligases | In the SCFFBXL5 pathway, loss of either CAND1 or CAND2 slows degradation of IRP2, indicating nonredundant contribution to optimal SCF function | FBXL5, IRP2, CUL1-based SCF | Cell | IRP2 half-life increased 2.8-fold in CAND1/CAND2 DKO, 1.7-fold in CAND1-KO, and 1.8-fold in CAND2-KO | Wang et al., 2025, https://doi.org/10.1038/s41467-025-57065-5 (pqac-00000001, pqac-00000008) |
| In cardiac muscle, Cand2 is translationally upregulated by mTORC1 and promotes adverse remodeling via Grk5 stabilization | Cand2 binds/sequesters unneddylated CUL1, altering the neddylated CUL1 pool and reducing Cul1-mediated degradation of Grk5; this links mTORC1-driven translational control to pathological cardiac growth | mTORC1, CUL1, GRK5 | Cell, animal, review | MLN4924 raises GRK5 protein ~2.5-fold; CUL1 knockdown raises GRK5 ~2-fold; Cand2 overexpression prolongs GRK5 half-life from ~18 h to ~27 h | Górska et al., 2021, https://doi.org/10.15252/embr.202052170; Diaz et al., 2022, https://doi.org/10.3390/biom12030416 (pqac-00000002, pqac-00000003) |
| CAND2 has human cardiovascular genetics support, especially for atrial fibrillation/postoperative AF risk | AF-associated intronic variant rs4642101 near/in CAND2 is associated with higher CAND2 expression and increased AF/POAF susceptibility in human cohorts; functional zebrafish validation implicated the locus in atrial electrophysiology | rs4642101; atrial fibrillation; postoperative AF | Genetics | AF GWAS: RR 1.10, 95% CI 1.06–1.14, P = 9.8×10^-9; cis-eQTL P = 2.6×10^-19; zebrafish Cand2 knockdown prolonged atrial APD by 45%; POAF after CABG OR 1.21 per minor allele, 95% CI 1.08–1.36, P = 9.8×10^-4 | Sinner et al., 2014, https://doi.org/10.1161/CIRCULATIONAHA.114.009892; Wei et al., 2016, https://doi.org/10.18632/oncotarget.9422 (pqac-00000003) |
| CAND proteins are integrated into the CRL neddylation/deneddylation cycle that controls SCF remodeling | In the general CRL cycle, CAND proteins bind unneddylated cullins; neddylation prevents stable CAND binding, whereas CSN-mediated deneddylation restores a state permissive for CAND-dependent receptor exchange and remodeling | NEDD8, CSN, CUL1/RBX1, SKP1·F-box modules | Review, biochemical | For CAND1-CUL2, neddylation increased dissociation rate ~5-fold (t1/2 20 min to 4 min), illustrating the principle that neddylation destabilizes CAND-cullin binding | Harper & Schulman, 2021, https://doi.org/10.1146/annurev-biochem-090120-013613; Zhang et al., 2024, https://doi.org/10.1038/s41392-024-01800-9; Wang et al., 2024, https://doi.org/10.1038/s41594-023-01167-5; Wang et al., 2020, https://doi.org/10.1007/978-981-15-1025-0_3 (pqac-00000012, pqac-00000013, pqac-00000016, pqac-00000017, pqac-00000018) |


*Table: This table summarizes validated functional annotation for human CAND2/TIP120B (UniProt O75155), including core molecular roles, key partners, localization, and disease-linked findings. It emphasizes primary-source evidence and quantitative data available from the provided context IDs.*