| Finding/role | Direct substrate/partner | Ubiquitin outcome (degradation vs non-proteolytic; linkage if known) | Key assays/evidence | Biological context/pathway | Publication (first author year) | URL/DOI |
|---|---|---|---|---|---|---|
| SCF^FBXO21 recognizes and degrades EID1 | EID1 (EP300-interacting inhibitor of differentiation 1) | Proteasomal degradation; polyubiquitylation shown, linkage not specified in the cited evidence | Differential proteomics (DiPIUS), FLAG-IP/LC-MS/MS, co-IP with SKP1/CUL1, interaction mapping, FBXO21 overexpression causing EID1 downregulation, CRISPR/Cas9 FBXO21 disruption stabilizing EID1, in vitro ubiquitylation; degradation reported predominantly in cytoplasm (pqac-00000001, pqac-00000002, pqac-00000006) | Protein turnover of a transcriptional repressor; SCF E3 ligase substrate recognition/degron biology | Watanabe 2015; Zhang 2015 | https://doi.org/10.1111/gtc.12260 ; https://doi.org/10.1073/pnas.1522006112 |
| SCF^FBXO21 activates antiviral signaling through ASK1 modification | ASK1 (MAP3K5) | Non-proteolytic polyubiquitylation; Lys29-linked chains required; no degradation effect detected (pqac-00000000, pqac-00000003, pqac-00000005) | Endogenous IP + LC-MS identification, co-IP, GST pull-down, domain mapping, Fbxo21 knockout/reconstitution, linkage-specific ubiquitination assays using K29-only ubiquitin mutants, viral infection models (VSV, HSV-1), cytokine and phospho-signaling readouts (pqac-00000000, pqac-00000003, pqac-00000005) | Antiviral innate immunity; ASK1-JNK/p38 signaling promotes type I IFN and IL-6 responses after viral nucleic acid sensing/infection (pqac-00000000, pqac-00000005) | Yu 2016 | URL/DOI not available in retrieved metadata |
| FBXO21 promotes p85α turnover in AML | p85α / PIK3R1 | Proteasomal degradation; ubiquitination supported with K48-reactive signal in cited evidence (pqac-00000013) | TMT proteomics and K-ε-GG ubiquitin-remnant IP/MS substrate nomination; co-expression/co-IP; ubiquitin IP in HEK293T and MOLM-13; MG132 rescue; ΔF-box mutant loses activity; in vitro ubiquitination with immunopurified FBXO21; stabilization upon FBXO21 knockdown (pqac-00000008, pqac-00000012, pqac-00000013) | AML proliferation/survival; loss of FBXO21 stabilizes p85α, decreases canonical PI3K/AKT signaling, promotes p85α homodimerization and ERK activation, increases CXCL10, and sensitizes to chemotherapy (pqac-00000007, pqac-00000008, pqac-00000009, pqac-00000016) | Dobish 2023 | https://doi.org/10.1038/s41375-023-02020-w |
| Clinical association of FBXO21 in AML | FBXO21 expression (not a direct substrate row, but disease association from same study) | Not applicable | AML datasets and experimental models showed higher FBXO21 expression associated with poorer outcomes; FBXO21 knockdown sensitized cells to cytarabine with IC50 shift from 42 nM to 23 nM; overexpression accelerated disease onset in NSG mice (pqac-00000009, pqac-00000012) | Prognostic association and therapy-response modulation in AML | Dobish 2023 | https://doi.org/10.1038/s41375-023-02020-w |
| FBXO21 targets multidrug transporter P-gp/ABCB1; CD44 protects it | ABCB1 / P-glycoprotein; CD44 (protective antagonist of degradation) | Proteasomal degradation of P-gp by FBXO21; CD44 Ser291-phosphorylated form inhibits FBXO21-directed degradation (abstract-level evidence in retrieved context) | Reported binding of FBXO21 to P-gp, in vivo ubiquitination of P-gp, in vitro ubiquitination assay, and functional protection by CD44 from FBXO21-mediated ubiquitination/degradation (retrieved abstract/snippet) (pqac-00000015) | Multidrug resistance; CD44 increases P-gp-mediated drug resistance by blocking FBXO21-driven turnover (pqac-00000015) | Ravindranath 2015 | https://doi.org/10.18632/oncotarget.4763 |
| Small-molecule disruption of FBXO21:p85α interaction (preprint) | FBXO21:p85α interface; compound 57-057 | Blocks FBXO21-mediated p85α ubiquitylation, thereby stabilizing p85α; reported K692 site and YccV-domain-dependent binding in cited excerpt (pqac-00000010, pqac-00000011) | In vitro ubiquitination assays; computational modeling of p85α degron; mutation analyses (K692R, Y467A); dose-dependent p85α accumulation in cells; pathway/dimerization assays; AML viability/colony assays; in vivo antileukemia activity claimed in excerpt (pqac-00000010, pqac-00000011, pqac-00000014) | Translational targeting concept in AML: reduced AKT/canonical PI3K signaling, altered p85/p110 vs p85/p85 dimerization, induction of AML cell death (pqac-00000010, pqac-00000011, pqac-00000014) | Dobish 2024 preprint | https://doi.org/10.1101/2024.12.13.628427 |
| Reported selectivity statistics for 57-057 (preprint) | Primary AML cells vs healthy CD34+ HSPCs | Not applicable | FBXO21:p85α disruptor 57-057 inhibited FBXO21-mediated p85α ubiquitination with IC50 2.4 nM; showed ~5-fold selectivity for primary AML versus CD34+ HSPCs, with reported activity 8 nM vs 39 nM (pqac-00000014) | Early preclinical therapeutic window estimate for targeting FBXO21 biology in AML | Dobish 2024 preprint | https://doi.org/10.1101/2024.12.13.628427 |


*Table: This table summarizes experimentally supported human FBXO21 functions, substrates, ubiquitin outcomes, and disease contexts. It highlights both foundational mechanistic studies and the recent AML-focused therapeutic preprint on the FBXO21:p85α interaction.*