GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

PMID:10531035

Identification of a family of human F-box proteins.

FBXL6 (FBL6) was identified as one of a family of human F-box proteins; F-box proteins act as substrate-recognition components of SCF ubiquitin ligase complexes.

PMID:19159283

Array MAPPIT: high-throughput interactome analysis in mammalian cells.

PMID:27705803

A High-Density Map for Navigating the Human Polycomb Complexome.

PMID:33234069

The FBXL family of F-box proteins: variations on a theme.

FBXL-family F-box proteins serve as substrate-recognition subunits of SCF E3 ubiquitin ligases, using their LRR domains for substrate binding and the F-box for SKP1/CUL1 recruitment.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

file:human/FBXL6/FBXL6-deep-research-falcon.md

Falcon deep research report for human FBXL6

FBXL6 acts as an SCF substrate receptor that both promotes proteasomal degradation of targets and adds non-degradative ubiquitin chains that stabilize/activate clients in oncogenic contexts.

"FBXL6’s most defensible “primary function” from the available literature is as an SCF-type ubiquitin ligase substrate receptor/adaptor that (i) promotes proteasomal degradation of certain targets and (ii) can also add non-degradative ubiquitin chains that stabilize/activate specific client proteins in oncogenic contexts."
FBXL6 binds phosphorylated p53 (Ser315) and promotes its polyubiquitination at K291/K292, leading to proteasomal degradation and dampened p53 signaling.

"FBXL6 binds phosphorylated p53 (S315) and promotes p53 polyubiquitination at K291/K292 leading to proteasomal degradation, consistent with a role in dampening p53 signaling."
FBXL6 promotes K63-linked ubiquitination of HSP90AA1, stabilizing it and sustaining c-MYC activation in hepatocellular carcinoma, illustrating a non-degradative outcome.

"FBXL6 promotes **K63-dependent ubiquitination** of HSP90AA1, stabilizing HSP90AA1 and indirectly sustaining c-MYC activation in hepatocellular carcinoma models; this illustrates a non-degradative ubiquitin outcome mediated by FBXL6."
VRK2-mediated phosphorylation of transketolase at Thr287 recruits FBXL6, whose F-box is required to promote TKT ubiquitination and activation.

"VRK2-mediated phosphorylation of TKT at **Thr287** recruits FBXL6 to promote TKT ubiquitination and activation; the FBXL6 F-box is required (FBXL6ΔF fails to increase ubiquitination)."
FBXL6 is a dependency in AML, especially FLT3-ITD-mutated lines, identified by CRISPR drop-out screening of the human F-box gene family.

"A 2024 Leukemia paper identified FBXL6 as a prominent dependency in AML cell lines using pooled CRISPR drop-out screening across the full set of 72 human F-box genes. FBXL6 knockout decreased proliferation/viability in multiple assays, with stronger effects in FLT3-ITD–mutated AML lines (e.g., MOLM-13/MV4-11) than OCI-AML3, suggesting genotype-dependent sensitivity."