Details for: FBXW12

Gene ID: 285231

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: FBXW12

Ensembl ID: ENSG00000164049

Description: F-box and WD repeat domain containing 12

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • melanocyte of skin CL1000458
    CSI 3.03
    rCSI 4.13%
    PRS 98.58

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [FBXW12](/details-gene/285231) (F-box and WD repeat domain containing 12) is a protein-coding gene located on chromosome 3. It functions as a component of an SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex, which targets substrate proteins for proteasomal degradation. This role places [FBXW12](/details-gene/285231) at the center of cellular protein turnover and quality control. Functionally, it is implicated in the regulation of the immune system, particularly in antigen processing and presentation pathways. Expression data indicates a highly specific role, with its significance being most pronounced in [melanocyte of skin](/details-cell/CL1000458), suggesting a specialized function in this cell type. ## Cellular Roles and Expression Landscape The expression profile of [FBXW12](/details-gene/285231) points towards a highly specialized function. **Overall**, the gene shows its most significant expression in [melanocyte of skin](/details-cell/CL1000458) (CSI: 3.03). This restricted expression pattern suggests that [FBXW12](/details-gene/285231) is not a broadly expressed housekeeping gene, but rather plays a specific role in melanocyte biology. This may involve the regulation of proteins critical for pigmentation, cell survival, or the unique immunological functions of melanocytes. While expression data highlights its role in melanocytes, research has also characterized [FBXW12](/details-gene/285231) as a negative regulator of the IL-22 receptor, functioning as an epithelial growth suppressor ([Link](https://doi.org/10.1155/2015/912713)). This suggests a potential role in mediating signals between the immune system and epithelial tissues, a critical function in skin homeostasis and pathology. The gene's specific activity in melanocytes, which reside in the epidermis, may be a key part of this regulatory network. ## Pathways and Molecular Function The primary molecular function of [FBXW12](/details-gene/285231) is to mediate [Protein ubiquitination](/details-go/GO:0016567) as a substrate-recognition component of an E3 ligase complex. This core function is consistent with its cytosolic localization ([GO:0005829](https://www.ebi.ac.uk/QuickGO/term/GO:0005829)). This ubiquitination activity is integral to several key processes within the [Immune system](/details-pathway/R-HSA-168256). Specifically, [FBXW12](/details-gene/285231) is annotated in pathways related to the [Adaptive immune system](/details-pathway/R-HSA-1280218), including [Antigen processing: ubiquitination & proteasome degradation](/details-pathway/R-HSA-983168) and [Class i mhc mediated antigen processing & presentation](/details-pathway/R-HSA-983169). This suggests that in cells where it is active, such as melanocytes, [FBXW12](/details-gene/285231) may be involved in processing intracellular proteins into peptides for presentation on MHC class I molecules, a critical step for cytotoxic T lymphocyte surveillance. Its involvement is also noted in broader protein metabolism pathways like [Post-translational protein modification](/details-pathway/R-HSA-597592) and [Neddylation](/details-pathway/R-HSA-8951664), which is essential for the activation of cullin-RING E3 ubiquitin ligases. ## Research Directions The specific expression of [FBXW12](/details-gene/285231) in melanocytes, combined with its known function as an epithelial growth suppressor and its role in antigen presentation, opens several avenues for future research. **Proposed Hypotheses:** 1. **[FBXW12](/details-gene/285231) acts as a tumor suppressor in melanocytes by targeting key pro-proliferative or anti-apoptotic proteins for degradation, and its loss or downregulation is a contributing event in the development or progression of melanoma.** This is based on its identified role as an epithelial growth suppressor ([Link](https://doi.org/10.1155/2015/912713)). 2. **In melanocytes, [FBXW12](/details-gene/285231) modulates immuno-surveillance by specifically regulating the turnover of proteins that are sources of melanoma-associated antigens presented on MHC class I molecules.** This hypothesis connects its high expression in melanocytes with its annotated role in [Class i mhc mediated antigen processing & presentation](/details-pathway/R-HSA-983169). **Key Experimental Approach:** To test the hypothesis that [FBXW12](/details-gene/285231) functions as a tumor suppressor in melanoma, one could employ a multi-step approach. First, perform CRISPR-Cas9-mediated knockout of [FBXW12](/details-gene/285231) in a panel of non-transformed primary human melanocytes and early-stage melanoma cell lines. Second, assess the functional consequences of the knockout on cellular phenotypes, including proliferation (e.g., via BrdU incorporation assays), anchorage-independent growth (soft agar assays), and resistance to apoptosis. Third, utilize quantitative mass spectrometry (e.g., TMT-based proteomics) combined with ubiquitin-remnant profiling (K-GG motif antibody enrichment) in knockout vs. wild-type cells to identify the direct ubiquitination substrates of [FBXW12](/details-gene/285231). This would reveal the specific signaling pathways it regulates to suppress malignant transformation. **Therapeutic Potential:** Given its putative role as a growth suppressor, [FBXW12](/details-gene/285231) is unlikely to be a direct target for inhibition. Instead, if its loss of function is validated in melanoma, it could represent a therapeutic vulnerability. Strategies could focus on restoring its function or targeting the downstream pathways that become dysregulated upon its loss. For instance, if [FBXW12](/details-gene/285231) is found to degrade a specific oncoprotein, small molecule inhibitors of that oncoprotein could be particularly effective in [FBXW12](/details-gene/285231)-deficient tumors. Therefore, its primary value may be as a biomarker for stratifying patients and guiding therapy rather than as a direct drug target itself.

Genular Protein ID: 3897472030

Symbol: FBW12_HUMAN

Name: F-box/WD repeat-containing protein 12

UniProtKB Accession Codes:

Q6X9E4 E9PG36 Q494Y9 Q494Z0

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 3 CDD 1 CTD 1 ChiTaRS 1 ComplexPortal 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 4 Ensembl 3 ExpressionAtlas 1 GO 2 Gene3D 2 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 RNAct 1 Reactome 2 RefSeq 4 SIGNOR 1 SMART 1 STRING 1 SUPFAM 2 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 15040455

Title: cDNA cloning and expression analysis of a novel human F-box domain containing gene.

PubMed ID: 15040455

DOI: 10.1023/b:mole.0000013502.72069.19

PubMed ID: 16641997

Title: The DNA sequence, annotation and analysis of human chromosome 3.

PubMed ID: 16641997

DOI: 10.1038/nature04728

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 26171402

Title: The Human IL-22 Receptor Is Regulated through the Action of the Novel E3 Ligase Subunit FBXW12, Which Functions as an Epithelial Growth Suppressor.

PubMed ID: 26171402

DOI: 10.1155/2015/912713

Sequence Information:

  • Length: 464
  • Mass: 53056
  • Checksum: DFF81F0D718CEF7B
  • Sequence:
    • MEIRLPDLAL KRIFSFLDLF GLLQVSQVNK HWNRIADSDY LWRSLSLQRW DCSNFTNQHL 
GTHTWKQFFL HQRRKELRLA LAQPHNFIYK VTKNIAFETE LAYLSGNRLT VDEQEKSIIC 
SVSPKQELCA WDVQEGTMIW SSPVQEFHFS NLVTLPQMHL AITMDRKKTI KVWNCQDRDA 
LAVLPMPQPC YCMEAYLTKD GPFLMVGDAA GDIYTFTLPG LRDVSKVTAF QYGIVLLHCS 
PDKKWVFACG TYSRTLPQVF LTESLLRPSE GSVPLSTFLP HKLCASACWT PKVKNRITLM 
SQSSTGKKTE FITFDLTTKK TGGQTVIQAY EIASFQVAAH LKCPIWMGAS DGYMIVFTSG 
PYLLLFSITG FLLQRFEDHQ AAINNFWVDP CYVLTTSENS VHVYMWEEGG RHPYLRSCCH 
LENTWHDHTT DSCISSVMCD NASIVLRVRK VSDSSILVMY SLNT