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Kinase Fusion Gene:USP7_MLKL |
Kinase Fusion Protein Summary |
 Kinase Fusion gene summary |
| Kinase Fusion partner gene information | Kinase Fusion gene name: USP7_MLKL | KinaseFusionDB ID: KFG7038 | FusionGDB2.0 ID: KFG7038 | Hgene | Tgene | Gene symbol | USP7 | MLKL | Gene ID | 7874 | 197259 | |
| Gene name | ubiquitin specific peptidase 7 | mixed lineage kinase domain like pseudokinase | ||||||||||
| Synonyms | C16DELp13.2|DEL16P13.2|HAFOUS|HAUSP|TEF1 | hMLKL | ||||||||||
| Cytomap | 16p13.2 | 16q23.1 | ||||||||||
| Type of gene | protein-coding | protein-coding | ||||||||||
| Description | ubiquitin carboxyl-terminal hydrolase 7Chromosome 16p13.2 deletion syndromeHerpes virus-associated ubiquitin-specific proteasedeubiquitinating enzyme 7ubiquitin specific peptidase 7 (herpes virus-associated)ubiquitin specific protease 7 (herpes virus | mixed lineage kinase domain-like protein | ||||||||||
| Modification date | 20240411 | 20240411 | ||||||||||
| UniProtAcc | Q93009 | Q8NB16 | ||||||||||
| Ensembl transtripts involved in fusion gene | ENST ids | ENST00000344836, ENST00000381886, ENST00000535863, ENST00000566224, | ENST00000306247, ENST00000308807, | |||||||||
| Context (manual curation of fusion genes in KinaseFusionDB) | PubMed: USP7 [Title/Abstract] AND MLKL [Title/Abstract] AND fusion [Title/Abstract] | |||||||||||
| Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0) | ||||||||||||
| Gene ontology of each fusion partner gene with evidence of Inferred from Direct Assay (IDA) from Entrez |
| Partner | Gene | GO ID | GO term | PubMed ID |
| Hgene | USP7 | GO:0006307 | DNA alkylation repair | 25944111 |
| Hgene | USP7 | GO:0016579 | protein deubiquitination | 16964248|21258371|21745816|25172512 |
| Hgene | USP7 | GO:0031647 | regulation of protein stability | 27123980 |
| Hgene | USP7 | GO:0032088 | negative regulation of NF-kappaB transcription factor activity | 11279055 |
| Hgene | USP7 | GO:0035520 | monoubiquitinated protein deubiquitination | 26280536 |
| Hgene | USP7 | GO:0042752 | regulation of circadian rhythm | 27123980 |
| Hgene | USP7 | GO:0045721 | negative regulation of gluconeogenesis | 28655758 |
| Hgene | USP7 | GO:0050821 | protein stabilization | 21258371|25172512|35216969 |
| Hgene | USP7 | GO:0051090 | regulation of DNA-binding transcription factor activity | 16964248 |
| Hgene | USP7 | GO:0075342 | symbiont-mediated disruption of host cell PML body | 20719947 |
| Hgene | USP7 | GO:1904262 | negative regulation of TORC1 signaling | 35216969 |
| Tgene | MLKL | GO:0070207 | protein homotrimerization | 24316671 |
| Tgene | MLKL | GO:0097528 | execution phase of necroptosis | 24316671 |
| Kinase Fusion gene breakpoints across USP7 (5'-gene) * Click on the image to open the UCSC genome browser with custom track showing this image in a new window. |
| Kinase Fusion gene breakpoints across MLKL (3'-gene) * Click on the image to open the UCSC genome browser with custom track showing this image in a new window. |
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Kinase Fusion Gene Sample Information |
| Kinase Fusion gene information. |
| Kinase Fusion gene information from four resources (ChiTars 5.0, ChimerDB 4.0, COSMIC, and CCLE) * All genome coordinats were lifted-over on hg19. * Click on the break point to see the gene structure around the break point region using the UCSC Genome Browser. |
| Source | Sample | Hgene | Hchr | Hbp | Tgene | Tchr | Tbp |
| CCLE | NCI-H1755 | USP7 | chr16 | 9024150 | MLKL | chr16 | 74712878 |
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Kinase Fusion ORF Analysis |
| Kinase Fusion information from ORFfinder translation from full-length transcript sequence from KinaseFusionDB. |
| Henst | Tenst | Hgene | Hchr | Hbp | Tgene | Tchr | Tbp | Seq length (transcript) | Seq length (amino acids) |
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Kinase Fusion Amino Acid Sequences |
| For individual full-length fusion transcript sequence from KinaseFusionDB, we ran ORFfinder and chose the longest ORF among the all predicted ones. |
| >Henst_Tenst_Hgene_Hchr_Hbp_Tgene_Tchr_Tbp_length(fusion AA)_AAseq |
Multiple Sequence Alignment of All Fusion Protein Isoforms |
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Kinase Fusion Protein Functional Features |
| Four levels of functional features of fusion genes Go to FGviewer search page for the most frequent breakpoint (https://ccsmweb.uth.edu/FGviewer/:/:) - FGviewer provides the online visualization of the retention search of the protein functional features across DNA, RNA, protein, and pathological levels. - How to search 1. Put your fusion gene symbol. 2. Press the tab key until there will be shown the breakpoint information filled. 4. Go down and press 'Search' tab twice. 4. Go down to have the hyperlink of the search result. 5. Click the hyperlink. 6. See the FGviewer result for your fusion gene. |
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| Main function of each fusion partner protein. (from UniProt) |
| Hgene | Tgene |
| USP7 | MLKL |
| FUNCTION: Hydrolase that deubiquitinates target proteins such as FOXO4, DEPTOR, KAT5, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN, KMT2E/MLL5 and DAXX (PubMed:11923872, PubMed:15053880, PubMed:16964248, PubMed:18716620, PubMed:25283148, PubMed:25865756, PubMed:26678539, PubMed:28655758, PubMed:35216969). Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation (PubMed:15053880, PubMed:16845383, PubMed:18566590, PubMed:20153724). Deubiquitinates p53/TP53, preventing degradation of p53/TP53, and enhances p53/TP53-dependent transcription regulation, cell growth repression and apoptosis (PubMed:25283148). Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis (PubMed:11923872, PubMed:26786098). Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity (PubMed:16964248). In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML (PubMed:18716620). Deubiquitinates KMT2E/MLL5 preventing KMT2E/MLL5 proteasomal-mediated degradation (PubMed:26678539). Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV-induced degradation of ERCC6 (PubMed:22466611, PubMed:22466612). Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1 (PubMed:21745816, PubMed:22411829). Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions (PubMed:25944111). Acts as a chromatin regulator via its association with the Polycomb group (PcG) multiprotein PRC1-like complex; may act by deubiquitinating components of the PRC1-like complex (PubMed:20601937). Able to mediate deubiquitination of histone H2B; it is however unsure whether this activity takes place in vivo (PubMed:20601937). Exhibits a preference towards 'Lys-48'-linked ubiquitin chains (PubMed:22689415). Increases regulatory T-cells (Treg) suppressive capacity by deubiquitinating and stabilizing the transcription factor FOXP3 which is crucial for Treg cell function (PubMed:23973222). Plays a role in the maintenance of the circadian clock periodicity via deubiquitination and stabilization of the CRY1 and CRY2 proteins (PubMed:27123980). Deubiquitinates REST, thereby stabilizing REST and promoting the maintenance of neural progenitor cells (PubMed:21258371). Deubiquitinates SIRT7, inhibiting SIRT7 histone deacetylase activity and regulating gluconeogenesis (PubMed:28655758). Involved in the regulation of WASH-dependent actin polymerization at the surface of endosomes and the regulation of endosomal protein recycling (PubMed:26365382). It maintains optimal WASH complex activity and precise F-actin levels via deubiquitination of TRIM27 and WASHC1 (PubMed:26365382). Mediates the deubiquitination of phosphorylated DEPTOR, promoting its stability and leading to decreased mTORC1 signaling (PubMed:35216969). {ECO:0000269|PubMed:11923872, ECO:0000269|PubMed:15053880, ECO:0000269|PubMed:16845383, ECO:0000269|PubMed:16964248, ECO:0000269|PubMed:18566590, ECO:0000269|PubMed:18716620, ECO:0000269|PubMed:20153724, ECO:0000269|PubMed:20601937, ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:21745816, ECO:0000269|PubMed:22411829, ECO:0000269|PubMed:22466611, ECO:0000269|PubMed:22466612, ECO:0000269|PubMed:22689415, ECO:0000269|PubMed:23973222, ECO:0000269|PubMed:25283148, ECO:0000269|PubMed:25865756, ECO:0000269|PubMed:25944111, ECO:0000269|PubMed:26365382, ECO:0000269|PubMed:26678539, ECO:0000269|PubMed:26786098, ECO:0000269|PubMed:27123980, ECO:0000269|PubMed:28655758, ECO:0000269|PubMed:35216969}.; FUNCTION: (Microbial infection) Contributes to the overall stabilization and trans-activation capability of the herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 during HSV-1 infection. {ECO:0000269|PubMed:14506283, ECO:0000269|PubMed:16160161, ECO:0000269|PubMed:18590780}.; FUNCTION: (Microbial infection) Upon infection with Epstein-Barr virus, the interaction with viral EBNA1 increases the association of USP7 with PML proteins, which is required for the polyubiquitylation and degradation of PML. {ECO:0000269|PubMed:20719947, ECO:0000269|PubMed:24216761}. | FUNCTION: Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). Does not have protein kinase activity (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). Activated following phosphorylation by RIPK3, leading to homotrimerization, localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: following activation by ZBP1, MLKL is phosphorylated by RIPK3 in the nucleus, triggering disruption of the nuclear envelope and leakage of cellular DNA into the cytosol.following ZBP1 activation, which senses double-stranded Z-RNA structures, nuclear RIPK3 catalyzes phosphorylation and activation of MLKL, promoting disruption of the nuclear envelope and leakage of cellular DNA into the cytosol (By similarity). Binds to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which is essential for its necroptotic function (PubMed:29883610). {ECO:0000250|UniProtKB:Q9D2Y4, ECO:0000269|PubMed:22265413, ECO:0000269|PubMed:22265414, ECO:0000269|PubMed:22421439, ECO:0000269|PubMed:24316671, ECO:0000269|PubMed:29883610}. |
| Retention analysis result of each fusion partner protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features. Here, because of limited space for viewing, we only show the protein feature retention information belong to the 13 regional features. All retention annotation result can be downloaded at * Minus value of BPloci means that the break pointn is located before the CDS. |
| - Retained domain in the 5'-partner of fusion protein (protein functional feature from UniProt). |
| Partner | Hgeneene | Hbp | Tgeneene | Tbp | ENST | BPexon | TotalExon | Protein feature loci | BPloci | TotalLen | Feature | Note |
| - Retained domain in the 3'-partner of fusion protein (protein functional feature from UniProt). |
| Partner | Hgeneene | Hbp | Tgeneene | Tbp | ENST | BPexon | TotalExon | Protein feature loci | BPloci | TotalLen | Feature | Note |
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Kinase-Substrate Information of USP7_MLKL |
| Phosphorylation target of the kinase (phosphosite, 03-17-2024) |
| Kinase | Kinase UniProt Acc | Kinase species | Substrate | Substrate UniProt Acc | Substrate phosphorylated residues | Substrate phosphorylated sites (+/-7AA) | Domain |
| MLKL | Q8NB16 | human | CNR2 | P34972 | S352 | kITPWPDsRDLDLSD |
| Biological Network Integration of This Kinase and Substrates (GeneMANIA website) |
| Enriched GO biological processes of the phosphorylation target genes of the kinase |
| Kinase | GOID | GO term | P.adjust |
| MLKL | ID | Description | 0.00e+00 |
| MLKL | GO:0033004 | negative regulation of mast cell activation | 9.03e-03 |
| MLKL | GO:0001975 | response to amphetamine | 9.03e-03 |
| MLKL | GO:0032228 | regulation of synaptic transmissio | 1.85e-03 |
| MLKL | GO:0014075 | response to amine | 9.03e-03 |
| MLKL | GO:0050805 | negative regulation of synaptic transmission | 9.03e-03 |
| MLKL | GO:0007187 | G protein-coupled receptor signaling pathwa | 2.97e-03 |
| MLKL | GO:0045576 | mast cell activation | 9.51e-03 |
| MLKL | GO:0001508 | action potential | 1.81e-02 |
| MLKL | GO:0007189 | adenylate cyclase-activating G protein-coupled receptor signaling pathway | 1.81e-02 |
| MLKL | GO:0002695 | negative regulation of leukocyte activation | 2.01e-02 |
| MLKL | GO:0050866 | negative regulation of cell activation | 2.01e-02 |
| MLKL | GO:0030595 | leukocyte chemotaxis | 2.01e-02 |
| MLKL | GO:0002274 | myeloid leukocyte activation | 2.01e-02 |
| MLKL | GO:0007188 | adenylate cyclase-modulating G protein-coupled receptor signaling pathway | 2.01e-02 |
| MLKL | GO:0060326 | cell chemotaxis | 2.49e-02 |
| MLKL | GO:0032496 | response to lipopolysaccharide | 2.52e-02 |
| MLKL | GO:0002237 | response to molecule of bacterial origin | 2.54e-02 |
| MLKL | GO:0050900 | leukocyte migration | 2.60e-02 |
| MLKL | GO:0042391 | regulation of membrane potential | 2.60e-02 |
| MLKL | GO:0006935 | chemotaxis | 2.60e-02 |
| MLKL | GO:0042330 | taxis | 2.60e-02 |
| MLKL | GO:0050804 | modulation of chemical synaptic transmission | 2.60e-02 |
| MLKL | GO:0099177 | regulation of trans-synaptic signaling | 2.60e-02 |
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Related Drugs to USP7_MLKL |
| Drugs used for this fusion-positive patient. (Manual curation of PubMed, 04-30-2022 + MyCancerGenome) |
| Hgene | Tgene | Drug | Source | PMID |
| Distribution of the number of studies mentioning USP7-MLKL and kinase inhibitors the PubMed Abstract (04-01-2024) |
| Fusion gene - drug pair 1 | Fusion gene - drug pair 2 | PMID | Publication date | DOI | Study title |
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Related Diseases to USP7_MLKL |
| Diseases that have this fusion gene. (Manual curation of PubMed, 04-30-2022 + MyCancerGenome) |
| Hgene | Tgene | Disease | Source | PMID |
| Related diseases from the literature mentioned this fusion gene and drug. (PubMed, 04-01-2024) |
| MeSH ID | MeSH term |
| Diseases associated with fusion partners. (DisGeNet 4.0) |
| Partner | Gene | Disease ID | Disease name | # pubmeds | Source |
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Clinical Trials of the Found Drugs/Small Molecules |
| Statistics of the Clinical Trials of the Found Kinase Inibitors from clinicaltrials.gov (06-17-2024) |
| Clinical Trials from clinicaltrials.gov (06-17-2024) |
| Fusion Gene | Kinase Inhibitor | NCT ID | Study Status | Phases | Disease | # Enrolment | Date |
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