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Center for Computational Systems Medicine
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Kinase Fusion Gene Summary

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Kinase Fusion Gene Sample Information

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Kinase Fusion ORF Analysis

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Kinase Fusion Amino Acid Sequences

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Multiple Sequence Alignment of All Fusion Protein Isoforms

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Kinase Fusion Protein Functional Features

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Kinase Fusion Protein Structures

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Comparison of Fusion Protein Isoforms

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Comparison of Fusion Protein Sequences/Structures with Known Sequences/Structures from PDB

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pLDDT Scores and Difference Analysis of pLDDT Scores Between the Active Sites (Best) and Non-Active Sites.

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Ramachandran Plot of Kinase Fusion Protein Structure

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Potential Active Site Information

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Virtual Screening Results

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Kinase-Substrate Information

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Related Drugs with This Kinase Fusion Protein

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Related Disease with This Kinase Fusion Protein

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Clinical Trials of the Found Drugs/Small Molecules

Kinase Fusion Gene:FRK_XRCC4

Kinase Fusion Protein Summary

check button Kinase Fusion gene summary
Kinase Fusion partner gene informationKinase Fusion gene name: FRK_XRCC4
KinaseFusionDB ID: KFG2427
FusionGDB2.0 ID: KFG2427
HgeneTgene
Gene symbol

FRK

XRCC4

Gene ID

2444

7518

Gene namefyn related Src family tyrosine kinaseX-ray repair cross complementing 4
SynonymsGTK|PTK5|RAKSSMED|hXRCC4
Cytomap

6q22.1

5q14.2

Type of geneprotein-codingprotein-coding
Descriptiontyrosine-protein kinase FRKPTK5 protein tyrosine kinase 5fyn-related kinasenuclear tyrosine protein kinase RAKprotein-tyrosine kinase 5DNA repair protein XRCC4X-ray repair complementing defective repair in Chinese hamster cells 4
Modification date2024041120240305
UniProtAcc

P42685

Q13426

Ensembl transtripts involved in fusion geneENST idsENST00000606080, ENST00000538210, 
ENST00000282268, ENST00000338635, 
ENST00000396027, ENST00000511817, 
ENST00000509268, 
Context (manual curation of fusion genes in KinaseFusionDB)

PubMed: FRK [Title/Abstract] AND XRCC4 [Title/Abstract] AND fusion [Title/Abstract]

Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)
check button Gene ontology of each fusion partner gene with evidence of Inferred from Direct Assay (IDA) from Entrez
PartnerGeneGO IDGO termPubMed ID
HgeneFRK

GO:0000122

negative regulation of transcription by RNA polymerase II

12837246

TgeneXRCC4

GO:0006302

double-strand break repair

9242410

TgeneXRCC4

GO:0006303

double-strand break repair via nonhomologous end joining

12517771|15385968|17290226|25597996|25934149|26774286|27437582|28500754

TgeneXRCC4

GO:0010165

response to X-ray

9242410

TgeneXRCC4

GO:0051103

DNA ligation involved in DNA repair

12517771|15385968|17290226|28453785

TgeneXRCC4

GO:0051351

positive regulation of ligase activity

9242410

TgeneXRCC4

GO:1990166

protein localization to site of double-strand break

31548606


check buttonKinase Fusion gene breakpoints across FRK (5'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.

check buttonKinase Fusion gene breakpoints across XRCC4 (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

check buttonKinase Fusion gene information.
check button 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.
SourceSampleHgeneHchrHbpTgeneTchrTbp
CCLECCLF_UPGI_0040_TFRKchr6

116288714

XRCC4chr5

82648944



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Kinase Fusion ORF Analysis


check buttonKinase Fusion information from ORFfinder translation from full-length transcript sequence from KinaseFusionDB.
HenstTenstHgeneHchrHbpTgeneTchrTbpSeq length
(transcript)
Seq length
(amino acids)
ENST00000606080ENST00000511817FRKchr6116288714XRCC4chr5826489441909289

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Kinase Fusion Amino Acid Sequences


check button 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

>ENST00000606080_ENST00000511817_FRK_chr6_116288714_XRCC4_chr5_82648944_length(amino acids)=289
MSNICQRLWEYLEPYLPCLSTEADKSTVIENPGALCSPQSQRHGHYFVALFDYQARTAEDLSFRAGDKLQVLDTLHEGWWFARHLEKRRD
GSSQQLQGYIPSNYVAEDRSLQAEPWFFGAIGRSDAEKQLLYSENKTGSFLIRESESQKGEFSLSVLDGAVVKHYRIKRLDEGGFFLTRR
RIFSTLNEFVSHYTKTSDGLCVKLGKPCLKIQVPAPFDLSYKTVDQWEIDRNSIQLLKRLGSGQFGEVWEGLWNNTTPVAVKTLKPVLGL

--------------------------------------------------------------

Multiple Sequence Alignment of All Fusion Protein Isoforms



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Kinase Fusion Protein Functional Features


check button Four levels of functional features of fusion genes
Go to FGviewer search page for the most frequent breakpoint (https://ccsmweb.uth.edu/FGviewer/chr6:/chr5:)
- 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.
FGviewer

check buttonMain function of each fusion partner protein. (from UniProt)
HgeneTgene
FRK

P42685

XRCC4

Q13426

FUNCTION: Non-receptor tyrosine-protein kinase that negatively regulates cell proliferation. Positively regulates PTEN protein stability through phosphorylation of PTEN on 'Tyr-336', which in turn prevents its ubiquitination and degradation, possibly by reducing its binding to NEDD4. May function as a tumor suppressor. {ECO:0000269|PubMed:19345329}.FUNCTION: [DNA repair protein XRCC4]: DNA non-homologous end joining (NHEJ) core factor, required for double-strand break repair and V(D)J recombination (PubMed:10757784, PubMed:10854421, PubMed:17124166, PubMed:16412978, PubMed:8548796, PubMed:25742519, PubMed:12517771, PubMed:17290226, PubMed:22228831, PubMed:25597996, PubMed:25934149, PubMed:26100018, PubMed:26774286). Acts as a scaffold protein that regulates recruitment of other proteins to DNA double-strand breaks (DSBs) (PubMed:15385968, PubMed:20852255, PubMed:26774286, PubMed:27437582). Associates with NHEJ1/XLF to form alternating helical filaments that bridge DNA and act like a bandage, holding together the broken DNA until it is repaired (PubMed:26100018, PubMed:27437582, PubMed:28500754, PubMed:21775435, PubMed:22287571, PubMed:21768349). The XRCC4-NHEJ1/XLF subcomplex binds to the DNA fragments of a DSB in a highly diffusive manner and robustly bridges two independent DNA molecules, holding the broken DNA fragments in close proximity to one other (PubMed:27437582). The mobility of the bridges ensures that the ends remain accessible for further processing by other repair factors (PubMed:27437582). Plays a key role in the NHEJ ligation step of the broken DNA during DSB repair via direct interaction with DNA ligase IV (LIG4): the LIG4-XRCC4 subcomplex reseals the DNA breaks after the gap filling is completed (PubMed:9242410, PubMed:10757784, PubMed:10854421, PubMed:12517771, PubMed:17290226, PubMed:19837014). XRCC4 stabilizes LIG4, regulates its subcellular localization and enhances LIG4's joining activity (PubMed:9242410, PubMed:10757784, PubMed:10854421, PubMed:12517771, PubMed:17290226, PubMed:21982441, PubMed:22228831). Binding of the LIG4-XRCC4 subcomplex to DNA ends is dependent on the assembly of the DNA-dependent protein kinase complex DNA-PK to these DNA ends (PubMed:10757784, PubMed:10854421). Promotes displacement of PNKP from processed strand break termini (PubMed:20852255, PubMed:28453785). {ECO:0000269|PubMed:10757784, ECO:0000269|PubMed:10854421, ECO:0000269|PubMed:12517771, ECO:0000269|PubMed:15385968, ECO:0000269|PubMed:16412978, ECO:0000269|PubMed:17124166, ECO:0000269|PubMed:17290226, ECO:0000269|PubMed:19837014, ECO:0000269|PubMed:20852255, ECO:0000269|PubMed:21768349, ECO:0000269|PubMed:21775435, ECO:0000269|PubMed:21982441, ECO:0000269|PubMed:22228831, ECO:0000269|PubMed:22287571, ECO:0000269|PubMed:25597996, ECO:0000269|PubMed:25742519, ECO:0000269|PubMed:25934149, ECO:0000269|PubMed:26100018, ECO:0000269|PubMed:26774286, ECO:0000269|PubMed:27437582, ECO:0000269|PubMed:28453785, ECO:0000269|PubMed:28500754, ECO:0000269|PubMed:8548796, ECO:0000269|PubMed:9242410}.; FUNCTION: [Protein XRCC4, C-terminus]: Acts as an activator of the phospholipid scramblase activity of XKR4 (PubMed:33725486). This form, which is generated upon caspase-3 (CASP3) cleavage, translocates into the cytoplasm and interacts with XKR4, thereby promoting phosphatidylserine scramblase activity of XKR4 and leading to phosphatidylserine exposure on apoptotic cell surface (PubMed:33725486). {ECO:0000269|PubMed:33725486}.

check buttonRetention 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

download page

* Minus value of BPloci means that the break pointn is located before the CDS.

check button - Retained domain in the 5'-partner of fusion protein (protein functional feature from UniProt).
266266
PartnerHgeneeneHbpTgeneeneTbpENSTBPexonTotalExonProtein feature lociBPlociTotalLenFeatureNote
HgeneFRK116288714XRCC482648944ENST0000060608048116_2081506DomainNote=SH2;Ontology_term=ECO:0000255;evidence=ECO:0000255|PROSITE-ProRule:PRU00191
HgeneFRK116288714XRCC482648944ENST000006060804842_1101506DomainNote=SH3;Ontology_term=ECO:0000255;evidence=ECO:0000255|PROSITE-ProRule:PRU00192


check button - Retained domain in the 3'-partner of fusion protein (protein functional feature from UniProt).
PartnerHgeneeneHbpTgeneeneTbpENSTBPexonTotalExonProtein feature lociBPlociTotalLenFeatureNote


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Kinase Fusion Protein Structures

check button CIF files of the predicted kinase fusion proteins
* Here we show the 3D structure of the fusion proteins using Mol*. AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. Model confidence is shown from the pLDDT values per residue. pLDDT corresponds to the model’s prediction of its score on the local Distance Difference Test. It is a measure of local accuracy (from AlphfaFold website). To color code individual residues, we transformed individual PDB files into CIF format.
Kinase Fusion protein CIF link (fusion AA seq ID in KinaseFusionDB)HenstTenstHgeneHchrHbpTgeneTchrTbpAA seqLen(AA seq)
PDB file >>>127_FRK_XRCC4ENST00000606080ENST00000511817FRKchr6116288714XRCC4chr582648944
MSNICQRLWEYLEPYLPCLSTEADKSTVIENPGALCSPQSQRHGHYFVALFDYQARTAEDLSFRAGDKLQVLDTLHEGWWFARHLEKRRD
GSSQQLQGYIPSNYVAEDRSLQAEPWFFGAIGRSDAEKQLLYSENKTGSFLIRESESQKGEFSLSVLDGAVVKHYRIKRLDEGGFFLTRR
RIFSTLNEFVSHYTKTSDGLCVKLGKPCLKIQVPAPFDLSYKTVDQWEIDRNSIQLLKRLGSGQFGEVWEGLWNNTTPVAVKTLKPVLGL
289
3D view using mol* of 127_FRK_XRCC4
PDB file >>>HKFP_186_FRK_XRCC4ENST00000606080ENST00000511817FRKchr6116288714XRCC4chr582648944
MSNICQRLWEYLEPYLPCLSTEADKSTVIENPGALCSPQSQRHGHYFVALFDYQARTAEDLSFRAGDKLQVLDTLHEGWWFARHLEKRRD
GSSQQLQGYIPSNYVAEDRSLQAEPWFFGAIGRSDAEKQLLYSENKTGSFLIRESESQKGEFSLSVLDGAVVKHYRIKRLDEGGFFLTRR
RIFSTLNEFVSHYTKTSDGLCVKLGKPCLKIQVPAPFDLSYKTVDQWEIDRNSIQLLKRLGSGQFGEVWEGLWNNTTPVAVKTLKPVLGL
289_FRK_XRCC4


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Comparison of Fusion Protein Isoforms

check button Superimpose the 3D Structures Among All Fusion Protein Isoforms
* Download the pdb file and open it from the molstar online viewer.

check button Comparison of the Secondary Structures of Fusion Protein Isoforms

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Comparison of Fusion Protein Sequences/Structures with Known Sequences/Structures from PDB

FRK_XRCC4 does not have any known PDB structures.

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pLDDT score distribution

check button pLDDT score distribution of the predicted fusion protein structures from AlphaFold2
* AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100.
* The blue color at the bottom marks the best active site residues.
127_FRK_XRCC4.png
all structure sitemap plddt 127_FRK_XRCC4.png
127_FRK_XRCC4.png
all structure sitemap plddt2 127_FRK_XRCC4.png


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Potential Active Site Information


check button The potential binding sites of these fusion proteins were identified using SiteMap, a module of the Schrodinger suite.
Kinase Fusion AA seq ID in KinaseFusionDBSite scoreSizeDscoreVolumeExposureEnclosureContactPhobicPhilicBalanceDon/AccResidues

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Ramachandran Plot of Kinase Fusion Protein Structure


check button Ramachandran plot of the torsional angles - phi (φ)and psi (ψ) - of the residues (amino acids) contained in this fusion protein peptide.

127_FRK_XRCC4_ramachandran.png
all structure FRK-XRCC4

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Virtual Screening Results


check button Distribution of the average docking score across all approved kinase inhibitors.
Distribution of the number of occurrence across all approved kinase inhibitors.
5'-kinase fusion protein case
all structure FRK-XRCC4
3'-kinase fusion protein case

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check button Drug information from DrugBank of the top 20 interacting small molecules.
* The detailed information of individual kinase inhibitors are available in the download page.
Fusion gene name infoDrugDocking scoreGlide g scoreGlide energy
127_FRK_XRCC4-DOCK_HTVS_1-001Lapatinib-7.86423-7.95303-66.5362
127_FRK_XRCC4-DOCK_HTVS_1-001Belumosudil-7.6405199999999995-7.648219999999999-54.1619
127_FRK_XRCC4-DOCK_HTVS_1-001Osimertinib-7.4747-7.4824-60.1601
127_FRK_XRCC4-DOCK_HTVS_1-001Ponatinib-7.25357-8.00827-55.7868
127_FRK_XRCC4-DOCK_HTVS_1-001Ponatinib-7.25357-8.00827-55.7868
127_FRK_XRCC4-DOCK_HTVS_1-001Ponatinib-7.25357-8.00827-55.7868
127_FRK_XRCC4-DOCK_HTVS_1-001Afatinib-7.247539999999999-7.4298399999999996-53.863
127_FRK_XRCC4-DOCK_HTVS_1-001Afatinib-7.247539999999999-7.4298399999999996-53.863
127_FRK_XRCC4-DOCK_HTVS_1-001Afatinib-7.24614-7.4298399999999996-53.863
127_FRK_XRCC4-DOCK_HTVS_1-001Belumosudil-7.182810000000001-7.190510000000001-52.3808
127_FRK_XRCC4-DOCK_HTVS_1-001Cabozantinib-7.157589999999999-7.20259-52.0787
127_FRK_XRCC4-DOCK_HTVS_1-001Cabozantinib-7.157589999999999-7.20259-52.0787
127_FRK_XRCC4-DOCK_HTVS_1-001Mobocertinib-7.0991100000000005-7.10681-58.2986
127_FRK_XRCC4-DOCK_HTVS_1-001Ponatinib-7.05057-7.2571699999999995-47.8522
127_FRK_XRCC4-DOCK_HTVS_1-001Ponatinib-7.05057-7.2571699999999995-47.8522
127_FRK_XRCC4-DOCK_HTVS_1-001Ponatinib-7.05057-7.2571699999999995-47.8522
127_FRK_XRCC4-DOCK_HTVS_1-001Lapatinib-7.042889999999999-7.131689999999999-65.6881
127_FRK_XRCC4-DOCK_HTVS_1-001Larotrectinib-6.8681399999999995-6.8681399999999995-43.621
127_FRK_XRCC4-DOCK_HTVS_1-001Neratinib-6.83812-7.02402-28.473000000000003
127_FRK_XRCC4-DOCK_HTVS_1-001Dacomitinib-6.805860000000001-6.914160000000001-48.6029

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Kinase-Substrate Information of FRK_XRCC4


check button Phosphorylation target of the kinase
(phosphosite, 03-17-2024)
KinaseKinase UniProt AccKinase speciesSubstrateSubstrate UniProt AccSubstrate phosphorylated residuesSubstrate phosphorylated sites (+/-7AA)Domain
FRKP42685humanYAP1P46937Y407sGLsMsSySVPRtPD
FRKP42685humanBRCA1P38398Y1552HDLtEtSyLPRQDLE
FRKP42685humanYAP1P46937Y444QQNRFPDyLEAIPGT
FRKP42685humanYAP1P46937Y391PFLNsGtyHSRDEst
FRKP42685humanPTENP60484Y336NKDkANRyFSPNFKVPTEN_C2


check button Biological Network Integration of This Kinase and Substrates
(GeneMANIA website)

check button Enriched GO biological processes of the phosphorylation target genes of the kinase
KinaseGOIDGO termP.adjust
FRKIDDescription0.00e+00
FRKGO:2001236regulation of extrinsic apoptotic signaling pathway3.04e-04
FRKGO:0097191extrinsic apoptotic signaling pathway4.65e-04
FRKGO:0071214cellular response to abiotic stimulus7.24e-04
FRKGO:0104004cellular response to environmental stimulus7.24e-04
FRKGO:2001233regulation of apoptotic signaling pathway8.80e-04
FRKGO:0033146regulation of intracellular estrogen receptor signaling pathway8.80e-04
FRKGO:1902116negative regulation of organelle assembly1.31e-03
FRKGO:1902041regulation of extrinsic apoptotic signaling pathway via death domain receptors1.36e-03
FRKGO:0030520intracellular estrogen receptor signaling pathway1.41e-03
FRKGO:0071479cellular response to ionizing radiation2.12e-03
FRKGO:0033143regulation of intracellular steroid hormone receptor signaling pathway2.12e-03
FRKGO:0008625extrinsic apoptotic signaling pathway via death domain receptors2.70e-03
FRKGO:0046620regulation of organ growth3.07e-03
FRKGO:2001237negative regulation of extrinsic apoptotic signaling pathway3.07e-03
FRKGO:0031398positive regulation of protein ubiquitination3.54e-03
FRKGO:0030518intracellular steroid hormone receptor signaling pathway4.08e-03
FRKGO:1903322positive regulation of protein modification by small protein conjugation or removal4.40e-03
FRKGO:0010212response to ionizing radiation4.40e-03
FRKGO:0043401steroid hormone mediated signaling pathway4.40e-03
FRKGO:1901875positive regulation of post-translational protein modification5.55e-03
FRKGO:0035265organ growth6.53e-03
FRKGO:0071478cellular response to radiation6.53e-03
FRKGO:0031345negative regulation of cell projection organization6.74e-03
FRKGO:0009755hormone-mediated signaling pathway6.74e-03
FRKGO:1901991negative regulation of mitotic cell cycle phase transition6.74e-03
FRKGO:0031396regulation of protein ubiquitination6.75e-03
FRKGO:0071383cellular response to steroid hormone stimulus7.03e-03
FRKGO:1902115regulation of organelle assembly7.44e-03
FRKGO:1903320regulation of protein modification by small protein conjugation or removal8.17e-03
FRKGO:2001234negative regulation of apoptotic signaling pathway8.17e-03
FRKGO:0033002muscle cell proliferation8.17e-03
FRKGO:0045926negative regulation of growth8.17e-03
FRKGO:0045930negative regulation of mitotic cell cycle8.17e-03
FRKGO:1901988negative regulation of cell cycle phase transition9.89e-03
FRKGO:1901873regulation of post-translational protein modification1.01e-02
FRKGO:0060070canonical Wnt signaling pathway1.19e-02
FRKGO:0010948negative regulation of cell cycle process1.19e-02
FRKGO:0060485mesenchyme development1.19e-02
FRKGO:0048638regulation of developmental growth1.19e-02
FRKGO:0048545response to steroid hormone1.19e-02
FRKGO:0030522intracellular receptor signaling pathway1.31e-02
FRKGO:1901990regulation of mitotic cell cycle phase transition1.31e-02
FRKGO:0010639negative regulation of organelle organization1.34e-02
FRKGO:0050767regulation of neurogenesis1.45e-02
FRKGO:0045786negative regulation of cell cycle1.45e-02
FRKGO:0140694non-membrane-bounded organelle assembly1.45e-02
FRKGO:0001558regulation of cell growth1.45e-02
FRKGO:0042060wound healing1.45e-02
FRKGO:0007059chromosome segregation1.45e-02

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Related Drugs to FRK_XRCC4


check button Drugs used for this fusion-positive patient.
(Manual curation of PubMed, 04-30-2022 + MyCancerGenome)
HgeneTgeneDrugSourcePMID

check button Distribution of the number of studies mentioning FRK-XRCC4 and kinase inhibitors the PubMed Abstract (04-01-2024)

Fusion gene - drug pair 1Fusion gene - drug pair 2PMIDPublication dateDOIStudy title

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Related Diseases to FRK_XRCC4


check button Diseases that have this fusion gene.
(Manual curation of PubMed, 04-30-2022 + MyCancerGenome)
HgeneTgeneDiseaseSourcePMID

check button Related diseases from the literature mentioned this fusion gene and drug.
(PubMed, 04-01-2024)
MeSH IDMeSH term

check button Diseases associated with fusion partners.
(DisGeNet 4.0)
PartnerGeneDisease IDDisease name# pubmedsSource


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Clinical Trials of the Found Drugs/Small Molecules


check button Statistics of the Clinical Trials of the Found Kinase Inibitors from clinicaltrials.gov (06-17-2024)

check button Clinical Trials from clinicaltrials.gov (06-17-2024)

Fusion GeneKinase InhibitorNCT IDStudy StatusPhasesDisease# EnrolmentDate