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Kinase Fusion Gene:TCF7L2_GRK5 |
Kinase Fusion Protein Summary |
 Kinase Fusion gene summary |
| Kinase Fusion partner gene information | Kinase Fusion gene name: TCF7L2_GRK5 | KinaseFusionDB ID: KFG6458 | FusionGDB2.0 ID: KFG6458 | Hgene | Tgene | Gene symbol | TCF7L2 | GRK5 | Gene ID | 6934 | 2869 | |
| Gene name | transcription factor 7 like 2 | G protein-coupled receptor kinase 5 | ||||||||||
| Synonyms | TCF-4|TCF4 | FP2025|GPRK5 | ||||||||||
| Cytomap | 10q25.2-q25.3 | 10q26.11 | ||||||||||
| Type of gene | protein-coding | protein-coding | ||||||||||
| Description | transcription factor 7-like 2HMG box transcription factor 4T-cell factor 4T-cell-specific transcription factor 4hTCF-4transcription factor 7-like 2 (T-cell specific, HMG-box) | G protein-coupled receptor kinase 5g protein-coupled receptor kinase GRK5 | ||||||||||
| Modification date | 20240413 | 20240305 | ||||||||||
| UniProtAcc | Q9NQB0 | P34947 | ||||||||||
| Ensembl transtripts involved in fusion gene | ENST ids | ENST00000349937, ENST00000355995, ENST00000534894, ENST00000536810, ENST00000538897, ENST00000543371, ENST00000545257, ENST00000352065, ENST00000355717, ENST00000369386, ENST00000369389, ENST00000369395, ENST00000369397, ENST00000466338, ENST00000542695, | ENST00000473264, ENST00000369108, ENST00000392870, | |||||||||
| Context (manual curation of fusion genes in KinaseFusionDB) | PubMed: TCF7L2 [Title/Abstract] AND GRK5 [Title/Abstract] AND fusion [Title/Abstract] | |||||||||||
| Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0) | TCF7L2(114724383)-GRK5(121207635), # samples:1 | |||||||||||
| 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 | TCF7L2 | GO:0000122 | negative regulation of transcription by RNA polymerase II | 12799378 |
| Hgene | TCF7L2 | GO:0006357 | regulation of transcription by RNA polymerase II | 9727977 |
| Hgene | TCF7L2 | GO:0032092 | positive regulation of protein binding | 12799378 |
| Hgene | TCF7L2 | GO:0032350 | regulation of hormone metabolic process | 15525634 |
| Hgene | TCF7L2 | GO:0042593 | glucose homeostasis | 15525634 |
| Hgene | TCF7L2 | GO:0043433 | negative regulation of DNA-binding transcription factor activity | 12799378 |
| Hgene | TCF7L2 | GO:0045444 | fat cell differentiation | 10937998 |
| Hgene | TCF7L2 | GO:0045892 | negative regulation of DNA-templated transcription | 12799378|15525634 |
| Hgene | TCF7L2 | GO:0045944 | positive regulation of transcription by RNA polymerase II | 9065401|19168596 |
| Hgene | TCF7L2 | GO:0048625 | myoblast fate commitment | 10937998 |
| Tgene | GRK5 | GO:0007217 | tachykinin receptor signaling pathway | 17986524 |
| Tgene | GRK5 | GO:0043066 | negative regulation of apoptotic process | 20124405 |
| Tgene | GRK5 | GO:0046777 | protein autophosphorylation | 14976207 |
| Kinase Fusion gene breakpoints across TCF7L2 (5'-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 breakpoints across GRK5 (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 |
| ChimerDB4 | TCGA-AA-3837-01A | TCF7L2 | chr10 | 114724383 | GRK5 | chr10 | 121207635 |
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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) |
| ENST00000534894 | ENST00000392870 | TCF7L2 | chr10 | 114724383 | GRK5 | chr10 | 121207635 | 2016 | 428 |
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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 >ENST00000534894_ENST00000392870_TCF7L2_chr10_114724383_GRK5_chr10_121207635_length(amino acids)=428 MTSCCCWCFFFFYPPFLFIIFLHIDRILGNERKKKPKLTRAEDLPPLPLPSSLFSPPQEKKTPKQKKVHLGLVFFLQYFLGGQNFLGVIF FGFSSSFIFLPKLLLVGEKKMPQLNGGGGDDLGANDELISFKDEGEQEEKSSENSSAERDLADVKSSLVNESETNQNSSSDSEAERRPPP RSESFRDKSRESLEEAAKRQDGGLFKGPPYPGYPFIMIPDLTSPYLPNGSLSPTARTLHFQSGSTHYSAYKTIEHQIAVQLLTKDAKQRL GCQEEGAAEVKRHPFFRNMNFKRLEAGMLDPPFVPDPRAVYCKDVLDIEQFSTVKGVNLDHTDDDFYSKFSTGSVSIPWQNEMIETECFK -------------------------------------------------------------- |
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/chr10:114724383/chr10:121207635) - 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 |
| TCF7L2 | GRK5 |
| FUNCTION: Participates in the Wnt signaling pathway and modulates MYC expression by binding to its promoter in a sequence-specific manner. Acts as a repressor in the absence of CTNNB1, and as activator in its presence. Activates transcription from promoters with several copies of the Tcf motif 5'-CCTTTGATC-3' in the presence of CTNNB1. TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by TCF7L2/TCF4 and CTNNB1. Expression of dominant-negative mutants results in cell-cycle arrest in G1. Necessary for the maintenance of the epithelial stem-cell compartment of the small intestine. {ECO:0000269|PubMed:12408868, ECO:0000269|PubMed:12727872, ECO:0000269|PubMed:19443654, ECO:0000269|PubMed:22699938, ECO:0000269|PubMed:9727977}. | FUNCTION: Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein-coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70-interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt signaling (in vitro). {ECO:0000269|PubMed:19661922, ECO:0000269|PubMed:19801552, ECO:0000269|PubMed:20038610, ECO:0000269|PubMed:20124405, ECO:0000269|PubMed:21728385}. |
| 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 |
| Tgene | TCF7L2 | 114724383 | GRK5 | 121207635 | ENST00000534894 | 11 | 16 | 449_514 | 422 | 591 | Domain | Note=AGC-kinase C-terminal;Ontology_term=ECO:0000255;evidence=ECO:0000255|PROSITE-ProRule:PRU00618 |
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Kinase Fusion Protein Structures |
| 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) | Henst | Tenst | Hgene | Hchr | Hbp | Tgene | Tchr | Tbp | AA seq | Len(AA seq) |
| PDB file >>>495_TCF7L2_GRK5 | ENST00000534894 | ENST00000392870 | TCF7L2 | chr10 | 114724383 | GRK5 | chr10 | 121207635 | MTSCCCWCFFFFYPPFLFIIFLHIDRILGNERKKKPKLTRAEDLPPLPLPSSLFSPPQEKKTPKQKKVHLGLVFFLQYFLGGQNFLGVIF FGFSSSFIFLPKLLLVGEKKMPQLNGGGGDDLGANDELISFKDEGEQEEKSSENSSAERDLADVKSSLVNESETNQNSSSDSEAERRPPP RSESFRDKSRESLEEAAKRQDGGLFKGPPYPGYPFIMIPDLTSPYLPNGSLSPTARTLHFQSGSTHYSAYKTIEHQIAVQLLTKDAKQRL GCQEEGAAEVKRHPFFRNMNFKRLEAGMLDPPFVPDPRAVYCKDVLDIEQFSTVKGVNLDHTDDDFYSKFSTGSVSIPWQNEMIETECFK | 428 |
| 3D view using mol* of 495_TCF7L2_GRK5 | ||||||||||
| PDB file >>>TKFP_833_TCF7L2_GRK5 | ENST00000534894 | ENST00000392870 | TCF7L2 | chr10 | 114724383 | GRK5 | chr10 | 121207635 | MTSCCCWCFFFFYPPFLFIIFLHIDRILGNERKKKPKLTRAEDLPPLPLPSSLFSPPQEKKTPKQKKVHLGLVFFLQYFLGGQNFLGVIF FGFSSSFIFLPKLLLVGEKKMPQLNGGGGDDLGANDELISFKDEGEQEEKSSENSSAERDLADVKSSLVNESETNQNSSSDSEAERRPPP RSESFRDKSRESLEEAAKRQDGGLFKGPPYPGYPFIMIPDLTSPYLPNGSLSPTARTLHFQSGSTHYSAYKTIEHQIAVQLLTKDAKQRL GCQEEGAAEVKRHPFFRNMNFKRLEAGMLDPPFVPDPRAVYCKDVLDIEQFSTVKGVNLDHTDDDFYSKFSTGSVSIPWQNEMIETECFK | 428_TCF7L2_GRK5 |
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Comparison of Fusion Protein Isoforms |
| Superimpose the 3D Structures Among All Fusion Protein Isoforms * Download the pdb file and open it from the molstar online viewer. |
| 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 |
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pLDDT score distribution |
| 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. |
| 495_TCF7L2_GRK5.png |
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| 495_TCF7L2_GRK5.png |
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Potential Active Site Information |
| The potential binding sites of these fusion proteins were identified using SiteMap, a module of the Schrodinger suite. |
| Kinase Fusion AA seq ID in KinaseFusionDB | Site score | Size | Dscore | Volume | Exposure | Enclosure | Contact | Phobic | Philic | Balance | Don/Acc | Residues |
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Ramachandran Plot of Kinase Fusion Protein Structure |
| Ramachandran plot of the torsional angles - phi (φ)and psi (ψ) - of the residues (amino acids) contained in this fusion protein peptide. |
| 495_TCF7L2_GRK5_ramachandran.png |
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Virtual Screening Results |
| 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 |
| 3'-kinase fusion protein case |
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| 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 info | Drug | Docking score | Glide g score | Glide energy |
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Kinase-Substrate Information of TCF7L2_GRK5 |
| 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 |
| GRK5 | P34947 | human | ADRB2 | P07550 | S396 | GHQGtVPsDNIDsQG | |
| GRK5 | P34947 | human | MSN | P26038 | T66 | LkLNKkVtAQDVrkE | FERM_N |
| GRK5 | P34947 | human | GRK5 | P34947 | T485 | LDIEQFstVkGVNLD | |
| GRK5 | P34947 | human | GPBAR1 | Q8TDU6 | S324 | YHPSsQssVDLDLN_ | |
| GRK5 | P34947 | human | ST13 | P50502 | S346 | AQNPANMskYQsNPk | STI1 |
| GRK5 | P34947 | human | GPBAR1 | Q8TDU6 | S323 | AYHPSsQssVDLDLN | |
| GRK5 | P34947 | human | ADRB2 | P07550 | S407 | DsQGRNCstNDsLL_ | |
| GRK5 | P34947 | human | FZD6 | O60353 | S648 | sVSESARsEGRIsPK | |
| GRK5 | P34947 | human | GRK5 | P34947 | T10 | LENIVANtVLLkARE | |
| GRK5 | P34947 | human | SNCA | P37840 | S129 | NEAyEMPsEEGyQDy | Synuclein |
| GRK5 | P34947 | human | ADRB2 | P07550 | S411 | RNCstNDsLL_____ | |
| GRK5 | P34947 | human | ADRB2 | P07550 | S355 | KAyGNGyssNGNtGE | |
| GRK5 | P34947 | human | ADRB2 | P07550 | T393 | DFVGHQGtVPsDNID | |
| GRK5 | P34947 | human | GPBAR1 | Q8TDU6 | S321 | SIAYHPSsQssVDLD | |
| GRK5 | P34947 | human | GPBAR1 | Q8TDU6 | S310 | WGRASRDsPGPSIAY | |
| GRK5 | P34947 | human | ADRB2 | P07550 | S401 | VPsDNIDsQGRNCst | |
| GRK5 | P34947 | human | ADRB2 | P07550 | S356 | AyGNGyssNGNtGEQ | |
| GRK5 | P34947 | human | ADRB2 | P07550 | T384 | LCEDLPGtEDFVGHQ | |
| GRK5 | P34947 | human | GRK5 | P34947 | S484 | VLDIEQFstVkGVNL | |
| GRK5 | P34947 | human | HDAC6 | Q9UBN7 | S22 | RsRQNPQsPPQDSsV | |
| GRK5 | P34947 | human | TP53 | P04637 | T55 | DDIEQWFtEDPGPDE | TAD2 |
| 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 |
| GRK5 | ID | Description | 0.00e+00 |
| GRK5 | GO:0061912 | selective autophagy | 6.42e-03 |
| GRK5 | GO:0010506 | regulation of autophagy | 6.42e-03 |
| GRK5 | GO:0043254 | regulation of protein-containing complex assembly | 6.42e-03 |
| GRK5 | GO:0010310 | regulation of hydrogen peroxide metabolic process | 6.42e-03 |
| GRK5 | GO:0008277 | regulation of G protein-coupled receptor signaling pathway | 6.42e-03 |
| GRK5 | GO:2000377 | regulation of reactive oxygen species metabolic process | 6.42e-03 |
| GRK5 | GO:0016241 | regulation of macroautophagy | 6.96e-03 |
| GRK5 | GO:0051354 | negative regulation of oxidoreductase activity | 9.57e-03 |
| GRK5 | GO:0031334 | positive regulation of protein-containing complex assembly | 9.57e-03 |
| GRK5 | GO:2000273 | positive regulation of signaling receptor activity | 9.57e-03 |
| GRK5 | GO:0031111 | negative regulation of microtubule polymerization or depolymerization | 1.07e-02 |
| GRK5 | GO:0000423 | mitophagy | 1.07e-02 |
| GRK5 | GO:0072593 | reactive oxygen species metabolic process | 1.07e-02 |
| GRK5 | GO:0045861 | negative regulation of proteolysis | 1.07e-02 |
| GRK5 | GO:1903146 | regulation of autophagy of mitochondrion | 1.07e-02 |
| GRK5 | GO:0045926 | negative regulation of growth | 1.07e-02 |
| GRK5 | GO:0045444 | fat cell differentiation | 1.07e-02 |
| GRK5 | GO:0034599 | cellular response to oxidative stress | 1.10e-02 |
| GRK5 | GO:1900542 | regulation of purine nucleotide metabolic process | 1.10e-02 |
| GRK5 | GO:0006140 | regulation of nucleotide metabolic process | 1.10e-02 |
| GRK5 | GO:0031648 | protein destabilization | 1.10e-02 |
| GRK5 | GO:2000378 | negative regulation of reactive oxygen species metabolic process | 1.10e-02 |
| GRK5 | GO:0042743 | hydrogen peroxide metabolic process | 1.22e-02 |
| GRK5 | GO:0045744 | negative regulation of G protein-coupled receptor signaling pathway | 1.22e-02 |
| GRK5 | GO:0062197 | cellular response to chemical stress | 1.50e-02 |
| GRK5 | GO:0031647 | regulation of protein stability | 1.55e-02 |
| GRK5 | GO:0016236 | macroautophagy | 1.58e-02 |
| GRK5 | GO:2000379 | positive regulation of reactive oxygen species metabolic process | 1.66e-02 |
| GRK5 | GO:0010639 | negative regulation of organelle organization | 1.92e-02 |
| GRK5 | GO:0051341 | regulation of oxidoreductase activity | 2.25e-02 |
| GRK5 | GO:0006979 | response to oxidative stress | 2.39e-02 |
| GRK5 | GO:0010507 | negative regulation of autophagy | 2.46e-02 |
| GRK5 | GO:0051262 | protein tetramerization | 2.46e-02 |
| GRK5 | GO:0001738 | morphogenesis of a polarized epithelium | 2.50e-02 |
| GRK5 | GO:0031110 | regulation of microtubule polymerization or depolymerization | 2.58e-02 |
| GRK5 | GO:0000422 | autophagy of mitochondrion | 2.60e-02 |
| GRK5 | GO:0061726 | mitochondrion disassembly | 2.60e-02 |
| GRK5 | GO:0033138 | positive regulation of peptidyl-serine phosphorylation | 2.85e-02 |
| GRK5 | GO:0060079 | excitatory postsynaptic potential | 2.94e-02 |
| GRK5 | GO:0010469 | regulation of signaling receptor activity | 2.96e-02 |
| GRK5 | GO:0043086 | negative regulation of catalytic activity | 2.96e-02 |
| GRK5 | GO:0048640 | negative regulation of developmental growth | 2.96e-02 |
| GRK5 | GO:0099565 | chemical synaptic transmissio | 1.29e-03 |
| GRK5 | GO:0099177 | regulation of trans-synaptic signaling | 2.96e-02 |
| GRK5 | GO:0022411 | cellular component disassembly | 3.02e-02 |
| GRK5 | GO:0007006 | mitochondrial membrane organization | 3.06e-02 |
| GRK5 | GO:0043244 | regulation of protein-containing complex disassembly | 3.14e-02 |
| GRK5 | GO:0031109 | microtubule polymerization or depolymerization | 3.65e-02 |
| GRK5 | GO:0033135 | regulation of peptidyl-serine phosphorylation | 3.75e-02 |
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Related Drugs to TCF7L2_GRK5 |
| 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 TCF7L2-GRK5 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 TCF7L2_GRK5 |
| 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 |
| Hgene | TCF7L2 | C0036341 | Schizophrenia | 4 | PSYGENET |
| Hgene | TCF7L2 | C0011860 | Diabetes Mellitus, Non-Insulin-Dependent | 3 | CTD_human |
| Hgene | TCF7L2 | C0009402 | Colorectal Carcinoma | 2 | CTD_human;UNIPROT |
| Hgene | TCF7L2 | C0009404 | Colorectal Neoplasms | 2 | CTD_human |
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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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