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Kinase Fusion Gene:GRHL2_MAP2K2 |
Kinase Fusion Protein Summary |
 Kinase Fusion gene summary |
| Kinase Fusion partner gene information | Kinase Fusion gene name: GRHL2_MAP2K2 | KinaseFusionDB ID: KFG2551 | FusionGDB2.0 ID: KFG2551 | Hgene | Tgene | Gene symbol | GRHL2 | MAP2K2 | Gene ID | 79977 | 5605 | |
| Gene name | grainyhead like transcription factor 2 | mitogen-activated protein kinase kinase 2 | ||||||||||
| Synonyms | BOM|DFNA28|ECTDS|PPCD4|TFCP2L3 | CFC4|MAPKK2|MEK2|MKK2|PRKMK2 | ||||||||||
| Cytomap | 8q22.3 | 19p13.3 | ||||||||||
| Type of gene | protein-coding | protein-coding | ||||||||||
| Description | grainyhead-like protein 2 homologbrother of mammalian grainyheadbrother-of-MGRgrainyhead-like 2transcription factor CP2-like 3 | dual specificity mitogen-activated protein kinase kinase 2ERK activator kinase 2MAP kinase kinase 2MAPK/ERK kinase 2mitogen-activated protein kinase kinase 2, p45 | ||||||||||
| Modification date | 20240403 | 20240411 | ||||||||||
| UniProtAcc | Q6ISB3 | P36507 | ||||||||||
| Ensembl transtripts involved in fusion gene | ENST ids | ENST00000251808, ENST00000395927, ENST00000517674, | ENST00000262948, ENST00000394867, ENST00000599345, | |||||||||
| Context (manual curation of fusion genes in KinaseFusionDB) | PubMed: GRHL2 [Title/Abstract] AND MAP2K2 [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 | GRHL2 | GO:0006357 | regulation of transcription by RNA polymerase II | 23254293 |
| Hgene | GRHL2 | GO:0030216 | keratinocyte differentiation | 23254293 |
| Hgene | GRHL2 | GO:0045944 | positive regulation of transcription by RNA polymerase II | 23814079 |
| Tgene | MAP2K2 | GO:0036289 | peptidyl-serine autophosphorylation | 8388392 |
| Tgene | MAP2K2 | GO:0071902 | positive regulation of protein serine/threonine kinase activity | 8388392 |
| Kinase Fusion gene breakpoints across GRHL2 (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 MAP2K2 (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 | LS1034 | GRHL2 | chr8 | 102565010 | MAP2K2 | chr19 | 4117627 |
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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) |
| ENST00000251808 | ENST00000262948 | GRHL2 | chr8 | 102565010 | MAP2K2 | chr19 | 4117627 | 2010 | 500 |
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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 >ENST00000251808_ENST00000262948_GRHL2_chr8_102565010_MAP2K2_chr19_4117627_length(amino acids)=500 MPSRALSHTFTCTDLKVQFHQRLRLQEKRSKFIGSNMSQESDNNKRLVALVPMPSDPPFNTRRAYTSEDEAWKSYLENPLTAATKAMMSI NGDEDSAAALGLLYDYYKVPRDKRLLSVSKASDSQEDQEKRANLVDLQKKLEELELDEQQKKRLEAFLTQKAKVGELKDDDFERISELGA GNGGVVTKVQHRPSGLIMARKLIHLEIKPAIRNQIIRELQVLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKEAKRIPEEIL GKVSIAVLRGLAYLREKHQIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMAPERLQGTHYSVQSDIWSMGLSLVEL AVGRYPIPPPDAKELEAIFGRPVVDGEEGEPHSISPRPRPPGRPVSGHGMDSRPAMAIFELLDYIVNEPPPKLPNGVFTPDFQEFVNKCL -------------------------------------------------------------- |
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/chr8:/chr19:) - 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 |
| GRHL2 | MAP2K2 |
| FUNCTION: Transcription factor playing an important role in primary neurulation and in epithelial development (PubMed:29309642, PubMed:25152456). Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' acting as an activator and repressor on distinct target genes (By similarity). During embryogenesis, plays unique and cooperative roles with GRHL3 in establishing distinct zones of primary neurulation. Essential for closure 3 (rostral end of the forebrain), functions cooperatively with GRHL3 in closure 2 (forebrain/midbrain boundary) and posterior neuropore closure (By similarity). Regulates epithelial morphogenesis acting as a target gene-associated transcriptional activator of apical junctional complex components. Up-regulates of CLDN3 and CLDN4, as well as of RAB25, which increases the CLDN4 protein and its localization at tight junctions (By similarity). Comprises an essential component of the transcriptional machinery that establishes appropriate expression levels of CLDN4 and CDH1 in different types of epithelia. Exhibits functional redundancy with GRHL3 in epidermal morphogenetic events and epidermal wound repair (By similarity). In lung, forms a regulatory loop with NKX2-1 that coordinates lung epithelial cell morphogenesis and differentiation (By similarity). In keratinocytes, plays a role in telomerase activation during cellular proliferation, regulates TERT expression by binding to TERT promoter region and inhibiting DNA methylation at the 5'-CpG island, possibly by interfering with DNMT1 enzyme activity (PubMed:19015635, PubMed:20938050). In addition, impairs keratinocyte differentiation and epidermal function by inhibiting the expression of genes clustered at the epidermal differentiation complex (EDC) as well as GRHL1 and GRHL3 through epigenetic mechanisms (PubMed:23254293). {ECO:0000250|UniProtKB:Q8K5C0, ECO:0000269|PubMed:19015635, ECO:0000269|PubMed:20938050, ECO:0000269|PubMed:20978075, ECO:0000269|PubMed:23254293, ECO:0000269|PubMed:25152456, ECO:0000269|PubMed:29309642, ECO:0000305|PubMed:12175488}. | FUNCTION: Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity). Activates BRAF in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF dimerization and BRAF activation (PubMed:29433126). {ECO:0000250|UniProtKB:Q63932, ECO:0000269|PubMed:29433126}. |
| 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 | GRHL2 | 102565010 | MAP2K2 | 4117627 | ENST00000251808 | 0 | 11 | 72_369 | 30 | 401 | Domain | Note=Protein kinase;Ontology_term=ECO:0000255;evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
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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 >>>TKFP_392_GRHL2_MAP2K2 | ENST00000251808 | ENST00000262948 | GRHL2 | chr8 | 102565010 | MAP2K2 | chr19 | 4117627 | MPSRALSHTFTCTDLKVQFHQRLRLQEKRSKFIGSNMSQESDNNKRLVALVPMPSDPPFNTRRAYTSEDEAWKSYLENPLTAATKAMMSI NGDEDSAAALGLLYDYYKVPRDKRLLSVSKASDSQEDQEKRANLVDLQKKLEELELDEQQKKRLEAFLTQKAKVGELKDDDFERISELGA GNGGVVTKVQHRPSGLIMARKLIHLEIKPAIRNQIIRELQVLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKEAKRIPEEIL GKVSIAVLRGLAYLREKHQIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMAPERLQGTHYSVQSDIWSMGLSLVEL AVGRYPIPPPDAKELEAIFGRPVVDGEEGEPHSISPRPRPPGRPVSGHGMDSRPAMAIFELLDYIVNEPPPKLPNGVFTPDFQEFVNKCL | 500_GRHL2_MAP2K2 |
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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. |
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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. |
| 222_GRHL2_MAP2K2_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 GRHL2_MAP2K2 |
| 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 |
| MAP2K2 | P36507 | human | KRT8 | P05787 | S74 | tVNQsLLsPLVLEVD | Keratin_2_head |
| MAP2K2 | P36507 | human | MAPK3 | P27361 | T202 | HDHtGFLtEyVAtRW | Pkinase |
| MAP2K2 | P36507 | human | MAPK3 | P27361 | Y204 | HtGFLtEyVAtRWyr | Pkinase |
| 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 |
| MAP2K2 | ID | Description | 0.00e+00 |
| MAP2K2 | GO:0071356 | cellular response to tumor necrosis factor | 1.87e-02 |
| MAP2K2 | GO:0034612 | response to tumor necrosis factor | 1.87e-02 |
| MAP2K2 | GO:0048568 | embryonic organ development | 2.11e-02 |
| MAP2K2 | GO:0060020 | Bergmann glial cell differentiation | 2.11e-02 |
| MAP2K2 | GO:0060439 | trachea morphogenesis | 2.11e-02 |
| MAP2K2 | GO:0072584 | caveolin-mediated endocytosis | 2.11e-02 |
| MAP2K2 | GO:0009415 | response to water | 2.11e-02 |
| MAP2K2 | GO:0061517 | macrophage proliferation | 2.11e-02 |
| MAP2K2 | GO:0098792 | xenophagy | 2.11e-02 |
| MAP2K2 | GO:0048308 | organelle inheritance | 2.11e-02 |
| MAP2K2 | GO:0048313 | Golgi inheritance | 2.11e-02 |
| MAP2K2 | GO:0061307 | cardiac neural crest cell differentiation involved in heart development | 2.11e-02 |
| MAP2K2 | GO:0061308 | cardiac neural crest cell development involved in heart development | 2.11e-02 |
| MAP2K2 | GO:1903358 | regulation of Golgi organization | 2.11e-02 |
| MAP2K2 | GO:1904355 | positive regulation of telomere capping | 2.11e-02 |
| MAP2K2 | GO:0038083 | peptidyl-tyrosine autophosphorylation | 2.11e-02 |
| MAP2K2 | GO:0010759 | positive regulation of macrophage chemotaxis | 2.11e-02 |
| MAP2K2 | GO:0060438 | trachea development | 2.11e-02 |
| MAP2K2 | GO:2000641 | regulation of early endosome to late endosome transport | 2.11e-02 |
| MAP2K2 | GO:0097284 | hepatocyte apoptotic process | 2.21e-02 |
| MAP2K2 | GO:0060706 | cell differentiation involved in embryonic placenta development | 2.23e-02 |
| MAP2K2 | GO:1904353 | regulation of telomere capping | 2.23e-02 |
| MAP2K2 | GO:1905523 | positive regulation of macrophage migration | 2.23e-02 |
| MAP2K2 | GO:0010758 | regulation of macrophage chemotaxis | 2.23e-02 |
| MAP2K2 | GO:0030878 | thyroid gland development | 2.23e-02 |
| MAP2K2 | GO:0070498 | interleukin-1-mediated signaling pathway | 2.23e-02 |
| MAP2K2 | GO:1903649 | regulation of cytoplasmic transport | 2.23e-02 |
| MAP2K2 | GO:0032212 | positive regulation of telomere maintenance via telomerase | 2.23e-02 |
| MAP2K2 | GO:0051973 | positive regulation of telomerase activity | 2.23e-02 |
| MAP2K2 | GO:0071276 | cellular response to cadmium ion | 2.23e-02 |
| MAP2K2 | GO:1904358 | positive regulation of telomere maintenance via telomere lengthening | 2.23e-02 |
| MAP2K2 | GO:0016233 | telomere capping | 2.23e-02 |
| MAP2K2 | GO:0031281 | positive regulation of cyclase activity | 2.23e-02 |
| MAP2K2 | GO:0048246 | macrophage chemotaxis | 2.23e-02 |
| MAP2K2 | GO:0045022 | early endosome to late endosome transport | 2.23e-02 |
| MAP2K2 | GO:0045214 | sarcomere organization | 2.23e-02 |
| MAP2K2 | GO:1905521 | regulation of macrophage migration | 2.23e-02 |
| MAP2K2 | GO:0051972 | regulation of telomerase activity | 2.23e-02 |
| MAP2K2 | GO:0070849 | response to epidermal growth factor | 2.23e-02 |
| MAP2K2 | GO:1904262 | negative regulation of TORC1 signaling | 2.23e-02 |
| MAP2K2 | GO:0043330 | response to exogenous dsRNA | 2.23e-02 |
| MAP2K2 | GO:0048538 | thymus development | 2.23e-02 |
| MAP2K2 | GO:0098927 | vesicle-mediated transport between endosomal compartments | 2.23e-02 |
| MAP2K2 | GO:0034198 | cellular response to amino acid starvation | 2.23e-02 |
| MAP2K2 | GO:0048009 | insulin-like growth factor receptor signaling pathway | 2.23e-02 |
| MAP2K2 | GO:0060324 | face development | 2.23e-02 |
| MAP2K2 | GO:0032210 | regulation of telomere maintenance via telomerase | 2.23e-02 |
| MAP2K2 | GO:0071622 | regulation of granulocyte chemotaxis | 2.23e-02 |
| MAP2K2 | GO:0031279 | regulation of cyclase activity | 2.23e-02 |
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Related Drugs to GRHL2_MAP2K2 |
| 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 GRHL2-MAP2K2 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 GRHL2_MAP2K2 |
| 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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