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Kinase Fusion Gene:ATF4_CDK12 |
Kinase Fusion Protein Summary |
Kinase Fusion gene summary |
Kinase Fusion partner gene information | Kinase Fusion gene name: ATF4_CDK12 | KinaseFusionDB ID: KFG466 | FusionGDB2.0 ID: KFG466 | Hgene | Tgene | Gene symbol | ATF4 | CDK12 | Gene ID | 468 | 51755 | |
Gene name | activating transcription factor 4 | cyclin dependent kinase 12 | ||||||||||
Synonyms | CREB-2|CREB2|TAXREB67|TXREB | CRK7|CRKR|CRKRS | ||||||||||
Cytomap | 22q13.1 | 17q12 | ||||||||||
Type of gene | protein-coding | protein-coding | ||||||||||
Description | cyclic AMP-dependent transcription factor ATF-4DNA-binding protein TAXREB67cAMP response element-binding protein 2cAMP-dependent transcription factor ATF-4cAMP-responsive element-binding protein 2cyclic AMP-responsive element-binding protein 2tax-re | cyclin-dependent kinase 12CDC2-related protein kinase 7Cdc2-related kinase, arginine/serine-richcell division cycle 2-related protein kinase 7cell division protein kinase 12 | ||||||||||
Modification date | 20240416 | 20240403 | ||||||||||
UniProtAcc | P18848 | Q9NYV4 | ||||||||||
Ensembl transtripts involved in fusion gene | ENST ids | ENST00000337304, ENST00000396680, ENST00000404241, | ENST00000430627, ENST00000447079, ENST00000559545, | |||||||||
Context (manual curation of fusion genes in KinaseFusionDB) | PubMed: ATF4 [Title/Abstract] AND CDK12 [Title/Abstract] AND fusion [Title/Abstract] | |||||||||||
Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0) | ATF4(39916756)-CDK12(37700502), # 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 | ATF4 | GO:0031667 | response to nutrient levels | 11960987 |
Hgene | ATF4 | GO:0034976 | response to endoplasmic reticulum stress | 12871976|19061639|33384352 |
Hgene | ATF4 | GO:0045667 | regulation of osteoblast differentiation | 15109498 |
Hgene | ATF4 | GO:0045893 | positive regulation of DNA-templated transcription | 15775988|18940792 |
Hgene | ATF4 | GO:0045944 | positive regulation of transcription by RNA polymerase II | 11478948|11960987|12871976|15109498|15775988|16343488|18940792|23123191 |
Hgene | ATF4 | GO:0070982 | L-asparagine metabolic process | 11960987 |
Hgene | ATF4 | GO:0140467 | integrated stress response signaling | 32132707 |
Hgene | ATF4 | GO:0140468 | HRI-mediated signaling | 32132707 |
Hgene | ATF4 | GO:1990253 | cellular response to leucine starvation | 17267404 |
Tgene | CDK12 | GO:0006366 | transcription by RNA polymerase II | 22988298 |
Tgene | CDK12 | GO:0032968 | positive regulation of transcription elongation by RNA polymerase II | 22988298 |
Tgene | CDK12 | GO:0046777 | protein autophosphorylation | 11683387 |
Kinase Fusion gene breakpoints across ATF4 (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 CDK12 (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-E2-A152-01A | ATF4 | chr22 | 39916756 | CDK12 | chr17 | 37700502 |
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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/:39916756/:37700502) - 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. |
Main function of each fusion partner protein. (from UniProt) |
Hgene | Tgene |
ATF4 | CDK12 |
FUNCTION: Transcription factor that binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3') and displays two biological functions, as regulator of metabolic and redox processes under normal cellular conditions, and as master transcription factor during integrated stress response (ISR) (PubMed:17684156, PubMed:16682973, PubMed:31444471, PubMed:32132707). Binds to asymmetric CRE's as a heterodimer and to palindromic CRE's as a homodimer (By similarity). Core effector of the ISR, which is required for adaptation to various stress such as endoplasmic reticulum (ER) stress, amino acid starvation, mitochondrial stress or oxidative stress (PubMed:32132707). During ISR, ATF4 translation is induced via an alternative ribosome translation re-initiation mechanism in response to EIF2S1/eIF-2-alpha phosphorylation, and stress-induced ATF4 acts as a master transcription factor of stress-responsive genes in order to promote cell recovery (PubMed:32132706, PubMed:32132707). Promotes the transcription of genes linked to amino acid sufficiency and resistance to oxidative stress to protect cells against metabolic consequences of ER oxidation (By similarity). Activates the transcription of NLRP1, possibly in concert with other factors in response to ER stress (PubMed:26086088). Activates the transcription of asparagine synthetase (ASNS) in response to amino acid deprivation or ER stress (PubMed:11960987). However, when associated with DDIT3/CHOP, the transcriptional activation of the ASNS gene is inhibited in response to amino acid deprivation (PubMed:18940792). Together with DDIT3/CHOP, mediates programmed cell death by promoting the expression of genes involved in cellular amino acid metabolic processes, mRNA translation and the terminal unfolded protein response (terminal UPR), a cellular response that elicits programmed cell death when ER stress is prolonged and unresolved (By similarity). Together with DDIT3/CHOP, activates the transcription of the IRS-regulator TRIB3 and promotes ER stress-induced neuronal cell death by regulating the expression of BBC3/PUMA in response to ER stress (PubMed:15775988). May cooperate with the UPR transcriptional regulator QRICH1 to regulate ER protein homeostasis which is critical for cell viability in response to ER stress (PubMed:33384352). In the absence of stress, ATF4 translation is at low levels and it is required for normal metabolic processes such as embryonic lens formation, fetal liver hematopoiesis, bone development and synaptic plasticity (By similarity). Acts as a regulator of osteoblast differentiation in response to phosphorylation by RPS6KA3/RSK2: phosphorylation in osteoblasts enhances transactivation activity and promotes expression of osteoblast-specific genes and post-transcriptionally regulates the synthesis of Type I collagen, the main constituent of the bone matrix (PubMed:15109498). Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production (By similarity). Activates transcription of SIRT4 (By similarity). Regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4 (By similarity). Binds in a circadian time-dependent manner to the cAMP response elements (CRE) in the SLC6A4 and PER2 promoters and periodically activates the transcription of these genes (By similarity). Mainly acts as a transcriptional activator in cellular stress adaptation, but it can also act as a transcriptional repressor: acts as a regulator of synaptic plasticity by repressing transcription, thereby inhibiting induction and maintenance of long-term memory (By similarity). Regulates synaptic functions via interaction with DISC1 in neurons, which inhibits ATF4 transcription factor activity by disrupting ATF4 dimerization and DNA-binding (PubMed:31444471). {ECO:0000250|UniProtKB:Q06507, ECO:0000269|PubMed:11960987, ECO:0000269|PubMed:15109498, ECO:0000269|PubMed:15775988, ECO:0000269|PubMed:16682973, ECO:0000269|PubMed:17684156, ECO:0000269|PubMed:18940792, ECO:0000269|PubMed:26086088, ECO:0000269|PubMed:31444471, ECO:0000269|PubMed:32132706, ECO:0000269|PubMed:32132707, ECO:0000269|PubMed:33384352}.; FUNCTION: (Microbial infection) Binds to a Tax-responsive enhancer element in the long terminal repeat of HTLV-I. {ECO:0000269|PubMed:1847461}. | FUNCTION: Cyclin-dependent kinase that phosphorylates the C-terminal domain (CTD) of the large subunit of RNA polymerase II (POLR2A), thereby acting as a key regulator of transcription elongation. Regulates the expression of genes involved in DNA repair and is required for the maintenance of genomic stability. Preferentially phosphorylates 'Ser-5' in CTD repeats that are already phosphorylated at 'Ser-7', but can also phosphorylate 'Ser-2'. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogen inhibitors. {ECO:0000269|PubMed:11683387, ECO:0000269|PubMed:19651820, ECO:0000269|PubMed:20952539, ECO:0000269|PubMed:22012619, ECO:0000269|PubMed:24662513}. |
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 ATF4_CDK12 |
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 |
CDK12 | Q9NYV4 | human | PAK2 | Q13177 | T134 | LkFyDsNtVkQKyLs | |
CDK12 | Q9NYV4 | human | POLR2A | P24928 | S1616 | TPQSPSysPtsPsYS | RNA_pol_Rpb1_R |
CDK12 | Q9NYV4 | human | PAK2 | Q13177 | T169 | TEAPAVVtEEEDDDE | |
CDK12 | Q9NYV4 | human | TP63 | Q9H3D4-2 | S68 | TFDALsPsPAIPSNT | |
CDK12 | Q9NYV4 | human | POLR2A | P24928 | S1619 | SPSysPtsPsYSPTS | RNA_pol_Rpb1_R |
CDK12 | Q9NYV4 | human | TP63 | Q9H3D4-2 | S66 | SSTFDALsPsPAIPS | |
CDK12 | Q9NYV4 | human | TP63 | Q9H3D4-2 | S301 | TSIKKRRsPDDELLY | P53_tetramer |
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 |
CDK12 | ID | Description | 0.00e+00 |
CDK12 | GO:2001235 | positive regulation of apoptotic signaling pathway | 2.92e-02 |
CDK12 | GO:2001233 | regulation of apoptotic signaling pathway | 2.92e-02 |
CDK12 | GO:0060525 | prostate glandular acinus development | 2.92e-02 |
CDK12 | GO:2000271 | positive regulation of fibroblast apoptotic process | 2.92e-02 |
CDK12 | GO:0060601 | lateral sprouting from an epithelium | 2.92e-02 |
CDK12 | GO:0060742 | epithelial cell differentiation involved in prostate gland development | 2.92e-02 |
CDK12 | GO:0035112 | genitalia morphogenesis | 2.92e-02 |
CDK12 | GO:0043589 | skin morphogenesis | 2.92e-02 |
CDK12 | GO:1904672 | regulation of somatic stem cell population maintenance | 2.92e-02 |
CDK12 | GO:0034333 | adherens junction assembly | 2.92e-02 |
CDK12 | GO:0045605 | negative regulation of epidermal cell differentiation | 2.92e-02 |
CDK12 | GO:0045683 | negative regulation of epidermis development | 2.92e-02 |
CDK12 | GO:0010838 | positive regulation of keratinocyte proliferation | 2.92e-02 |
CDK12 | GO:0033147 | negative regulation of intracellular estrogen receptor signaling pathway | 2.92e-02 |
CDK12 | GO:0060572 | morphogenesis of an epithelial bud | 2.92e-02 |
CDK12 | GO:0030540 | female genitalia development | 2.92e-02 |
CDK12 | GO:0036342 | post-anal tail morphogenesis | 2.92e-02 |
CDK12 | GO:2000269 | regulation of fibroblast apoptotic process | 2.92e-02 |
CDK12 | GO:0048485 | sympathetic nervous system development | 2.92e-02 |
CDK12 | GO:0150105 | protein localization to cell-cell junction | 2.92e-02 |
CDK12 | GO:1900118 | negative regulation of execution phase of apoptosis | 2.92e-02 |
CDK12 | GO:0002223 | stimulatory C-type lectin receptor signaling pathway | 2.92e-02 |
CDK12 | GO:1990840 | response to lectin | 2.92e-02 |
CDK12 | GO:1990858 | cellular response to lectin | 2.92e-02 |
CDK12 | GO:0060571 | morphogenesis of an epithelial fold | 2.92e-02 |
CDK12 | GO:0030859 | polarized epithelial cell differentiation | 2.92e-02 |
CDK12 | GO:0044346 | fibroblast apoptotic process | 2.92e-02 |
CDK12 | GO:0060740 | prostate gland epithelium morphogenesis | 2.92e-02 |
CDK12 | GO:0035116 | embryonic hindlimb morphogenesis | 2.92e-02 |
CDK12 | GO:0060512 | prostate gland morphogenesis | 2.92e-02 |
CDK12 | GO:0006353 | DNA-templated transcription termination | 2.92e-02 |
CDK12 | GO:1900117 | regulation of execution phase of apoptosis | 2.92e-02 |
CDK12 | GO:0031069 | hair follicle morphogenesis | 2.92e-02 |
CDK12 | GO:0035115 | embryonic forelimb morphogenesis | 2.92e-02 |
CDK12 | GO:0051497 | negative regulation of stress fiber assembly | 2.92e-02 |
CDK12 | GO:0061436 | establishment of skin barrier | 2.92e-02 |
CDK12 | GO:0009954 | proximal/distal pattern formation | 2.92e-02 |
CDK12 | GO:0008340 | determination of adult lifespan | 2.92e-02 |
CDK12 | GO:0033146 | regulation of intracellular estrogen receptor signaling pathway | 2.92e-02 |
CDK12 | GO:0032232 | negative regulation of actin filament bundle assembly | 2.92e-02 |
CDK12 | GO:0035137 | hindlimb morphogenesis | 2.92e-02 |
CDK12 | GO:0033144 | negative regulation of intracellular steroid hormone receptor signaling pathway | 2.92e-02 |
CDK12 | GO:0048730 | epidermis morphogenesis | 2.92e-02 |
CDK12 | GO:0045616 | regulation of keratinocyte differentiation | 3.09e-02 |
CDK12 | GO:0035136 | forelimb morphogenesis | 3.09e-02 |
CDK12 | GO:0042771 | intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator | 3.14e-02 |
CDK12 | GO:0033120 | positive regulation of RNA splicing | 3.14e-02 |
CDK12 | GO:0048483 | autonomic nervous system development | 3.14e-02 |
CDK12 | GO:0010837 | regulation of keratinocyte proliferation | 3.14e-02 |
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Related Drugs to ATF4_CDK12 |
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 ATF4-CDK12 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 ATF4_CDK12 |
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 |