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Center for Computational Systems Medicine
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Fusion Gene and Fusion Protein Summary

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Fusion Amino Acid Sequences (multiple BPs and multiple gene isoforms)

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Fusion Protein Breakpoint Sequences - (for the Screening of the FusionNeoAntigens)

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Potential FusionNeoAntigens in HLA I - (netMHCpan v4.1 + deepHLApan v1.1)

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Potential FusionNeoAntigens in HLA II - (netMHCIIpan v4.1)

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Fusion Breakpoint 14 AA Peptide Structure - (RoseTTAFold)

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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D - (Glide)

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Vaccine Design for the FusionNeoAntigens (RNA/protein sequences)

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Potential target of CAR-T therapy development

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Information on the samples that have these potential fusion neoantigens

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Fusion Protein Targeting Drugs - (Manual Curation)

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Fusion Protein Related diseases - (Manual Curation)

Fusion Protein:MAP2K2-INSR

Fusion Gene and Fusion Protein Summary

check button Fusion gene summary
Fusion partner gene informationFusion gene name: MAP2K2-INSR
FusionPDB ID: 51187
FusionGDB2.0 ID: 51187
HgeneTgene
Gene symbol

MAP2K2

INSR

Gene ID

5605

3643

Gene namemitogen-activated protein kinase kinase 2insulin receptor
SynonymsCFC4|MAPKK2|MEK2|MKK2|PRKMK2CD220|HHF5
Cytomap

19p13.3

19p13.2

Type of geneprotein-codingprotein-coding
Descriptiondual specificity mitogen-activated protein kinase kinase 2ERK activator kinase 2MAP kinase kinase 2MAPK/ERK kinase 2mitogen-activated protein kinase kinase 2, p45insulin receptorIR
Modification date2020032720200313
UniProtAcc

P36507

Main function of 5'-partner protein: 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}.

P06213

Main function of 5'-partner protein: FUNCTION: Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosine residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. In adipocytes, inhibits lipolysis (By similarity). {ECO:0000250|UniProtKB:P15208, ECO:0000269|PubMed:12138094, ECO:0000269|PubMed:16314505, ECO:0000269|PubMed:16831875, ECO:0000269|PubMed:8257688, ECO:0000269|PubMed:8276809, ECO:0000269|PubMed:8452530, ECO:0000269|PubMed:9428692}.
Ensembl transtripts involved in fusion geneENST idsENST00000599345, ENST00000394867, 
ENST00000262948, 
ENST00000302850, 
ENST00000341500, 
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)* DoF score10 X 6 X 6=36020 X 13 X 8=2080
# samples 1020
** MAII scorelog2(10/360*10)=-1.84799690655495
possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs).
DoF>8 and MAII<0
log2(20/2080*10)=-3.37851162325373
possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs).
DoF>8 and MAII<0
Fusion gene context

PubMed: MAP2K2 [Title/Abstract] AND INSR [Title/Abstract] AND fusion [Title/Abstract]

Fusion neoantigen context

PubMed: MAP2K2 [Title/Abstract] AND INSR [Title/Abstract] AND neoantigen [Title/Abstract]

Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)MAP2K2(4110507)-INSR(7132328), # samples:2
Anticipated loss of major functional domain due to fusion event.MAP2K2-INSR seems lost the major protein functional domain in Hgene partner, which is a CGC by not retaining the major functional domain in the partially deleted in-frame ORF.
MAP2K2-INSR seems lost the major protein functional domain in Hgene partner, which is a CGC by not retaining the major functional domain in the partially deleted in-frame ORF.
MAP2K2-INSR seems lost the major protein functional domain in Hgene partner, which is a essential gene by not retaining the major functional domain in the partially deleted in-frame ORF.
MAP2K2-INSR seems lost the major protein functional domain in Hgene partner, which is a essential gene by not retaining the major functional domain in the partially deleted in-frame ORF.
MAP2K2-INSR seems lost the major protein functional domain in Hgene partner, which is a CGC due to the frame-shifted ORF.
MAP2K2-INSR seems lost the major protein functional domain in Hgene partner, which is a IUPHAR drug target due to the frame-shifted ORF.
MAP2K2-INSR seems lost the major protein functional domain in Hgene partner, which is a kinase due to the frame-shifted ORF.
MAP2K2-INSR seems lost the major protein functional domain in Tgene partner, which is a IUPHAR drug target due to the frame-shifted ORF.
MAP2K2-INSR seems lost the major protein functional domain in Tgene partner, which is a kinase due to the frame-shifted ORF.
* DoF score (Degree of Frequency) = # partners X # break points X # cancer types
** MAII score (Major Active Isofusion Index) = log2(# samples/DoF score*10)

check button Gene ontology of each fusion partner gene with evidence of Inferred from Direct Assay (IDA) from Entrez
PartnerGeneGO IDGO termPubMed ID
HgeneMAP2K2

GO:0036289

peptidyl-serine autophosphorylation

8388392

HgeneMAP2K2

GO:0071902

positive regulation of protein serine/threonine kinase activity

8388392

TgeneINSR

GO:0001934

positive regulation of protein phosphorylation

7556070

TgeneINSR

GO:0002092

positive regulation of receptor internalization

25401701

TgeneINSR

GO:0007186

G protein-coupled receptor signaling pathway

9092559

TgeneINSR

GO:0008284

positive regulation of cell proliferation

17925406

TgeneINSR

GO:0008286

insulin receptor signaling pathway

6849137|8440175|20455999

TgeneINSR

GO:0018108

peptidyl-tyrosine phosphorylation

8496180

TgeneINSR

GO:0032148

activation of protein kinase B activity

7556070

TgeneINSR

GO:0032869

cellular response to insulin stimulus

8440175

TgeneINSR

GO:0043410

positive regulation of MAPK cascade

20455999

TgeneINSR

GO:0045725

positive regulation of glycogen biosynthetic process

17925406

TgeneINSR

GO:0046326

positive regulation of glucose import

3518947

TgeneINSR

GO:0046777

protein autophosphorylation

6849137|8496180

TgeneINSR

GO:0060267

positive regulation of respiratory burst

9092559



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/chr19:4110507/chr19:7132328)
- 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 buttonRetention analysis results 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, are available here.

check buttonFusion gene breakpoints across MAP2K2 (5'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.
all structure

check buttonFusion gene breakpoints across INSR (3'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.
all structure


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Fusion Amino Acid Sequences


check buttonFusion information from ORFfinder translation from full-length transcript sequence from FusionPDB.
HenstTenstHgeneHchrHbpHstrandTgeneTchrTbpTstrandSeq length
(transcript)
BP loci
(transcript)
Predicted start
(transcript)
Predicted stop
(transcript)
Seq length
(amino acids)
ENST00000262948MAP2K2chr194110507-ENST00000341500INSRchr197132328-69727042542170638
ENST00000262948MAP2K2chr194110507-ENST00000302850INSRchr197132328-26007042542170638
ENST00000262948MAP2K2chr194110506-ENST00000341500INSRchr197132328-69727042542170638
ENST00000262948MAP2K2chr194110506-ENST00000302850INSRchr197132328-26007042542170638

check buttonDeepORF prediction of the coding potential based on the fusion transcript sequence of in-frame fusion genes. DeepORF is a coding potential classifier based on convolutional neural network by comparing the real Ribo-seq data. If the no-coding score < 0.5 and coding score > 0.5, then the in-frame fusion transcript is predicted as being likely translated.
HenstTenstHgeneHchrHbpHstrandTgeneTchrTbpTstrandNo-coding scoreCoding score
ENST00000262948ENST00000341500MAP2K2chr194110507-INSRchr197132328-0.0008052650.9991948
ENST00000262948ENST00000302850MAP2K2chr194110507-INSRchr197132328-0.0076571130.9923429
ENST00000262948ENST00000341500MAP2K2chr194110506-INSRchr197132328-0.0008052650.9991948
ENST00000262948ENST00000302850MAP2K2chr194110506-INSRchr197132328-0.0076571130.9923429

check button Predicted full-length fusion amino acid sequences. For individual full-length fusion transcript sequence from FusionPDB, we ran ORFfinder and chose the longest ORF among all the predicted ones.

Get the fusion protein sequences from here.

Fusion protein sequence information is available in the fasta format.
>FusionGDB ID_FusionGDB isoform ID_FGname_Hgene_Hchr_Hbp_Henst_Tgene_Tchr_Tbp_Tenst_length(fusion AA) seq_BP

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Fusion Protein Breakpoint Sequences for MAP2K2-INSR

check button +/-13 AA sequence from the breakpoints of the fusion protein sequences.
HgeneHchrHbpTgeneTchrTbpLength(fusion protein)BP in fusion proteinPeptide
MAP2K2chr194110506INSRchr197132328704150YSDGEISICMEHMELHLCVSRKHFAL
MAP2K2chr194110507INSRchr197132328704150YSDGEISICMEHMELHLCVSRKHFAL

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Potential FusionNeoAntigen Information of MAP2K2-INSR in HLA I

check button Multiple sequence alignments of the potential FusionNeoAntigens per fusion breakpoints. If the MSA is empty, then it means that there were predicted fusion neoantigens in this fusion breakpoint, but those predicted fusion neoantigens were not across the breakpoint, which is not fusion-specific.
MAP2K2-INSR_4110506_7132328.msa

check button Potential FusionNeoAntigen Information
* We used NetMHCpan v4.1 (%rank<0.5) and deepHLApan v1.1 (immunogenic score>0.5)
Fusion geneHchrHbpTgeneTchrTbpHLA IFusionNeoAntigen peptideBinding scoreImmunogenic scoreNeoantigen start (at BP 13)Neoantigen end (at BP 13)
MAP2K2-INSRchr194110506chr197132328704HLA-B39:06EHMELHLC0.99940.63461018
MAP2K2-INSRchr194110506chr197132328704HLA-B18:01MEHMELHL0.99740.7341917
MAP2K2-INSRchr194110506chr197132328704HLA-B39:06EHMELHLCV0.99890.85841019
MAP2K2-INSRchr194110506chr197132328704HLA-B39:01EHMELHLCV0.99870.88011019
MAP2K2-INSRchr194110506chr197132328704HLA-B38:01EHMELHLCV0.99860.89281019
MAP2K2-INSRchr194110506chr197132328704HLA-B38:02EHMELHLCV0.99850.91261019
MAP2K2-INSRchr194110506chr197132328704HLA-B14:02EHMELHLCV0.98930.63731019
MAP2K2-INSRchr194110506chr197132328704HLA-B14:01EHMELHLCV0.98930.63731019
MAP2K2-INSRchr194110506chr197132328704HLA-B45:01MEHMELHLC0.9840.8235918
MAP2K2-INSRchr194110506chr197132328704HLA-B15:10EHMELHLCV0.98290.51621019
MAP2K2-INSRchr194110506chr197132328704HLA-B15:37EHMELHLCV0.71910.51761019
MAP2K2-INSRchr194110506chr197132328704HLA-B15:18EHMELHLCV0.640.58571019
MAP2K2-INSRchr194110506chr197132328704HLA-B41:01MEHMELHLC0.42520.9689918
MAP2K2-INSRchr194110506chr197132328704HLA-B50:01MEHMELHLC0.13320.6131918
MAP2K2-INSRchr194110506chr197132328704HLA-B08:09EHMELHLCV0.06860.84741019
MAP2K2-INSRchr194110506chr197132328704HLA-B39:09EHMELHLCV0.99860.6691019
MAP2K2-INSRchr194110506chr197132328704HLA-B39:12EHMELHLCV0.99850.88261019
MAP2K2-INSRchr194110506chr197132328704HLA-B39:05EHMELHLCV0.99820.86611019
MAP2K2-INSRchr194110506chr197132328704HLA-B40:06MEHMELHLC0.9940.5179918
MAP2K2-INSRchr194110506chr197132328704HLA-B73:01EHMELHLCV0.38890.61631019
MAP2K2-INSRchr194110506chr197132328704HLA-B14:03EHMELHLCV0.21550.75031019
MAP2K2-INSRchr194110506chr197132328704HLA-B40:04MEHMELHL0.99960.6169917
MAP2K2-INSRchr194110506chr197132328704HLA-B18:05MEHMELHL0.99740.7341917
MAP2K2-INSRchr194110506chr197132328704HLA-B18:03MEHMELHL0.99630.7185917
MAP2K2-INSRchr194110506chr197132328704HLA-B18:11MEHMELHL0.97210.7394917
MAP2K2-INSRchr194110506chr197132328704HLA-B41:03MEHMELHL0.95250.6737917
MAP2K2-INSRchr194110506chr197132328704HLA-B38:05EHMELHLCV0.99860.89281019
MAP2K2-INSRchr194110506chr197132328704HLA-B39:31EHMELHLCV0.99830.87661019
MAP2K2-INSRchr194110506chr197132328704HLA-B39:11EHMELHLCV0.83730.83531019
MAP2K2-INSRchr194110506chr197132328704HLA-B50:05MEHMELHLC0.13320.6131918
MAP2K2-INSRchr194110506chr197132328704HLA-B50:04MEHMELHLC0.13320.6131918

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Potential FusionNeoAntigen Information of MAP2K2-INSR in HLA II

check button Multiple sequence alignments of the potential FusionNeoAntigens per fusion breakpoints. If the MSA is empty, then it means that there were predicted fusion neoantigens in this fusion breakpoint, but those predicted fusion neoantigens were not across the breakpoint, which is not fusion-specific.

check button Potential FusionNeoAntigen Information
* We used NetMHCIIpan v4.1 (%rank<0.5).
Fusion geneHchrHbpTgeneTchrTbpHLA IIFusionNeoAntigen peptideNeoantigen start (at BP 13)Neoantigen end (at BP 13)

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Fusion breakpoint peptide structures of MAP2K2-INSR

check button3D structures of the fusion breakpoint peptide of 14AA sequence that have potential fusion neoantigens
* The minimum length of the amino acid sequence in RoseTTAFold is 14AA. Here, we predicted the 14AA fusion protein breakpoint sequence not the fusion neoantigen peptide, which is shorter than 14 AA.
File nameBPseqHgeneTgeneHchrHbpTchrTbpAAlen
8635SICMEHMELHLCVSMAP2K2INSRchr194110506chr197132328704

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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D of MAP2K2-INSR

check buttonVirtual screening between 25 HLAs (from PDB) and FusionNeoAntigens
* We used Glide to predict the interaction between HLAs and neoantigens.
HLA allelePDB IDFile nameBPseqDocking scoreGlide score
HLA-B14:023BVN8635SICMEHMELHLCVS-7.15543-7.26883
HLA-B14:023BVN8635SICMEHMELHLCVS-4.77435-5.80965
HLA-B52:013W398635SICMEHMELHLCVS-6.80875-6.92215
HLA-B52:013W398635SICMEHMELHLCVS-4.20386-5.23916
HLA-A11:014UQ28635SICMEHMELHLCVS-7.5194-8.5547
HLA-A11:014UQ28635SICMEHMELHLCVS-6.9601-7.0735
HLA-A24:025HGA8635SICMEHMELHLCVS-7.52403-7.63743
HLA-A24:025HGA8635SICMEHMELHLCVS-5.82433-6.85963
HLA-B27:056PYJ8635SICMEHMELHLCVS-3.28285-4.31815
HLA-B44:053DX88635SICMEHMELHLCVS-5.91172-6.94702
HLA-B44:053DX88635SICMEHMELHLCVS-4.24346-4.35686

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Vaccine Design for the FusionNeoAntigens of MAP2K2-INSR

check button mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-Is.
Fusion geneHchrHbpTchrTbpStart in +/-13AAEnd in +/-13AAFusionNeoAntigen peptide sequenceFusionNeoAntigen RNA sequence
MAP2K2-INSRchr194110506chr1971323281018EHMELHLCGAACACATGGAGCTGCATCTCTGC
MAP2K2-INSRchr194110506chr1971323281019EHMELHLCVGAACACATGGAGCTGCATCTCTGCGTC
MAP2K2-INSRchr194110506chr197132328917MEHMELHLATGGAACACATGGAGCTGCATCTC
MAP2K2-INSRchr194110506chr197132328918MEHMELHLCATGGAACACATGGAGCTGCATCTCTGC

check button mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-IIs.
Fusion geneHchrHbpTchrTbpStart in +/-13AAEnd in +/-13AAFusionNeoAntigen peptideFusionNEoAntigen RNA sequence

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Information of the samples that have these potential fusion neoantigens of MAP2K2-INSR

check button These samples were reported as having these fusion breakpoints. For individual breakpoints, we checked the open reading frames considering multiple gene isoforms and chose the in-frame fusion genes only. Then, we made fusion protein sequences and predicted the fusion neoantigens. These fusion-positive samples may have these potential fusion neoantigens.
Cancer typeFusion geneHchrHbpHenstTchrTbpTenstSample
OVMAP2K2-INSRchr194110506ENST00000262948chr197132328ENST00000302850TCGA-13-1410

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Potential target of CAR-T therapy development for MAP2K2-INSR

check button Predicted 3D structure. We used RoseTTAFold.

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, to provide the retention of the transmembrane domain, we only show the protein feature retention information of those transmembrane features


* Minus value of BPloci means that the break point is located before the CDS.
- In-frame and retained 'Transmembrane'.
PartnerGeneHbpTbpENSTStrandBPexonTotalExonProtein feature loci*BPlociTotalLenProtein featureProtein feature note
TgeneINSRchr19:4110506chr19:7132328ENST000003028501222957_97901383.0TransmembraneHelical
TgeneINSRchr19:4110506chr19:7132328ENST000003415001121957_97901371.0TransmembraneHelical
TgeneINSRchr19:4110507chr19:7132328ENST000003028501222957_97901383.0TransmembraneHelical
TgeneINSRchr19:4110507chr19:7132328ENST000003415001121957_97901371.0TransmembraneHelical

check button Subcellular localization prediction of the transmembrane domain retained fusion proteins
* We used DeepLoc 1.0. The order of the X-axis of the barplot is as follows: Entry_ID, Localization, Type, Nucleus, Cytoplasm, Extracellular, Mitochondrion, Cell_membrane, Endoplasmic_reticulum, Plastid, Golgi.apparatus, Lysosome.Vacuole, Peroxisome. Y-axis is the output score of DeepLoc. Clicking the image will open a new tab with a large image.
HgeneHchrHbpHenstTgeneTchrTbpTenstDeepLoc result

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Related Drugs to MAP2K2-INSR

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

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Related Diseases to MAP2K2-INSR

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

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