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Fusion Protein:ITSN2-ESRP1

Fusion Gene and Fusion Protein Summary

Fusion gene summary

Fusion partner gene information	Fusion gene name: ITSN2-ESRP1
	FusionPDB ID: 40768
	FusionGDB2.0 ID: 40768
		Hgene	Tgene
	Gene symbol	ITSN2	ESRP1
	Gene ID	50618	54845
	Gene name	intersectin 2	epithelial splicing regulatory protein 1
	Synonyms	PRO2015\|SH3D1B\|SH3P18\|SWA\|SWAP	DFNB109\|RBM35A\|RMB35A
	Cytomap	2p23.3	8q22.1
	Type of gene	protein-coding	protein-coding
	Description	intersectin-2SH3 domain-containing protein 1BSH3P18-like WASP-associated protein	epithelial splicing regulatory protein 1RNA-binding motif protein 35ARNA-binding protein 35A
	Modification date	20200313	20200313
	UniProtAcc	Q9NZM3 Main function of 5'-partner protein: FUNCTION: Adapter protein that may provide indirect link between the endocytic membrane traffic and the actin assembly machinery. May regulate the formation of clathrin-coated vesicles (CCPs). Seems to be involved in CCPs maturation including invagination or budding. Involved in endocytosis of integrin beta-1 (ITGB1) and transferrin receptor (TFR). Plays a role in dendrite formation by melanocytes (PubMed:23999003). {ECO:0000269\|PubMed:19458185, ECO:0000269\|PubMed:22648170, ECO:0000269\|PubMed:23999003}.	Q6NXG1 Main function of 5'-partner protein: FUNCTION: mRNA splicing factor that regulates the formation of epithelial cell-specific isoforms. Specifically regulates the expression of FGFR2-IIIb, an epithelial cell-specific isoform of FGFR2. Also regulates the splicing of CD44, CTNND1, ENAH, 3 transcripts that undergo changes in splicing during the epithelial-to-mesenchymal transition (EMT). Acts by directly binding specific sequences in mRNAs. Binds the GU-rich sequence motifs in the ISE/ISS-3, a cis-element regulatory region present in the mRNA of FGFR2 (PubMed:19285943). Regulates splicing and expression of genes involved in inner ear development, auditory hair cell differentiation, and cell fate specification in the cochlear epithelium (By similarity). {ECO:0000250\|UniProtKB:Q3US41, ECO:0000269\|PubMed:19285943}.
Ensembl transtripts involved in fusion gene	ENST ids	ENST00000355123, ENST00000361999, ENST00000406921, ENST00000407704,	ENST00000523347, ENST00000358397, ENST00000423620, ENST00000433389, ENST00000454170,
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)	* DoF score	13 X 16 X 6=1248	14 X 16 X 7=1568
	# samples	18	15
	** MAII score	log2(18/1248*10)=-2.79354912253257 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0	log2(15/1568*10)=-3.38589115361933 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0
Fusion gene context	PubMed: ITSN2 [Title/Abstract] AND ESRP1 [Title/Abstract] AND fusion [Title/Abstract]
Fusion neoantigen context	PubMed: ITSN2 [Title/Abstract] AND ESRP1 [Title/Abstract] AND neoantigen [Title/Abstract]
Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)	ITSN2(24550921)-ESRP1(95683681), # samples:1
Anticipated loss of major functional domain due to fusion event.	ITSN2-ESRP1 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. ITSN2-ESRP1 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. ITSN2-ESRP1 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. ITSN2-ESRP1 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.

* DoF score (Degree of Frequency) = # partners X # break points X # cancer types
** MAII score (Major Active Isofusion Index) = log2(# samples/DoF score*10)

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	ITSN2	GO:1903861	positive regulation of dendrite extension	23999003
Tgene	ESRP1	GO:0043484	regulation of RNA splicing	19285943

Four levels of functional features of fusion genes
Go to FGviewer search page for the most frequent breakpoint (https://ccsmweb.uth.edu/FGviewer/chr2:24550921/chr8:95683681)
- 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.

Retention 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.

Fusion gene breakpoints across ITSN2 (5'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.

Fusion gene breakpoints across ESRP1 (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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Fusion Amino Acid Sequences

Fusion information from ORFfinder translation from full-length transcript sequence from FusionPDB.

Henst	Tenst	Hgene	Hchr	Hbp	Hstrand	Tgene	Tchr	Tbp	Tstrand	Seq length (transcript)	BP loci (transcript)	Predicted start (transcript)	Predicted stop (transcript)	Seq length (amino acids)
ENST00000361999	ITSN2	chr2	24550921	-	ENST00000423620	ESRP1	chr8	95683681	+	2338	70	67	816	249
ENST00000361999	ITSN2	chr2	24550921	-	ENST00000433389	ESRP1	chr8	95683681	+	2417	70	67	882	271
ENST00000361999	ITSN2	chr2	24550921	-	ENST00000358397	ESRP1	chr8	95683681	+	2448	70	67	870	267
ENST00000361999	ITSN2	chr2	24550921	-	ENST00000454170	ESRP1	chr8	95683681	+	2199	70	67	663	198
ENST00000355123	ITSN2	chr2	24550921	-	ENST00000423620	ESRP1	chr8	95683681	+	2743	475	472	1221	249
ENST00000355123	ITSN2	chr2	24550921	-	ENST00000433389	ESRP1	chr8	95683681	+	2822	475	472	1287	271
ENST00000355123	ITSN2	chr2	24550921	-	ENST00000358397	ESRP1	chr8	95683681	+	2853	475	472	1275	267
ENST00000355123	ITSN2	chr2	24550921	-	ENST00000454170	ESRP1	chr8	95683681	+	2604	475	472	1068	198
ENST00000406921	ITSN2	chr2	24550921	-	ENST00000423620	ESRP1	chr8	95683681	+	2537	269	266	1015	249
ENST00000406921	ITSN2	chr2	24550921	-	ENST00000433389	ESRP1	chr8	95683681	+	2616	269	266	1081	271
ENST00000406921	ITSN2	chr2	24550921	-	ENST00000358397	ESRP1	chr8	95683681	+	2647	269	266	1069	267
ENST00000406921	ITSN2	chr2	24550921	-	ENST00000454170	ESRP1	chr8	95683681	+	2398	269	266	862	198

DeepORF 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.

Henst	Tenst	Hgene	Hchr	Hbp	Hstrand	Tgene	Tchr	Tbp	Tstrand	No-coding score	Coding score
ENST00000361999	ENST00000423620	ITSN2	chr2	24550921	-	ESRP1	chr8	95683681	+	0.000509295	0.99949074
ENST00000361999	ENST00000433389	ITSN2	chr2	24550921	-	ESRP1	chr8	95683681	+	0.000430376	0.9995696
ENST00000361999	ENST00000358397	ITSN2	chr2	24550921	-	ESRP1	chr8	95683681	+	0.000359195	0.9996408
ENST00000361999	ENST00000454170	ITSN2	chr2	24550921	-	ESRP1	chr8	95683681	+	0.001162365	0.99883765
ENST00000355123	ENST00000423620	ITSN2	chr2	24550921	-	ESRP1	chr8	95683681	+	0.000768475	0.9992316
ENST00000355123	ENST00000433389	ITSN2	chr2	24550921	-	ESRP1	chr8	95683681	+	0.000781653	0.99921834
ENST00000355123	ENST00000358397	ITSN2	chr2	24550921	-	ESRP1	chr8	95683681	+	0.000548793	0.9994512
ENST00000355123	ENST00000454170	ITSN2	chr2	24550921	-	ESRP1	chr8	95683681	+	0.002005787	0.9979942
ENST00000406921	ENST00000423620	ITSN2	chr2	24550921	-	ESRP1	chr8	95683681	+	0.000509363	0.9994906
ENST00000406921	ENST00000433389	ITSN2	chr2	24550921	-	ESRP1	chr8	95683681	+	0.000592658	0.9994073
ENST00000406921	ENST00000358397	ITSN2	chr2	24550921	-	ESRP1	chr8	95683681	+	0.000377671	0.99962234
ENST00000406921	ENST00000454170	ITSN2	chr2	24550921	-	ESRP1	chr8	95683681	+	0.000914001	0.999086

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 ITSN2-ESRP1

+/-13 AA sequence from the breakpoints of the fusion protein sequences.

Hgene

Hchr

Hbp

Tgene

Tchr

Tbp

Length(fusion protein)

BP in fusion protein

Peptide

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Potential FusionNeoAntigen Information of ITSN2-ESRP1 in HLA I

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.

Potential FusionNeoAntigen Information
* We used NetMHCpan v4.1 (%rank<0.5) and deepHLApan v1.1 (immunogenic score>0.5)

Fusion gene

Hchr

Hbp

Tgene

Tchr

Tbp

HLA I

FusionNeoAntigen peptide

Binding score

Immunogenic score

Neoantigen start (at BP 13)

Neoantigen end (at BP 13)

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Potential FusionNeoAntigen Information of ITSN2-ESRP1 in HLA II

Potential FusionNeoAntigen Information
* We used NetMHCIIpan v4.1 (%rank<0.5).

Fusion gene

Hchr

Hbp

Tgene

Tchr

Tbp

HLA II

FusionNeoAntigen peptide

Neoantigen start (at BP 13)

Neoantigen end (at BP 13)

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Fusion breakpoint peptide structures of ITSN2-ESRP1

3D 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.

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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D of ITSN2-ESRP1

Virtual screening between 25 HLAs (from PDB) and FusionNeoAntigens
* We used Glide to predict the interaction between HLAs and neoantigens.

HLA allele

PDB ID

File name

BPseq

Docking score

Glide score

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Vaccine Design for the FusionNeoAntigens of ITSN2-ESRP1

mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-Is.

Fusion gene

Hchr

Hbp

Tchr

Tbp

Start in +/-13AA

End in +/-13AA

FusionNeoAntigen peptide sequence

FusionNeoAntigen RNA sequence

mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-IIs.

Fusion gene

Hchr

Hbp

Tchr

Tbp

Start in +/-13AA

End in +/-13AA

FusionNeoAntigen peptide

FusionNEoAntigen RNA sequence

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Information of the samples that have these potential fusion neoantigens of ITSN2-ESRP1

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 type

Fusion gene

Hchr

Hbp

Henst

Tchr

Tbp

Tenst

Sample

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Potential target of CAR-T therapy development for ITSN2-ESRP1

Predicted 3D structure. We used RoseTTAFold.

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, 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'.

Partner

Gene

Hbp

Tbp

ENST

Strand

BPexon

TotalExon

Protein feature loci

*BPloci

TotalLen

Protein feature

Protein feature note

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.

Hgene

Hchr

Hbp

Henst

Tgene

Tchr

Tbp

Tenst

DeepLoc result

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Related Drugs to ITSN2-ESRP1

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

Hgene

Tgene

Drug

Source

PMID

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Related Diseases to ITSN2-ESRP1

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

Hgene

Tgene

Disease

Source

PMID

Diseases associated with fusion partners.
(DisGeNet 4.0)

Partner	Gene	Disease ID	Disease name	# pubmeds	Source
Tgene	ESRP1	C4693935	DEAFNESS, AUTOSOMAL RECESSIVE 109	1	GENOMICS_ENGLAND;UNIPROT

	Fusion Gene and Fusion Protein Summary
	Fusion Amino Acid Sequences (multiple BPs and multiple gene isoforms)
	Fusion Protein Breakpoint Sequences - (for the Screening of the FusionNeoAntigens)
	Potential FusionNeoAntigens in HLA I - (netMHCpan v4.1 + deepHLApan v1.1)
	Potential FusionNeoAntigens in HLA II - (netMHCIIpan v4.1)
	Fusion Breakpoint 14 AA Peptide Structure - (RoseTTAFold)
	Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D - (Glide)
	Vaccine Design for the FusionNeoAntigens (RNA/protein sequences)
	Potential target of CAR-T therapy development
	Information on the samples that have these potential fusion neoantigens
	Fusion Protein Targeting Drugs - (Manual Curation)
	Fusion Protein Related diseases - (Manual Curation)