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	Fusion Gene Summary
	Fusion Gene ORF analysis
	Fusion Genomic Features
	Fusion Protein Features
	Fusion Gene Sequence
	Fusion Gene PPI analysis
	Related Drugs
	Related Diseases

Fusion gene:EIF2AK1-MAP2K5 (FusionGDB2 ID:25655)

Fusion Gene Summary for EIF2AK1-MAP2K5

Fusion gene summary

Fusion gene information	Fusion gene name: EIF2AK1-MAP2K5
	Fusion gene ID: 25655
		Hgene	Tgene
	Gene symbol	EIF2AK1	MAP2K5
	Gene ID	27102	5607
	Gene name	eukaryotic translation initiation factor 2 alpha kinase 1	mitogen-activated protein kinase kinase 5
	Synonyms	HCR\|HRI	HsT17454\|MAPKK5\|MEK5\|PRKMK5
	Cytomap	7p22.1	15q23
	Type of gene	protein-coding	protein-coding
	Description	eukaryotic translation initiation factor 2-alpha kinase 1heme regulated initiation factor 2 alpha kinaseheme sensitive initiation factor 2a kinaseheme-controlled repressorheme-regulated eukaryotic initiation factor eIF-2-alpha kinaseheme-regulated in	dual specificity mitogen-activated protein kinase kinase 5MAP kinase kinase 5MAP kinase kinase MEK5bMAPK/ERK kinase 5MAPKK 5MEK 5
	Modification date	20200313	20200327
	UniProtAcc	Q9BQI3	Q13163
	Ensembl transtripts involved in fusion gene	ENST00000199389, ENST00000536084, ENST00000495565,	ENST00000340972, ENST00000354498, ENST00000395476, ENST00000560591, ENST00000178640,
Fusion gene scores	* DoF score	11 X 8 X 8=704	13 X 18 X 12=2808
	# samples	11	19
	** MAII score	log2(11/704*10)=-2.67807190511264 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0	log2(19/2808*10)=-3.88547161197361 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0
Context	PubMed: EIF2AK1 [Title/Abstract] AND MAP2K5 [Title/Abstract] AND fusion [Title/Abstract]
Most frequent breakpoint	EIF2AK1(6077055)-MAP2K5(68098984), # samples:3
Anticipated loss of major functional domain due to fusion event.	EIF2AK1-MAP2K5 seems lost the major protein functional domain in Hgene partner, which is a IUPHAR drug target due to the frame-shifted ORF. EIF2AK1-MAP2K5 seems lost the major protein functional domain in Hgene partner, which is a kinase due to the frame-shifted ORF. EIF2AK1-MAP2K5 seems lost the major protein functional domain in Tgene partner, which is a IUPHAR drug target due to the frame-shifted ORF. EIF2AK1-MAP2K5 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)

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	EIF2AK1	GO:1990641	response to iron ion starvation	11036079

Fusion gene breakpoints across EIF2AK1 (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 MAP2K5 (3'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.

Fusion gene information from two resources (ChiTars 5.0 and ChimerDB 4.0)
* 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	Disease	Sample	Hgene	Hchr	Hbp	Hstrand	Tgene	Tchr	Tbp	Tstrand
ChimerDB4	PRAD	TCGA-V1-A8WV-01A	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+
ChimerDB4	PRAD	TCGA-V1-A8WV	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+

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Fusion Gene ORF analysis for EIF2AK1-MAP2K5

Open reading frame (ORF) analsis of fusion genes based on Ensembl gene isoform structure.
* Click on the break point to see the gene structure around the break point region using the UCSC Genome Browser.

ORF	Henst	Tenst	Hgene	Hchr	Hbp	Hstrand	Tgene	Tchr	Tbp	Tstrand
5CDS-intron	ENST00000199389	ENST00000340972	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+
5CDS-intron	ENST00000199389	ENST00000354498	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+
5CDS-intron	ENST00000199389	ENST00000395476	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+
5CDS-intron	ENST00000199389	ENST00000560591	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+
5CDS-intron	ENST00000536084	ENST00000340972	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+
5CDS-intron	ENST00000536084	ENST00000354498	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+
5CDS-intron	ENST00000536084	ENST00000395476	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+
5CDS-intron	ENST00000536084	ENST00000560591	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+
Frame-shift	ENST00000199389	ENST00000178640	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+
In-frame	ENST00000536084	ENST00000178640	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+
intron-3CDS	ENST00000495565	ENST00000178640	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+
intron-intron	ENST00000495565	ENST00000340972	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+
intron-intron	ENST00000495565	ENST00000354498	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+
intron-intron	ENST00000495565	ENST00000395476	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+
intron-intron	ENST00000495565	ENST00000560591	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+

ORFfinder result based on the fusion transcript sequence of in-frame fusion genes.

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)

ENST00000536084

EIF2AK1

chr7

6077055

ENST00000178640

MAP2K5

chr15

68098984

1757

1279

319

1383

354

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
ENST00000536084	ENST00000178640	EIF2AK1	chr7	6077055	-	MAP2K5	chr15	68098984	+	0.001619109	0.9983809

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Fusion Genomic Features for EIF2AK1-MAP2K5

FusionAI prediction of the potential fusion gene breakpoint based on the pre-mature RNA sequence context (+/- 5kb of individual partner genes, total 20kb length sequence). FusionAI is a fusion gene breakpoint classifier based on convolutional neural network by comparing the fusion positive and negative sequence context of ~ 20K fusion gene data. From here, we can have the relative potentency of the 20K genomic sequence how individual sequnce will be likely used as the gene fusion breakpoints.

Hgene	Hchr	Hbp	Hstrand	Tgene	Tchr	Tbp	Tstrand	1-p	p (fusion gene breakpoint)
EIF2AK1	chr7	6077054	-	MAP2K5	chr15	68098983	+	4.17E-07	0.99999964
EIF2AK1	chr7	6077054	-	MAP2K5	chr15	68098983	+	4.17E-07	0.99999964
EIF2AK1	chr7	6077054	-	MAP2K5	chr15	68098983	+	4.17E-07	0.99999964
EIF2AK1	chr7	6077054	-	MAP2K5	chr15	68098983	+	4.17E-07	0.99999964

Distribution of 44 human genomic features loci across 20kb length fusion breakpoint regions. We integrated a total of 44 different types of human genomic feature loci information across five big categories including virus integration sites, repeats, structural variants, chromatin states, and gene expression regulation. More details are in help page.

Distribution of 44 human genomic features loci across 20kb length fusion breakpoint regions that are ovelapped with the top 1% feature importance score regions. More details are in help page.

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Fusion Protein Features for EIF2AK1-MAP2K5

Four levels of functional features of fusion genes
Go to FGviewer search page for the most frequent breakpoint (https://ccsmweb.uth.edu/FGviewer/chr7:6077055/chr15:68098984)
- 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
EIF2AK1 Q9BQI3	MAP2K5 Q13163
FUNCTION: Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions (PubMed:32132706, PubMed:32132707). Key activator of the integrated stress response (ISR) required for adaptation to various stress, such as heme deficiency, oxidative stress, osmotic shock, mitochondrial dysfunction and heat shock (PubMed:32132706, PubMed:32132707). EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming (PubMed:32132706, PubMed:32132707). Acts as a key sensor of heme-deficiency: in normal conditions, binds hemin via a cysteine thiolate and histidine nitrogenous coordination, leading to inhibit the protein kinase activity (By similarity). This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell: heme depletion relieves inhibition and stimulates kinase activity, activating the ISR (By similarity). Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions (By similarity). In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties (By similarity). It thereby plays an essential protective role for RBC survival in anemias of iron deficiency (By similarity). Similarly, in hepatocytes, involved in heme-mediated translational control of CYP2B and CYP3A and possibly other hepatic P450 cytochromes (By similarity). May also regulate endoplasmic reticulum (ER) stress during acute heme-deficient conditions (By similarity). Also activates the ISR in response to mitochondrial dysfunction: HRI/EIF2AK1 protein kinase activity is activated upon binding to the processed form of DELE1 (S-DELE1), thereby promoting the ATF4-mediated reprogramming (PubMed:32132706, PubMed:32132707). {ECO:0000250\|UniProtKB:Q9Z2R9, ECO:0000269\|PubMed:32132706, ECO:0000269\|PubMed:32132707, ECO:0000269\|PubMed:32197074}.	FUNCTION: Acts as a scaffold for the formation of a ternary MAP3K2/MAP3K3-MAP3K5-MAPK7 signaling complex. Activation of this pathway appears to play a critical role in protecting cells from stress-induced apoptosis, neuronal survival and cardiac development and angiogenesis. {ECO:0000269\|PubMed:7759517, ECO:0000269\|PubMed:9384584}.

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
download page

* Minus value of BPloci means that the break pointn is located before the CDS.

- In-frame and retained protein feature among the 13 regional features.

Partner

Gene

Hbp

Tbp

ENST

Strand

BPexon

TotalExon

Protein feature loci

*BPloci

TotalLen

Protein feature

Protein feature note

Hgene

EIF2AK1

chr7:6077055

chr15:68098984

ENST00000199389

173_181

444

631.0

Nucleotide binding

ATP

Hgene

EIF2AK1

chr7:6077055

chr15:68098984

ENST00000199389

410_415

444

631.0

Repeat

Note=HRM 1

- In-frame and not-retained protein feature among the 13 regional features.

Partner

Gene

Hbp

Tbp

ENST

Strand

BPexon

TotalExon

Protein feature loci

*BPloci

TotalLen

Protein feature

Protein feature note

Hgene

EIF2AK1

chr7:6077055

chr15:68098984

ENST00000199389

167_583

444

631.0

Domain

Protein kinase

Hgene

EIF2AK1

chr7:6077055

chr15:68098984

ENST00000199389

552_557

444

631.0

Repeat

Note=HRM 2

Tgene

MAP2K5

chr7:6077055

chr15:68098984

ENST00000178640

166_409

414

449.0

Domain

Protein kinase

Tgene

MAP2K5

chr7:6077055

chr15:68098984

ENST00000178640

18_109

414

449.0

Domain

PB1

Tgene

MAP2K5

chr7:6077055

chr15:68098984

ENST00000354498

166_409

378

413.0

Domain

Protein kinase

Tgene

MAP2K5

chr7:6077055

chr15:68098984

ENST00000354498

18_109

378

413.0

Domain

PB1

Tgene

MAP2K5

chr7:6077055

chr15:68098984

ENST00000395476

166_409

404

439.0

Domain

Protein kinase

Tgene

MAP2K5

chr7:6077055

chr15:68098984

ENST00000395476

18_109

404

439.0

Domain

PB1

Tgene

MAP2K5

chr7:6077055

chr15:68098984

ENST00000178640

172_180

414

449.0

Nucleotide binding

ATP

Tgene

MAP2K5

chr7:6077055

chr15:68098984

ENST00000354498

172_180

378

413.0

Nucleotide binding

ATP

Tgene

MAP2K5

chr7:6077055

chr15:68098984

ENST00000395476

172_180

404

439.0

Nucleotide binding

ATP

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Fusion Gene Sequence for EIF2AK1-MAP2K5

For in-frame fusion transcripts, we provide the fusion transcript sequences and fusion amino acid sequences. To have fusion amino acid sequence, we ran ORFfinder and chose the longest ORF among the all predicted ones.

>25655_25655_1_EIF2AK1-MAP2K5_EIF2AK1_chr7_6077055_ENST00000536084_MAP2K5_chr15_68098984_ENST00000178640_length(transcript)=1757nt_BP=1279nt
GGACGGCGCTAGCTGCAGCATCGGAGTGTGGCAGTGCTGGGCTGGCCGGCGGGCTGGGCTGCGGCCCGCGCGCGGCCGGCGATGCAGGGG
GGCAACTCCGGGGTCCGCAAGCGCGAAGAGGAGGGCGACGGGGCTGGGGCTGTGGCTGCGCCGCCGGCCATCGACTTTCCCGCCGAGGGC
CCGGACCCCGAATATGACGAATCTGATGTTCCAGCAGAAATCCAGGTGTTAAAAGAACCCCTACAACAGCCAACCTTCCCTTTTGCAGTT
GCAAACCAACTCTTGCTGGTTTCTTTGCTGGAGCACTTGAGCCACGTGCATGAACCAAACCCACTTCGTTCAAGACAGGTGTTTAAGCGA
TCCTTGTGAGGATATTTCTCGTATCCAGAAAATCAGATCAAGGGAAGTAGCCTTGGAAGCACAAACTTCACGTTACTTAAATGAATTTGA
AGAACTTGCCATCTTAGGAAAAGGTGGATACGGAAGAGTATACAAGGTCAGGAATAAATTAGATGGTCAGTATTATGCAATAAAAAAAAT
CCTGATTAAGGGTGCAACTAAAACAGTTTGCATGAAGGTCCTACGGGAAGTGAAGGTGCTGGCAGGTCTTCAGCACCCCAATATTGTTGG
CTATCACACCGCGTGGATAGAACATGTTCATGTGATTCAGCCACGAGCAGACAGAGCTGCCATTGAGTTGCCATCTCTGGAAGTGCTCTC
CGACCAGGAAGAGGACAGAGAGCAATGTGGTGTTAAAAATGATGAAAGTAGCAGCTCATCCATTATCTTTGCTGAGCCCACCCCAGAAAA
AGAAAAACGCTTTGGAGAATCTGACACTGAAAATCAGAATAACAAGTCGGTGAAGTACACCACCAATTTAGTCATAAGAGAATCTGGTGA
ACTTGAGTCGACCCTGGAGCTCCAGGAAAATGGCTTGGCTGGTTTGTCTGCCAGTTCAATTGTGGAACAGCAGCTGCCACTCAGGCGTAA
TTCCCACCTAGAGGAGAGTTTCACATCCACCGAAGAATCTTCCGAAGAAAATGTCAACTTTTTGGGTCAGACAGAGGCACAGTACCACCT
GATGCTGCACATCCAGATGCAGCTGTGTGAGCTCTCGCTGTGGGATTGGATAGTCGAGAGAAACAAGCGGGGCCGGGAGTATGTGGACGA
GTCTGCCTGTCCTTATGTTATGGCCAATGTTGCAACAAAAATTTTTCAAGAATTGGTAGAAGGTGTGTTTTACATACATAACATGGGAAT
TGTGCACCGAGATCTGAAGGGCCACCCGTTCATCGTGCAGTTCAATGATGGAAATGCCGCCGTGGTGTCCATGTGGGTGTGCCGGGCGCT
GGAGGAGAGGCGGAGCCAGCAGGGGCCCCCGTGAGGCTGCCGCAGGGCACTGAAAGCCCAGGACCAGTAACCAAGGAGAACAACCCACCC
GTCGCCCTTCTCCGTATGCTGCCTGCGCCAGAAGAGCTTTGCTGGGCCCTGGCTTCCCTGCCCTCGCCTTCACCTCTGTCAGCAGGTGGC
CTTGCCTGGGGAGCCCCATGTGTGGCCCACCCCACCAGGCCATCCCCATACCTTCTGGTTTGAAGGCGCTGACACTGGCAGAGAGGTAAA
GGGTGGGGCATTGAGAATGGAGGCTCCCAGGGTCCCTGCCCACTTCTGTTTTCCTAATGTTTTTCTCTATAAAGGGTCAGGCCCGTCAGC

>25655_25655_1_EIF2AK1-MAP2K5_EIF2AK1_chr7_6077055_ENST00000536084_MAP2K5_chr15_68098984_ENST00000178640_length(amino acids)=354AA_BP=320
MNQTHFVQDRCLSDPCEDISRIQKIRSREVALEAQTSRYLNEFEELAILGKGGYGRVYKVRNKLDGQYYAIKKILIKGATKTVCMKVLRE
VKVLAGLQHPNIVGYHTAWIEHVHVIQPRADRAAIELPSLEVLSDQEEDREQCGVKNDESSSSSIIFAEPTPEKEKRFGESDTENQNNKS
VKYTTNLVIRESGELESTLELQENGLAGLSASSIVEQQLPLRRNSHLEESFTSTEESSEENVNFLGQTEAQYHLMLHIQMQLCELSLWDW

--------------------------------------------------------------

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Fusion Gene PPI Analysis for EIF2AK1-MAP2K5

Go to ChiPPI (Chimeric Protein-Protein interactions) to see the chimeric PPI interaction in
ChiPPI page.

Protein-protein interactors with each fusion partner protein in wild-type (BIOGRID-3.4.160)

Hgene

Hgene's interactors

Tgene

Tgene's interactors

- Retained PPIs in in-frame fusion.

Partner

Gene

Hbp

Tbp

ENST

Strand

BPexon

TotalExon

Protein feature loci

*BPloci

TotalLen

Still interaction with

- Lost PPIs in in-frame fusion.

Partner	Gene	Hbp	Tbp	ENST	Strand	BPexon	TotalExon	Protein feature loci	*BPloci	TotalLen	Interaction lost with
Tgene	MAP2K5	chr7:6077055	chr15:68098984	ENST00000178640		20	22	64_68	414.0	449.0	MAP3K2/MAP3K3
Tgene	MAP2K5	chr7:6077055	chr15:68098984	ENST00000354498		20	22	64_68	378.0	413.0	MAP3K2/MAP3K3
Tgene	MAP2K5	chr7:6077055	chr15:68098984	ENST00000395476		19	21	64_68	404.0	439.0	MAP3K2/MAP3K3
Tgene	MAP2K5	chr7:6077055	chr15:68098984	ENST00000178640		20	22	117_131	414.0	449.0	MAPK7
Tgene	MAP2K5	chr7:6077055	chr15:68098984	ENST00000178640		20	22	18_25	414.0	449.0	MAPK7
Tgene	MAP2K5	chr7:6077055	chr15:68098984	ENST00000354498		20	22	117_131	378.0	413.0	MAPK7
Tgene	MAP2K5	chr7:6077055	chr15:68098984	ENST00000354498		20	22	18_25	378.0	413.0	MAPK7
Tgene	MAP2K5	chr7:6077055	chr15:68098984	ENST00000395476		19	21	117_131	404.0	439.0	MAPK7
Tgene	MAP2K5	chr7:6077055	chr15:68098984	ENST00000395476		19	21	18_25	404.0	439.0	MAPK7

- Retained PPIs, but lost function due to frame-shift fusion.

Partner

Gene

Hbp

Tbp

ENST

Strand

BPexon

TotalExon

Protein feature loci

*BPloci

TotalLen

Interaction lost with

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Related Drugs for EIF2AK1-MAP2K5

Drugs targeting genes involved in this fusion gene.
(DrugBank Version 5.1.8 2021-05-08)

Partner

Gene

UniProtAcc

DrugBank ID

Drug name

Drug activity

Drug type

Drug status

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Related Diseases for EIF2AK1-MAP2K5

Diseases associated with fusion partners.
(DisGeNet 4.0)

Partner

Gene

Disease ID

Disease name

# pubmeds

Source