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Fusion Protein:MAP4K4-MBNL2

Fusion Gene and Fusion Protein Summary

Fusion gene summary

Fusion partner gene information	Fusion gene name: MAP4K4-MBNL2
	FusionPDB ID: 51408
	FusionGDB2.0 ID: 51408
		Hgene	Tgene
	Gene symbol	MAP4K4	MBNL2
	Gene ID	9448	10150
	Gene name	mitogen-activated protein kinase kinase kinase kinase 4	muscleblind like splicing regulator 2
	Synonyms	FLH21957\|HEL-S-31\|HGK\|MEKKK4\|NIK	MBLL\|MBLL39\|PRO2032
	Cytomap	2q11.2	13q32.1
	Type of gene	protein-coding	protein-coding
	Description	mitogen-activated protein kinase kinase kinase kinase 4HPK/GCK-like kinase HGKMAPK/ERK kinase kinase kinase 4MEK kinase kinase 4Ste20 group protein kinase HGKepididymis secretory protein Li 31hepatocyte progenitor kinase-like/germinal center kinase-	muscleblind-like protein 2muscleblind-like 2muscleblind-like protein 1muscleblind-like protein-like 39
	Modification date	20200315	20200313
	UniProtAcc	O95819 Main function of 5'-partner protein: FUNCTION: Serine/threonine kinase that may play a role in the response to environmental stress and cytokines such as TNF-alpha. Appears to act upstream of the JUN N-terminal pathway. Phosphorylates SMAD1 on Thr-322. {ECO:0000269\|PubMed:21690388, ECO:0000269\|PubMed:9890973}.	Q5VZF2 Main function of 5'-partner protein: FUNCTION: Mediates pre-mRNA alternative splicing regulation. Acts either as activator or repressor of splicing on specific pre-mRNA targets. Inhibits cardiac troponin-T (TNNT2) pre-mRNA exon inclusion but induces insulin receptor (IR) pre-mRNA exon inclusion in muscle. Antagonizes the alternative splicing activity pattern of CELF proteins. RNA-binding protein that binds to 5'ACACCC-3' core sequence, termed zipcode, within the 3'UTR of ITGA3. Binds to CUG triplet repeat expansion in myotonic dystrophy muscle cells by sequestering the target RNAs. Seems to regulate expression and localization of ITGA3 by transporting it from the nucleus to cytoplasm at adhesion plaques. May play a role in myotonic dystrophy pathophysiology (DM). {ECO:0000269\|PubMed:15257297, ECO:0000269\|PubMed:16273094, ECO:0000269\|PubMed:16946708}.
Ensembl transtripts involved in fusion gene	ENST ids	ENST00000302217, ENST00000324219, ENST00000347699, ENST00000350198, ENST00000413150, ENST00000425019, ENST00000456652, ENST00000350878, ENST00000498066,	ENST00000376673, ENST00000397601, ENST00000445661, ENST00000343600, ENST00000345429,
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)	* DoF score	16 X 11 X 9=1584	7 X 8 X 5=280
	# samples	16	9
	** MAII score	log2(16/1584*10)=-3.30742852519225 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0	log2(9/280*10)=-1.63742992061529 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0
Fusion gene context	PubMed: MAP4K4 [Title/Abstract] AND MBNL2 [Title/Abstract] AND fusion [Title/Abstract]
Fusion neoantigen context	PubMed: MAP4K4 [Title/Abstract] AND MBNL2 [Title/Abstract] AND neoantigen [Title/Abstract]
Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)	MAP4K4(102315000)-MBNL2(98043576), # samples:1
Anticipated loss of major functional domain due to fusion event.	MAP4K4-MBNL2 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. MAP4K4-MBNL2 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. MAP4K4-MBNL2 seems lost the major protein functional domain in Hgene partner, which is a IUPHAR drug target due to the frame-shifted ORF. MAP4K4-MBNL2 seems lost the major protein functional domain in Hgene partner, which is a kinase due to the frame-shifted ORF. MAP4K4-MBNL2 seems lost the major protein functional domain in Tgene partner, which is a essential gene due to the frame-shifted ORF. MAP4K4-MBNL2 seems lost the major protein functional domain in Tgene partner, which is a transcription factor 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	MAP4K4	GO:0006468	protein phosphorylation	9890973
Hgene	MAP4K4	GO:0035556	intracellular signal transduction	9890973
Hgene	MAP4K4	GO:0046328	regulation of JNK cascade	14966141
Tgene	MBNL2	GO:0043484	regulation of RNA splicing	15257297\|16946708

Four levels of functional features of fusion genes
Go to FGviewer search page for the most frequent breakpoint (https://ccsmweb.uth.edu/FGviewer/chr2:102315000/chr13:98043576)
- 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 MAP4K4 (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 MBNL2 (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)
ENST00000425019	MAP4K4	chr2	102315000	+	ENST00000343600	MBNL2	chr13	98043576	+	3258	460	481	2	160
ENST00000425019	MAP4K4	chr2	102315000	+	ENST00000345429	MBNL2	chr13	98043576	+	3259	460	374	0	125
ENST00000324219	MAP4K4	chr2	102315000	+	ENST00000343600	MBNL2	chr13	98043576	+	2995	197	1474	1698	74
ENST00000324219	MAP4K4	chr2	102315000	+	ENST00000345429	MBNL2	chr13	98043576	+	2996	197	1474	1698	74
ENST00000350198	MAP4K4	chr2	102315000	+	ENST00000343600	MBNL2	chr13	98043576	+	2995	197	1474	1698	74
ENST00000350198	MAP4K4	chr2	102315000	+	ENST00000345429	MBNL2	chr13	98043576	+	2996	197	1474	1698	74
ENST00000302217	MAP4K4	chr2	102315000	+	ENST00000343600	MBNL2	chr13	98043576	+	2995	197	1474	1698	74
ENST00000302217	MAP4K4	chr2	102315000	+	ENST00000345429	MBNL2	chr13	98043576	+	2996	197	1474	1698	74
ENST00000413150	MAP4K4	chr2	102315000	+	ENST00000343600	MBNL2	chr13	98043576	+	2976	178	1455	1679	74
ENST00000413150	MAP4K4	chr2	102315000	+	ENST00000345429	MBNL2	chr13	98043576	+	2977	178	1455	1679	74
ENST00000347699	MAP4K4	chr2	102315000	+	ENST00000343600	MBNL2	chr13	98043576	+	2921	123	1400	1624	74
ENST00000347699	MAP4K4	chr2	102315000	+	ENST00000345429	MBNL2	chr13	98043576	+	2922	123	1400	1624	74
ENST00000456652	MAP4K4	chr2	102315000	+	ENST00000343600	MBNL2	chr13	98043576	+	2921	123	1400	1624	74
ENST00000456652	MAP4K4	chr2	102315000	+	ENST00000345429	MBNL2	chr13	98043576	+	2922	123	1400	1624	74

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
ENST00000425019	ENST00000343600	MAP4K4	chr2	102315000	+	MBNL2	chr13	98043576	+	0.48217636	0.51782364
ENST00000425019	ENST00000345429	MAP4K4	chr2	102315000	+	MBNL2	chr13	98043576	+	0.45893586	0.54106414
ENST00000324219	ENST00000343600	MAP4K4	chr2	102315000	+	MBNL2	chr13	98043576	+	0.7650391	0.23496087
ENST00000324219	ENST00000345429	MAP4K4	chr2	102315000	+	MBNL2	chr13	98043576	+	0.7659475	0.23405254
ENST00000350198	ENST00000343600	MAP4K4	chr2	102315000	+	MBNL2	chr13	98043576	+	0.7650391	0.23496087
ENST00000350198	ENST00000345429	MAP4K4	chr2	102315000	+	MBNL2	chr13	98043576	+	0.7659475	0.23405254
ENST00000302217	ENST00000343600	MAP4K4	chr2	102315000	+	MBNL2	chr13	98043576	+	0.7650391	0.23496087
ENST00000302217	ENST00000345429	MAP4K4	chr2	102315000	+	MBNL2	chr13	98043576	+	0.7659475	0.23405254
ENST00000413150	ENST00000343600	MAP4K4	chr2	102315000	+	MBNL2	chr13	98043576	+	0.6638201	0.33617988
ENST00000413150	ENST00000345429	MAP4K4	chr2	102315000	+	MBNL2	chr13	98043576	+	0.6376417	0.36235824
ENST00000347699	ENST00000343600	MAP4K4	chr2	102315000	+	MBNL2	chr13	98043576	+	0.40285352	0.5971465
ENST00000347699	ENST00000345429	MAP4K4	chr2	102315000	+	MBNL2	chr13	98043576	+	0.40130973	0.5986903
ENST00000456652	ENST00000343600	MAP4K4	chr2	102315000	+	MBNL2	chr13	98043576	+	0.40285352	0.5971465
ENST00000456652	ENST00000345429	MAP4K4	chr2	102315000	+	MBNL2	chr13	98043576	+	0.40130973	0.5986903

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 MAP4K4-MBNL2

+/-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 MAP4K4-MBNL2 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 MAP4K4-MBNL2 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 MAP4K4-MBNL2

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 MAP4K4-MBNL2

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 MAP4K4-MBNL2

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 MAP4K4-MBNL2

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 MAP4K4-MBNL2

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 MAP4K4-MBNL2

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 MAP4K4-MBNL2

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

	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)