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	Kinase Fusion Gene Summary
	Kinase Fusion Gene Sample Information
	Kinase Fusion ORF Analysis
	Kinase Fusion Amino Acid Sequences
	Multiple Sequence Alignment of All Fusion Protein Isoforms
	Kinase Fusion Protein Functional Features
	Kinase Fusion Protein Structures
	Comparison of Fusion Protein Isoforms
	Comparison of Fusion Protein Sequences/Structures with Known Sequences/Structures from PDB
	pLDDT Scores and Difference Analysis of pLDDT Scores Between the Active Sites (Best) and Non-Active Sites.
	Ramachandran Plot of Kinase Fusion Protein Structure
	Potential Active Site Information
	Virtual Screening Results
	Kinase-Substrate Information
	Related Drugs with This Kinase Fusion Protein
	Related Disease with This Kinase Fusion Protein
	Clinical Trials of the Found Drugs/Small Molecules

Kinase Fusion Gene:NCOA4_RET

Kinase Fusion Protein Summary

Kinase Fusion gene summary

Kinase Fusion partner gene information	Kinase Fusion gene name: NCOA4_RET
	KinaseFusionDB ID: KFG4079
	FusionGDB2.0 ID: KFG4079
		Hgene	Tgene
	Gene symbol	NCOA4	RET
	Gene ID	8031	5979
	Gene name	nuclear receptor coactivator 4	ret proto-oncogene
	Synonyms	ARA70\|ELE1\|PTC3\|RFG	CDHF12\|CDHR16\|HSCR1\|MEN2A\|MEN2B\|MTC1\|PTC\|RET-ELE1
	Cytomap	10q11.22	10q11.21
	Type of gene	protein-coding	protein-coding
	Description	nuclear receptor coactivator 470 kDa AR-activator70 kDa androgen receptor coactivatorNCoA-4RET-activating gene ELE1androgen receptor-associated protein of 70 kDaret fused	proto-oncogene tyrosine-protein kinase receptor RetRET receptor tyrosine kinasecadherin family member 12cadherin-related family member 16proto-oncogene c-Retrearranged during transfectionret proto-oncogene (multiple endocrine neoplasia and medullary
	Modification date	20240407	20240416
	UniProtAcc	Q13772	P07949
Ensembl transtripts involved in fusion gene	ENST ids	ENST00000498586, ENST00000414907, ENST00000344348, ENST00000374082, ENST00000374087, ENST00000430396, ENST00000438493, ENST00000443446, ENST00000452682,	ENST00000340058, ENST00000355710,
Context (manual curation of fusion genes in KinaseFusionDB)	PubMed: NCOA4 [Title/Abstract] AND RET [Title/Abstract] AND fusion [Title/Abstract]
Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)	NCOA4(51582939)-RET(43612032), # samples:12 RET(43610184)-NCOA4(51584616), # samples:3

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	NCOA4	GO:0006622	protein targeting to lysosome	25327288
Tgene	RET	GO:0030155	regulation of cell adhesion	21357690
Tgene	RET	GO:0030335	positive regulation of cell migration	20702524
Tgene	RET	GO:0033619	membrane protein proteolysis	21357690
Tgene	RET	GO:0033630	positive regulation of cell adhesion mediated by integrin	20702524
Tgene	RET	GO:0035860	glial cell-derived neurotrophic factor receptor signaling pathway	24560924\|25242331\|28953886\|31535977
Tgene	RET	GO:0043410	positive regulation of MAPK cascade	28846099

Kinase Fusion gene breakpoints across NCOA4 (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 RET (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-CE-A482-01A	NCOA4	chr10	51582939	RET	chr10	43612032
ChimerDB4	TCGA-EM-A2CU	NCOA4	chr10	51582939	RET	chr10	43612031
ChimerKB3	.	NCOA4	chr10	51581378	RET	chr10	43612031
ChimerKB3	.	NCOA4	chr10	51582272	RET	chr10	43612031
ChimerKB3	.	NCOA4	chr10	51582939	RET	chr10	43609927
ChimerKB3	.	NCOA4	chr10	51582939	RET	chr10	43612031
ChiTaRS5.0	S71225	NCOA4	chr10	51582940	RET	chr10	43612030
ChiTaRS5.0	S82976	NCOA4	chr10	51584125	RET	chr10	43610089
ChimerKB3	.	NCOA4	chr10	51252946	RET	chr10	42932035
ChiTaRS5.0	S74821	NCOA4	chr10	51584251	RET	chr10	43610593
COSMIC	1809971	NCOA4	chr10	51582468	RET	chr10	43610462
COSMIC	2042903	NCOA4	chr10	51582314	RET	chr10	43610359
COSMIC	2042904	NCOA4	chr10	51582468	RET	chr10	43610462
COSMIC	2042905	NCOA4	chr10	51582468	RET	chr10	43610462
COSMIC	2042906	NCOA4	chr10	51582921	RET	chr10	43610185
COSMIC	2060692	NCOA4	chr10	51582960	RET	chr10	43610441

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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)
ENST00000438493	ENST00000355710	NCOA4	chr10	51582939	RET	chr10	43612032	4305	656
ENST00000438493	ENST00000355710	NCOA4	chr10	51582939	RET	chr10	43612031	4305	656
ENST00000438493	ENST00000355710	NCOA4	chr10	51582940	RET	chr10	43612030	4305	656
ENST00000438493	ENST00000355710	NCOA4	chr10	51581378	RET	chr10	43612031	4071	578
ENST00000438493	ENST00000355710	NCOA4	chr10	51582272	RET	chr10	43612031	4161	608

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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

>ENST00000438493_ENST00000355710_NCOA4_chr10_51582939_RET_chr10_43612032_length(amino acids)=656
MGAQLTTFALAGAVRRMNTFQDQSGSSSNREPLLRCSDARRDLELAIGGVLRAEQQIKDNLREVKAQIHSCISRHLECLRSREVWLYEQV
DLIYQLKEETLQQQAQQLYSLLGQFNCLTHQLECTQNKDLANQVSVCLERLGSLTLKPEDSTVLLFEADTITLRQTITTFGSLKTIQIPE
HLMAHASSANIGPFLEKRGCISMPEQKSASGIVAVPFSEWLLGSKPASGYQAPYIPSTDPQDWLTQKQTLENSQEDPKWEFPRKNLVLGK
TLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRE
SRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLSRDVYEEDSYVKR
SQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERLFNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVF
ADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVPLTRADGTNTGFP

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

>ENST00000438493_ENST00000355710_NCOA4_chr10_51582939_RET_chr10_43612031_length(amino acids)=656
MGAQLTTFALAGAVRRMNTFQDQSGSSSNREPLLRCSDARRDLELAIGGVLRAEQQIKDNLREVKAQIHSCISRHLECLRSREVWLYEQV
DLIYQLKEETLQQQAQQLYSLLGQFNCLTHQLECTQNKDLANQVSVCLERLGSLTLKPEDSTVLLFEADTITLRQTITTFGSLKTIQIPE
HLMAHASSANIGPFLEKRGCISMPEQKSASGIVAVPFSEWLLGSKPASGYQAPYIPSTDPQDWLTQKQTLENSQEDPKWEFPRKNLVLGK
TLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRE
SRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLSRDVYEEDSYVKR
SQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERLFNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVF
ADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVPLTRADGTNTGFP

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

>ENST00000438493_ENST00000355710_NCOA4_chr10_51582940_RET_chr10_43612030_length(amino acids)=656
MGAQLTTFALAGAVRRMNTFQDQSGSSSNREPLLRCSDARRDLELAIGGVLRAEQQIKDNLREVKAQIHSCISRHLECLRSREVWLYEQV
DLIYQLKEETLQQQAQQLYSLLGQFNCLTHQLECTQNKDLANQVSVCLERLGSLTLKPEDSTVLLFEADTITLRQTITTFGSLKTIQIPE
HLMAHASSANIGPFLEKRGCISMPEQKSASGIVAVPFSEWLLGSKPASGYQAPYIPSTDPQDWLTQKQTLENSQEDPKWEFPRKNLVLGK
TLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRE
SRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLSRDVYEEDSYVKR
SQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERLFNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVF
ADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVPLTRADGTNTGFP

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

>ENST00000438493_ENST00000355710_NCOA4_chr10_51581378_RET_chr10_43612031_length(amino acids)=578
MGAQLTTFALAGAVRRMNTFQDQSGSSSNREPLLRCSDARRDLELAIGGVLRAEQQIKDNLREVKAQIHSCISRHLECLRSREVWLYEQV
DLIYQLKEETLQQQAQQLYSLLGQFNCLTHQLECTQNKDLANQVSVCLERLGSLTLKPEDSTVLLFEADTITLRQTITTFGSLKTIEDPK
WEFPRKNLVLGKTLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLKQVNHPHVIKLYGACSQDGPLLLIVEY
AKYGSLRGFLRESRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLS
RDVYEEDSYVKRSQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERLFNLLKTGHRMERPDNCSEEMYRLMLQ
CWKQEPDKRPVFADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVP

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

>ENST00000438493_ENST00000355710_NCOA4_chr10_51582272_RET_chr10_43612031_length(amino acids)=608
MGAQLTTFALAGAVRRMNTFQDQSGSSSNREPLLRCSDARRDLELAIGGVLRAEQQIKDNLREVKAQIHSCISRHLECLRSREVWLYEQV
DLIYQLKEETLQQQAQQLYSLLGQFNCLTHQLECTQNKDLANQVSVCLERLGSLTLKPEDSTVLLFEADTITLRQTITTFGSLKTIQIPE
HLMAHASSANIGPFLEKRGCISMPEQEDPKWEFPRKNLVLGKTLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEF
NVLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRESRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLA
EMKLVHRDLAARNILVAEGRKMKISDFGLSRDVYEEDSYVKRSQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIP
PERLFNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVFADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNA

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

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/chr10:51582939/chr10:43612032)
- 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
NCOA4 Q13772	RET P07949
FUNCTION: Enhances the androgen receptor transcriptional activity in prostate cancer cells. Ligand-independent coactivator of the peroxisome proliferator-activated receptor (PPAR) gamma. {ECO:0000269\|PubMed:10347167}.	FUNCTION: Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration. Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which induces inhibition of food-intake. Activates MAPK- and AKT-signaling pathways (PubMed:28846097, PubMed:28953886, PubMed:28846099). Isoform 1 in complex with GFRAL induces higher activation of MAPK-signaling pathway than isoform 2 in complex with GFRAL (PubMed:28846099). {ECO:0000269\|PubMed:20064382, ECO:0000269\|PubMed:20616503, ECO:0000269\|PubMed:20702524, ECO:0000269\|PubMed:21357690, ECO:0000269\|PubMed:21454698, ECO:0000269\|PubMed:28846097, ECO:0000269\|PubMed:28846099, ECO:0000269\|PubMed:28953886}.

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.

- 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
Tgene	NCOA4	51581378	RET	43612031	ENST00000438493	10	19	724_1016	712	1073	Domain	Note=Protein kinase;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU00159
Tgene	NCOA4	51581378	RET	43612031	ENST00000438493	10	20	724_1016	712	1115	Domain	Note=Protein kinase;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU00159
Tgene	NCOA4	51582272	RET	43612031	ENST00000438493	10	19	724_1016	712	1073	Domain	Note=Protein kinase;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU00159
Tgene	NCOA4	51582272	RET	43612031	ENST00000438493	10	20	724_1016	712	1115	Domain	Note=Protein kinase;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU00159
Tgene	NCOA4	51582939	RET	43612031	ENST00000438493	10	19	724_1016	712	1073	Domain	Note=Protein kinase;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU00159
Tgene	NCOA4	51582939	RET	43612031	ENST00000438493	10	20	724_1016	712	1115	Domain	Note=Protein kinase;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU00159
Tgene	NCOA4	51582939	RET	43612032	ENST00000438493	10	19	724_1016	712	1073	Domain	Note=Protein kinase;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU00159
Tgene	NCOA4	51582939	RET	43612032	ENST00000438493	10	20	724_1016	712	1115	Domain	Note=Protein kinase;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU00159
Tgene	NCOA4	51582940	RET	43612030	ENST00000438493	10	19	724_1016	712	1073	Domain	Note=Protein kinase;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU00159
Tgene	NCOA4	51582940	RET	43612030	ENST00000438493	10	20	724_1016	712	1115	Domain	Note=Protein kinase;Ontology_term=ECO:0000255;evidence=ECO:0000255\|PROSITE-ProRule:PRU00159

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Kinase Fusion Protein Structures

CIF files of the predicted kinase fusion proteins
* Here we show the 3D structure of the fusion proteins using Mol*. AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. Model confidence is shown from the pLDDT values per residue. pLDDT corresponds to the model’s prediction of its score on the local Distance Difference Test. It is a measure of local accuracy (from AlphfaFold website). To color code individual residues, we transformed individual PDB files into CIF format.

Kinase Fusion protein CIF link (fusion AA seq ID in KinaseFusionDB)	Henst	Tenst	Hgene	Hchr	Hbp	Tgene	Tchr	Tbp	AA seq	Len(AA seq)
PDB file >>>328_NCOA4_RET	ENST00000438493	ENST00000355710	NCOA4	chr10	51582272	RET	chr10	43612031	MGAQLTTFALAGAVRRMNTFQDQSGSSSNREPLLRCSDARRDLELAIGGVLRAEQQIKDNLREVKAQIHSCISRHLECLRSREVWLYEQV DLIYQLKEETLQQQAQQLYSLLGQFNCLTHQLECTQNKDLANQVSVCLERLGSLTLKPEDSTVLLFEADTITLRQTITTFGSLKTIQIPE HLMAHASSANIGPFLEKRGCISMPEQEDPKWEFPRKNLVLGKTLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEF NVLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRESRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLA EMKLVHRDLAARNILVAEGRKMKISDFGLSRDVYEEDSYVKRSQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIP PERLFNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVFADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNA	608
3D view using mol* of 328_NCOA4_RET

PDB file >>>TKFP_561_NCOA4_RET	ENST00000438493	ENST00000355710	NCOA4	chr10	51582939	RET	chr10	43612032	MGAQLTTFALAGAVRRMNTFQDQSGSSSNREPLLRCSDARRDLELAIGGVLRAEQQIKDNLREVKAQIHSCISRHLECLRSREVWLYEQV DLIYQLKEETLQQQAQQLYSLLGQFNCLTHQLECTQNKDLANQVSVCLERLGSLTLKPEDSTVLLFEADTITLRQTITTFGSLKTIQIPE HLMAHASSANIGPFLEKRGCISMPEQKSASGIVAVPFSEWLLGSKPASGYQAPYIPSTDPQDWLTQKQTLENSQEDPKWEFPRKNLVLGK TLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRE SRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLSRDVYEEDSYVKR SQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERLFNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVF ADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVPLTRADGTNTGFP	656_NCOA4_RET
PDB file >>>TKFP_562_NCOA4_RET	ENST00000438493	ENST00000355710	NCOA4	chr10	51582939	RET	chr10	43612031	MGAQLTTFALAGAVRRMNTFQDQSGSSSNREPLLRCSDARRDLELAIGGVLRAEQQIKDNLREVKAQIHSCISRHLECLRSREVWLYEQV DLIYQLKEETLQQQAQQLYSLLGQFNCLTHQLECTQNKDLANQVSVCLERLGSLTLKPEDSTVLLFEADTITLRQTITTFGSLKTIQIPE HLMAHASSANIGPFLEKRGCISMPEQKSASGIVAVPFSEWLLGSKPASGYQAPYIPSTDPQDWLTQKQTLENSQEDPKWEFPRKNLVLGK TLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRE SRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLSRDVYEEDSYVKR SQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERLFNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVF ADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVPLTRADGTNTGFP	656_NCOA4_RET
PDB file >>>TKFP_563_NCOA4_RET	ENST00000438493	ENST00000355710	NCOA4	chr10	51582940	RET	chr10	43612030	MGAQLTTFALAGAVRRMNTFQDQSGSSSNREPLLRCSDARRDLELAIGGVLRAEQQIKDNLREVKAQIHSCISRHLECLRSREVWLYEQV DLIYQLKEETLQQQAQQLYSLLGQFNCLTHQLECTQNKDLANQVSVCLERLGSLTLKPEDSTVLLFEADTITLRQTITTFGSLKTIQIPE HLMAHASSANIGPFLEKRGCISMPEQKSASGIVAVPFSEWLLGSKPASGYQAPYIPSTDPQDWLTQKQTLENSQEDPKWEFPRKNLVLGK TLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRE SRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLSRDVYEEDSYVKR SQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERLFNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVF ADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVPLTRADGTNTGFP	656_NCOA4_RET
PDB file >>>TKFP_564_NCOA4_RET	ENST00000438493	ENST00000355710	NCOA4	chr10	51581378	RET	chr10	43612031	MGAQLTTFALAGAVRRMNTFQDQSGSSSNREPLLRCSDARRDLELAIGGVLRAEQQIKDNLREVKAQIHSCISRHLECLRSREVWLYEQV DLIYQLKEETLQQQAQQLYSLLGQFNCLTHQLECTQNKDLANQVSVCLERLGSLTLKPEDSTVLLFEADTITLRQTITTFGSLKTIEDPK WEFPRKNLVLGKTLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLKQVNHPHVIKLYGACSQDGPLLLIVEY AKYGSLRGFLRESRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLS RDVYEEDSYVKRSQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERLFNLLKTGHRMERPDNCSEEMYRLMLQ CWKQEPDKRPVFADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVP	578_NCOA4_RET
3D view using mol* of TKFP_564_NCOA4_RET

PDB file >>>TKFP_565_NCOA4_RET	ENST00000438493	ENST00000355710	NCOA4	chr10	51582272	RET	chr10	43612031	MGAQLTTFALAGAVRRMNTFQDQSGSSSNREPLLRCSDARRDLELAIGGVLRAEQQIKDNLREVKAQIHSCISRHLECLRSREVWLYEQV DLIYQLKEETLQQQAQQLYSLLGQFNCLTHQLECTQNKDLANQVSVCLERLGSLTLKPEDSTVLLFEADTITLRQTITTFGSLKTIQIPE HLMAHASSANIGPFLEKRGCISMPEQEDPKWEFPRKNLVLGKTLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEF NVLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRESRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLA EMKLVHRDLAARNILVAEGRKMKISDFGLSRDVYEEDSYVKRSQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIP PERLFNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVFADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNA	608_NCOA4_RET
3D view using mol* of TKFP_565_NCOA4_RET

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Comparison of Fusion Protein Isoforms

Superimpose the 3D Structures Among All Fusion Protein Isoforms
* Download the pdb file and open it from the molstar online viewer.

3D view using mol* of viewer/superimpose_isoforms/HKFP_331_RET_NCOA4_vs_HKFP_332_RET_NCOA4_superimposed.pdb.html
3D view using mol* of viewer/superimpose_isoforms/HKFP_331_RET_NCOA4_vs_HKFP_333_RET_NCOA4_superimposed.pdb.html
3D view using mol* of viewer/superimpose_isoforms/HKFP_332_RET_NCOA4_vs_HKFP_333_RET_NCOA4_superimposed.pdb.html
3D view using mol* of viewer/superimpose_isoforms/TKFP_561_NCOA4_RET_vs_TKFP_564_NCOA4_RET_superimposed.pdb.html
3D view using mol* of viewer/superimpose_isoforms/TKFP_561_NCOA4_RET_vs_TKFP_565_NCOA4_RET_superimposed.pdb.html
3D view using mol* of viewer/superimpose_isoforms/TKFP_564_NCOA4_RET_vs_TKFP_565_NCOA4_RET_superimposed.pdb.html

Comparison of the Secondary Structures of Fusion Protein Isoforms

./secondary_str/TKFP_564_NCOA4_RET_vs_TKFP_561_NCOA4_RET.png

./secondary_str/TKFP_565_NCOA4_RET_vs_TKFP_561_NCOA4_RET.png

./secondary_str/TKFP_565_NCOA4_RET_vs_TKFP_564_NCOA4_RET.png

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Comparison of Fusion Protein Sequences/Structures with Known Sequences/Structures from PDB

NCOA4_RET does not have any known PDB structures.

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pLDDT score distribution

all_data/KinaseFusionDB_T_Results/KinaseFusionDB_T_ViolinPlots/328_NCOA4_RET.pngall_data/KinaseFusionDB_T_Results/KinaseFusionDB_T_ViolinPlots/TKFP_564_NCOA4_RET_updated_violin_plot.pngall_data/KinaseFusionDB_T_Results/KinaseFusionDB_T_ViolinPlots/TKFP_565_NCOA4_RET_updated_violin_plot.png

pLDDT score distribution of the predicted fusion protein structures from AlphaFold2
* AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100.
* The blue color at the bottom marks the best active site residues.

328_NCOA4_RET.png

TKFP_564_NCOA4_RET.png

TKFP_565_NCOA4_RET.png

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Potential Active Site Information

The potential binding sites of these fusion proteins were identified using SiteMap, a module of the Schrodinger suite.

Kinase Fusion AA seq ID in KinaseFusionDB	Site score	Size	Dscore	Volume	Exposure	Enclosure	Contact	Phobic	Philic	Balance	Don/Acc	Residues
TKFP_564_NCOA4_RET	1.035	146	1.059	462.021	0.558	0.736	0.937	1.036	0.989	1.048	0.687	Chain A: 194,195,196,197,198,199,200,201,202,220,2 22,239,243,252,266,268,269,270,271,272,274,275,338 ,342,343,345,355,356,357,371,375,376,377,378,379,3 80,381,421
TKFP_565_NCOA4_RET	1.058	431	1.109	1185.751	0.527	0.715	0.891	1.124	0.796	1.411	1.112	Chain A: 1,2,3,6,7,10,11,13,14,15,17,39,40,42,43,4 6,50,53,56,57,60,92,95,96,97,99,100,101,102,103,10 4,106,107,108,110,111,115,138,141,142,144,145,146, 147,148,149,150,151,152,153,154,155,156,158,159,16 0,163,164,268,271,272,275,364,391,392,394,395,396, 398,399,400,401,402

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Ramachandran Plot of Kinase Fusion Protein Structure

Ramachandran plot of the torsional angles - phi (φ)and psi (ψ) - of the residues (amino acids) contained in this fusion protein peptide.

328_NCOA4_RET_ramachandran.png

TKFP_564_NCOA4_RET_ramachandran.png

TKFP_565_NCOA4_RET_ramachandran.png

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Virtual Screening Results

Distribution of the average docking score across all approved kinase inhibitors.
Distribution of the number of occurrence across all approved kinase inhibitors.

5'-kinase fusion protein case

3'-kinase fusion protein case

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Drug information from DrugBank of the top 20 interacting small molecules.
* The detailed information of individual kinase inhibitors are available in the download page.

Fusion gene name info

Drug

Docking score

Glide g score

Glide energy

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Kinase-Substrate Information of NCOA4_RET

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
RET	Q15300	human	STAT3	P40763	Y705	DPGsAAPyLktKFIC
RET	Q15300	human	RET	Q15300	Y586	TWIENKLyGRISHAF
RET	P07949	human	RET	P07949	Y981	DNCSEEMyRLMLQCW	PK_Tyr_Ser-Thr
RET	P07949	human	PTK2	Q05397	Y925	DRsNDkVyENVtGLV	Focal_AT
RET	P07949	human	RET	P07949	Y1090	TNTGFPRyPNDSVyA
RET	P07949	human	ATF4	P18848	T107	LGIDDLEtMPDDLLt
RET	P07949	human	PTK2	Q05397	Y577	yMEDstyyKAsKGKL	PK_Tyr_Ser-Thr
RET	P07949	human	ATF4	P18848	T115	MPDDLLttLDDtCDL
RET	P07949	human	MAPK9	P45984	Y185	tNFMMtPyVVtRYYR	Pkinase
RET	P07949	human	RET	P07949	Y1096	RyPNDSVyANWMLSP
RET	P07949	human	MAPK8	P45983	Y185	tsFMMtPyVVtRYYR	Pkinase
RET	P07949	human	PIK3R1	P27986	Y203	PVIPAAVySEMIsLA	RhoGAP
RET	P07949	human	RET	P07949	Y826	SRKVGPGyLGSGGSR	PK_Tyr_Ser-Thr
RET	P07949	human	RET	P07949	Y1015	MMVKRRDyLDLAAST
RET	P07949	human	PDPK1	O15530	Y9	ARTTSQLyDAVPIQS
RET	P07949	human	ATF4	P18848	T114	tMPDDLLttLDDtCD
RET	P07949	human	DOK1	Q99704	Y398	ARVkEEGyELPyNPA
RET	P07949	human	RET	P07949	Y809	LIVEyAKyGSLRGFL	PK_Tyr_Ser-Thr
RET	P07949	human	PTK2	Q05397	Y861	PIGNQHIyQPVGKPD
RET	P07949	human	ATF4	P18848	T119	LLttLDDtCDLFAPL
RET	P07949	human	RET	P07949	Y1029	TPSDSLIyDDGLSEE
RET	P07949	human	RET	P07949	Y687	AQAFPVsysSSGARR
RET	P07949	human	PLCG1	P19174	Y783	EGRNPGFyVEANPMP
RET	P07949	human	MAPK3	P27361	T202	HDHtGFLtEyVAtRW	Pkinase
RET	P07949	human	AFAP1L2	Q8N4X5	Y54	SSSsDEEyIyMNKVt
RET	P07949	human	AKT1	P31749	Y315	tFCGtPEyLAPEVLE	Pkinase
RET	P07949	human	RET	P07949	Y806	PLLLIVEyAKyGSLR	PK_Tyr_Ser-Thr
RET	P07949	human	RET	P07949	Y900	FGLSRDVyEEDsyVK	PK_Tyr_Ser-Thr
RET	P07949	human	MAPK1	P28482	Y187	HtGFLtEyVAtRWyr	Pkinase
RET	P07949	human	RET	P07949	Y905	DVyEEDsyVKRsQGR	PK_Tyr_Ser-Thr
RET	P07949	human	PTK2	Q05397	Y576	RyMEDstyyKAsKGK	PK_Tyr_Ser-Thr
RET	P07949	human	MAPK3	P27361	Y204	HtGFLtEyVAtRWyr	Pkinase
RET	P07949	human	RET	P07949	Y1062	TWIENkLyGMsDPNW
RET	P07949	human	MAPK14	Q16539	Y182	tDDEMtGyVAtRWYR	Pkinase

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
RET	ID	Description	0.00e+00
RET	GO:0071276	cellular response to cadmium ion	8.65e-08
RET	GO:0070849	response to epidermal growth factor	1.02e-07
RET	GO:0038127	ERBB signaling pathway	1.02e-07
RET	GO:0043434	response to peptide hormone	1.02e-07
RET	GO:0048009	insulin-like growth factor receptor signaling pathway	1.02e-07
RET	GO:0046686	response to cadmium ion	1.64e-07
RET	GO:0018105	peptidyl-serine phosphorylation	2.35e-07
RET	GO:0018209	peptidyl-serine modification	2.58e-07
RET	GO:0071375	cellular response to peptide hormone stimulus	2.58e-07
RET	GO:0071248	cellular response to metal ion	7.74e-07
RET	GO:1901653	cellular response to peptide	7.74e-07
RET	GO:0071241	cellular response to inorganic substance	1.52e-06
RET	GO:0007173	epidermal growth factor receptor signaling pathway	1.57e-06
RET	GO:0060416	response to growth hormone	1.79e-06
RET	GO:0034599	cellular response to oxidative stress	2.31e-06
RET	GO:0008286	insulin receptor signaling pathway	2.80e-06
RET	GO:0032868	response to insulin	2.80e-06
RET	GO:0002764	immune response-regulating signaling pathway	3.49e-06
RET	GO:0043491	phosphatidylinositol 3-kinase/protein kinase B signal transduction	3.92e-06
RET	GO:0034198	cellular response to amino acid starvation	4.22e-06
RET	GO:1990928	response to amino acid starvation	5.08e-06
RET	GO:0009411	response to UV	5.10e-06
RET	GO:0038093	Fc receptor signaling pathway	5.10e-06
RET	GO:0062197	cellular response to chemical stress	5.10e-06
RET	GO:0034614	cellular response to reactive oxygen species	5.10e-06
RET	GO:0031663	lipopolysaccharide-mediated signaling pathway	5.49e-06
RET	GO:0061517	macrophage proliferation	5.72e-06
RET	GO:0002768	immune response-regulating cell surface receptor signaling pathway	7.56e-06
RET	GO:0010038	response to metal ion	9.07e-06
RET	GO:0050900	leukocyte migration	1.56e-05
RET	GO:0006979	response to oxidative stress	1.59e-05
RET	GO:0010759	positive regulation of macrophage chemotaxis	1.59e-05
RET	GO:0000302	response to reactive oxygen species	1.59e-05
RET	GO:0032869	cellular response to insulin stimulus	1.59e-05
RET	GO:0071674	mononuclear cell migration	1.59e-05
RET	GO:0051347	positive regulation of transferase activity	1.69e-05
RET	GO:0034764	positive regulation of transmembrane transport	1.90e-05
RET	GO:0071222	cellular response to lipopolysaccharide	2.26e-05
RET	GO:0001503	ossification	2.28e-05
RET	GO:0002685	regulation of leukocyte migration	2.28e-05
RET	GO:0051403	stress-activated MAPK cascade	2.28e-05
RET	GO:0031098	stress-activated protein kinase signaling cascade	2.63e-05
RET	GO:0071219	cellular response to molecule of bacterial origin	2.63e-05
RET	GO:0038095	Fc-epsilon receptor signaling pathway	2.75e-05
RET	GO:0060396	growth hormone receptor signaling pathway	2.75e-05
RET	GO:0018107	peptidyl-threonine phosphorylation	2.76e-05
RET	GO:0048863	stem cell differentiation	2.76e-05
RET	GO:0002757	immune response-activating signaling pathway	2.76e-05
RET	GO:0071378	cellular response to growth hormone stimulus	2.79e-05

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Related Drugs to NCOA4_RET

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 NCOA4-RET 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
CCDC6-RET AND Alectinib	NCOA4-RET AND Alectinib	29088743	2017-05-16	10.18632/oncotarget.17900	In vitro and in vivo anti-tumor activity of alectinib in tumor cells with NCOA4-RET.
NCOA4-RET AND Selpercatinib		37565829	2023-08-11	10.1097/mph.0000000000002743	Sustained Response with Dose-reduced Selpercatinib in a Pediatric Patient with Metastatic NCOA4-RET Fusion Papillary Thyroid Carcinoma.
NCOA4-RET AND Selpercatinib		37315261	2023-9	10.1200/po.23.00420	Intracranial Activity of Selpercatinib in Chinese Patients With Advanced RET Fusion-Positive Non-Small-Cell Lung Cancer in the Phase II LIBRETTO-321 Trial.
NCOA4-RET AND Selpercatinib		33272981	2021-03-01	10.1158/1078-0432.ccr-20-3208	A Performance Comparison of Commonly Used Assays to Detect RET Fusions.

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Related Diseases to NCOA4_RET

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

Hgene	Tgene	Disease	Source	PMID
NCOA4	RET	Thyroid Gland Papillary Carcinoma	MyCancerGenome
NCOA4	RET	Lung Adenocarcinoma	MyCancerGenome
NCOA4	RET	Breast Invasive Ductal Carcinoma	MyCancerGenome
NCOA4	RET	Colon Adenocarcinoma	MyCancerGenome
NCOA4	RET	Adenocarcinoma Of Unknown Primary	MyCancerGenome

Related diseases from the literature mentioned this fusion gene and drug.
(PubMed, 04-01-2024)

MeSH ID	MeSH term
D000077273	Thyroid Cancer, Papillary

Diseases associated with fusion partners.
(DisGeNet 4.0)

Partner	Gene	Disease ID	Disease name	# pubmeds	Source
Hgene	NCOA4	C0238463	Papillary thyroid carcinoma	2	ORPHANET
Tgene	RET	C1833921	Familial medullary thyroid carcinoma	23	CTD_human;GENOMICS_ENGLAND;ORPHANET;UNIPROT
Tgene	RET	C3888239	HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 1	16	GENOMICS_ENGLAND;UNIPROT
Tgene	RET	C0025268	Multiple Endocrine Neoplasia Type 2a	15	CTD_human;GENOMICS_ENGLAND;ORPHANET;UNIPROT
Tgene	RET	C1708353	Hereditary Paraganglioma-Pheochromocytoma Syndrome	12	CLINGEN
Tgene	RET	C0025269	Multiple Endocrine Neoplasia Type 2b	10	CTD_human;GENOMICS_ENGLAND;ORPHANET;UNIPROT
Tgene	RET	C0238463	Papillary thyroid carcinoma	3	CTD_human;ORPHANET
Tgene	RET	C1275808	Congenital central hypoventilation	3	CTD_human;GENOMICS_ENGLAND;UNIPROT
Tgene	RET	C1859049	CCHS WITH HIRSCHSPRUNG DISEASE	3	CTD_human;ORPHANET
Tgene	RET	C0009402	Colorectal Carcinoma	2	CTD_human;UNIPROT
Tgene	RET	C0009404	Colorectal Neoplasms	2	CTD_human
Tgene	RET	C0019569	Hirschsprung Disease	2	CTD_human
Tgene	RET	C0027662	Multiple Endocrine Neoplasia	2	CTD_human;GENOMICS_ENGLAND
Tgene	RET	C0085758	Aganglionosis, Colonic	2	CTD_human
Tgene	RET	C0266294	Unilateral agenesis of kidney	2	ORPHANET
Tgene	RET	C1257840	Aganglionosis, Rectosigmoid Colon	2	CTD_human
Tgene	RET	C3661523	Congenital Intestinal Aganglionosis	2	CTD_human

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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
NCOA4-RET	Selpercatinib	NCT03157128	Recruiting	Phase 1	Non-Small Cell Lung Cancer	875	February 28, 2026
NCOA4-RET	Selpercatinib	NCT03899792	Recruiting	Phase 1	Medullary Thyroid Cancer	50	May 31, 2029