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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:BCR_RET

Kinase Fusion Protein Summary

Kinase Fusion gene summary

Kinase Fusion partner gene information	Kinase Fusion gene name: BCR_RET
	KinaseFusionDB ID: KFG605
	FusionGDB2.0 ID: KFG605
		Hgene	Tgene
	Gene symbol	BCR	RET
	Gene ID	613	5979
	Gene name	BCR activator of RhoGEF and GTPase	ret proto-oncogene
	Synonyms	ALL\|BCR1\|CML\|D22S11\|D22S662\|PHL	CDHF12\|CDHR16\|HSCR1\|MEN2A\|MEN2B\|MTC1\|PTC\|RET-ELE1
	Cytomap	22q11.23	10q11.21
	Type of gene	protein-coding	protein-coding
	Description	breakpoint cluster region proteinBCR, RhoGEF and GTPase activating proteinBCR/FGFR1 chimera proteinFGFR1/BCR chimera proteinbreakpoint cluster regionrenal carcinoma antigen NY-REN-26	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	20240416	20240416
	UniProtAcc	P11274	P07949
Ensembl transtripts involved in fusion gene	ENST ids	ENST00000305877, ENST00000359540, ENST00000398512, ENST00000436990,	ENST00000340058, ENST00000355710,
Context (manual curation of fusion genes in KinaseFusionDB)	PubMed: BCR [Title/Abstract] AND RET [Title/Abstract] AND fusion [Title/Abstract]
Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)

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	BCR	GO:0090630	activation of GTPase activity	7479768
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 BCR (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
ChimerKB4	.	BCR	chr22	23603541	RET	chr10	23603541

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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)

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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

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/:/:)
- 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
BCR P11274	RET P07949
FUNCTION: Protein with a unique structure having two opposing regulatory activities toward small GTP-binding proteins. The C-terminus is a GTPase-activating protein (GAP) domain which stimulates GTP hydrolysis by RAC1, RAC2 and CDC42. Accelerates the intrinsic rate of GTP hydrolysis of RAC1 or CDC42, leading to down-regulation of the active GTP-bound form (PubMed:7479768, PubMed:1903516, PubMed:17116687). The central Dbl homology (DH) domain functions as guanine nucleotide exchange factor (GEF) that modulates the GTPases CDC42, RHOA and RAC1. Promotes the conversion of CDC42, RHOA and RAC1 from the GDP-bound to the GTP-bound form (PubMed:7479768, PubMed:23940119). The amino terminus contains an intrinsic kinase activity (PubMed:1657398). Functions as an important negative regulator of neuronal RAC1 activity (By similarity). Regulates macrophage functions such as CSF1-directed motility and phagocytosis through the modulation of RAC1 activity (PubMed:17116687). Plays a major role as a RHOA GEF in keratinocytes being involved in focal adhesion formation and keratinocyte differentiation (PubMed:23940119). {ECO:0000250\|UniProtKB:Q6PAJ1, ECO:0000269\|PubMed:1657398, ECO:0000269\|PubMed:17116687, ECO:0000269\|PubMed:1903516, ECO:0000269\|PubMed:23940119, ECO:0000269\|PubMed:7479768}.	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

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Kinase-Substrate Information of BCR_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
BCR	P11274	human	YWHAQ	P27348	S232	LTLWtsDsAGEECDA
BCR	P11274	human	YWHAZ	P63104	T232	LTLWtsDtQGDEAEA
BCR	P11274	human	AFDN	P55196	T909	VVTVAENtADELARS
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
BCR	ID	Description	0.00e+00
BCR	GO:0007265	Ras protein signal transduction	4.45e-04
BCR	GO:2000404	regulation of T cell migration	8.95e-04
BCR	GO:0007264	small GTPase mediated signal transduction	8.95e-04
BCR	GO:0002685	regulation of leukocyte migration	1.08e-03
BCR	GO:2000401	regulation of lymphocyte migration	1.11e-03
BCR	GO:0072678	T cell migration	1.11e-03
BCR	GO:0048041	focal adhesion assembly	1.50e-03
BCR	GO:0007044	cell-substrate junction assembly	1.54e-03
BCR	GO:0034446	substrate adhesion-dependent cell spreading	1.54e-03
BCR	GO:0150115	cell-substrate junction organization	1.54e-03
BCR	GO:0032956	regulation of actin cytoskeleton organization	1.54e-03
BCR	GO:0110020	regulation of actomyosin structure organization	1.54e-03
BCR	GO:1905244	regulation of modification of synaptic structure	1.54e-03
BCR	GO:0031589	cell-substrate adhesion	1.74e-03
BCR	GO:0003188	heart valve formation	1.81e-03
BCR	GO:0032970	regulation of actin filament-based process	1.81e-03
BCR	GO:0072676	lymphocyte migration	1.81e-03
BCR	GO:0071675	regulation of mononuclear cell migration	1.81e-03
BCR	GO:1902903	regulation of supramolecular fiber organization	1.81e-03
BCR	GO:0050900	leukocyte migration	1.84e-03
BCR	GO:0007266	Rho protein signal transduction	2.09e-03
BCR	GO:2000377	regulation of reactive oxygen species metabolic process	2.47e-03
BCR	GO:0034329	cell junction assembly	2.55e-03
BCR	GO:0030010	establishment of cell polarity	2.70e-03
BCR	GO:0006312	mitotic recombination	3.06e-03
BCR	GO:0000724	double-strand break repair via homologous recombination	3.36e-03
BCR	GO:1902905	positive regulation of supramolecular fiber organization	3.36e-03
BCR	GO:0099563	modification of synaptic structure	3.36e-03
BCR	GO:0000725	recombinational repair	3.36e-03
BCR	GO:0051495	positive regulation of cytoskeleton organization	3.52e-03
BCR	GO:0061138	morphogenesis of a branching epithelium	3.58e-03
BCR	GO:0042770	signal transduction in response to DNA damage	3.58e-03
BCR	GO:0033688	regulation of osteoblast proliferation	3.59e-03
BCR	GO:0045907	positive regulation of vasoconstriction	3.71e-03
BCR	GO:0001763	morphogenesis of a branching structure	3.90e-03
BCR	GO:0050851	antigen receptor-mediated signaling pathway	3.90e-03
BCR	GO:0071674	mononuclear cell migration	3.90e-03
BCR	GO:2000406	positive regulation of T cell migration	3.90e-03
BCR	GO:0031032	actomyosin structure organization	3.90e-03
BCR	GO:0033687	osteoblast proliferation	4.01e-03
BCR	GO:0006282	regulation of DNA repair	4.09e-03
BCR	GO:0010810	regulation of cell-substrate adhesion	4.27e-03
BCR	GO:0071222	cellular response to lipopolysaccharide	4.52e-03
BCR	GO:0007163	establishment or maintenance of cell polarity	4.53e-03
BCR	GO:0072593	reactive oxygen species metabolic process	4.65e-03
BCR	GO:1900026	positive regulation of substrate adhesion-dependent cell spreading	4.65e-03
BCR	GO:2000403	positive regulation of lymphocyte migration	4.65e-03
BCR	GO:0007160	cell-matrix adhesion	4.67e-03
BCR	GO:0071219	cellular response to molecule of bacterial origin	4.67e-03

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Related Drugs to BCR_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 BCR-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

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Related Diseases to BCR_RET

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

Hgene

Tgene

Disease

Source

PMID

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

MeSH ID

MeSH term

Diseases associated with fusion partners.
(DisGeNet 4.0)

Partner	Gene	Disease ID	Disease name	# pubmeds	Source
Hgene	BCR	C0005586	Bipolar Disorder	4	PSYGENET
Hgene	BCR	C0023473	Myeloid Leukemia, Chronic	3	CTD_human;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