BCR (gene)

The breakpoint cluster region protein (BCR) also known as renal carcinoma antigen NY-REN-26 is a protein that in humans is encoded by the BCR gene. BCR is one of the two genes in the BCR-ABL fusion protein, which is associated with the Philadelphia chromosome. Two transcript variants encoding different isoforms have been found for this gene.

BCR
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1K1F, 2AIN
Identifiers
Aliases	BCR, Bcr, 5133400C09Rik, AI561783, AI853148, mKIAA3017, ALL, BCR1, CML, D22S11, D22S662, PHL, RhoGEF and GTPase activating protein, BCR gene, BCR activator of RhoGEF and GTPase
External IDs	OMIM: 151410 MGI: 88141 HomoloGene: 3192 GeneCards: BCR
Gene location (Human) Chr. Chromosome 22 (human)^[1] Band 22q11.23 Start 23,179,704 bp^[1] End 23,318,037 bp^[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)^[2] Band 10 C1|10 38.49 cM Start 74,896,424 bp^[2] End 75,020,753 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in nucleus accumbens caudate nucleus putamen anterior pituitary sural nerve prefrontal cortex amygdala right lobe of thyroid gland cingulate gyrus ganglionic eminence Top expressed in olfactory tubercle nucleus accumbens superior frontal gyrus globus pallidus visual cortex ventromedial nucleus subiculum intestinal villus substantia nigra paraventricular nucleus of hypothalamus More reference expression data BioGPS n/a
Gene ontology Molecular function transferase activity nucleotide binding guanyl-nucleotide exchange factor activity kinase activity protein serine/threonine kinase activity protein binding enzyme binding protein tyrosine kinase activity ATP binding GTPase activator activity Cellular component cytoplasm cytosol postsynaptic membrane membrane postsynaptic density plasma membrane synapse cell junction extracellular exosome protein-containing complex Schaffer collateral - CA1 synapse glutamatergic synapse postsynaptic density, intracellular component intracellular anatomical structure Biological process positive regulation of phagocytosis intracellular signal transduction neuromuscular process controlling balance phosphorylation regulation of cell cycle negative regulation of blood vessel remodeling protein phosphorylation negative regulation of cellular extravasation response to lipopolysaccharide brain development regulation of vascular permeability negative regulation of cell migration negative regulation of neutrophil degranulation inner ear morphogenesis protein autophosphorylation platelet-derived growth factor receptor signaling pathway regulation of Rho protein signal transduction regulation of small GTPase mediated signal transduction negative regulation of inflammatory response actin cytoskeleton organization signal transduction peptidyl-tyrosine phosphorylation renal system process homeostasis of number of cells regulation of nitrogen compound metabolic process definitive hemopoiesis negative regulation of respiratory burst intracellular protein transmembrane transport cellular response to lipopolysaccharide negative regulation of reactive oxygen species metabolic process positive regulation of GTPase activity modulation of chemical synaptic transmission small GTPase mediated signal transduction keratinocyte differentiation focal adhesion assembly activation of GTPase activity Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 613 110279 Ensembl ENSG00000186716 ENSMUSG00000009681 UniProt P11274 Q6PAJ1 RefSeq (mRNA) NM_004327 NM_021574 NM_001081412 RefSeq (protein) NP_004318 NP_067585 NP_001074881 Location (UCSC) Chr 22: 23.18 – 23.32 Mb Chr 10: 74.9 – 75.02 Mb PubMed search ^[3] ^[4]
Wikidata
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Bcr-Abl oncoprotein oligomerisation domain
structure of the bcr-abl oncoprotein oligomerization domain
Identifiers
Symbol	Bcr-Abl_Oligo
Pfam	PF09036
InterPro	IPR015123
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Function

Although the BCR-ABL fusion protein has been much studied, the function of the normal BCR gene product is still not clear. The protein has serine/threonine kinase activity and is a guanine nucleotide exchange factor for the Rho family of GTPases including RhoA.^[5][6]

Clinical significance

A reciprocal translocation between chromosomes 22 and 9 produces the Philadelphia chromosome, which is often found in patients with chronic myelogenous leukemia. The chromosome 22 breakpoint for this translocation is located within the BCR gene. The translocation produces a fusion protein that is encoded by sequence from both BCR and ABL, the gene at the chromosome 9 breakpoint.^[7]

Structure

 

Schematic of the BCR-ABL formation through chromosomal translocation

The BCR-ABL oncoprotein oligomerisation domain found at the N-terminus of BCR is essential for the oncogenicity of the BCR-ABL fusion protein. The BCR-ABL oncoprotein oligomerisation domain consists of a short N-terminal helix (alpha-1), a flexible loop and a long C-terminal helix (alpha-2). Together these form an N-shaped structure, with the loop allowing the two helices to assume a parallel orientation. The monomeric domains associate into a dimer through the formation of an antiparallel coiled coil between the alpha-2 helices and domain swapping of two alpha-1 helices, where one alpha-1 helix swings back and packs against the alpha-2 helix from the second monomer. Two dimers then associate into a tetramer.^[8] Structure-based engineering starting from the antiparallel coiled coil domain of the BCR-ABL oncoprotein (BCR30-65) resulted in a new pH-sensitive homodimeric antiparallel coiled coil.^[9]

Interactions

The BCR protein has been shown to interact with:

• Abl gene,^[10][11][12]
• CD117,^[13]
• CRKL^{[14][15][16][17]}
• FES,^[18][19]
• Grb2,^{[10][14][15][19][20][21]}
• GRB10,^[14]
• HCK,^[22][23]
• MLLT4,^[24]
• PXN,^[25][26]
• PIK3CG,^[14][25][27]
• PTPN6,^[28]
• PTPRT(PTPrho)^[29]
• SOS1,^[10][19] and
• XPB.^[30]

See also

• Abl gene

References

1. GRCh38: Ensembl release 89: ENSG00000186716 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000009681 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Dubash AD, Koetsier JL, Amargo EV, Najor NA, Harmon RM, Green KJ (August 2013). "The GEF Bcr activates RhoA/MAL signaling to promote keratinocyte differentiation via desmoglein-1". The Journal of Cell Biology. 202 (4): 653–666. doi:10.1083/jcb.201304133. PMC 3747303. PMID 23940119.
6. "Entrez Gene: Breakpoint cluster region".
7. "Entrez Gene: BCR breakpoint cluster region".
8. Zhao X, Ghaffari S, Lodish H, Malashkevich VN, Kim PS (February 2002). "Structure of the Bcr-Abl oncoprotein oligomerization domain". Nature Structural Biology. 9 (2): 117–120. doi:10.1038/nsb747. PMID 11780146. S2CID 17453012.
9. Nagarkar RP, Fichman G, Schneider JP (2020-08-14). "Engineering and characterization of a<scp>pH</scp>-sensitive homodimeric antiparallel coiled coil". Peptide Science. 112 (5). doi:10.1002/pep2.24180. ISSN 2475-8817. S2CID 221920164.
10. Puil L, Liu J, Gish G, Mbamalu G, Bowtell D, Pelicci PG, et al. (February 1994). "Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway". The EMBO Journal. 13 (4): 764–773. doi:10.1002/j.1460-2075.1994.tb06319.x. PMC 394874. PMID 8112292.
11. Ling X, Ma G, Sun T, Liu J, Arlinghaus RB (January 2003). "Bcr and Abl interaction: oncogenic activation of c-Abl by sequestering Bcr". Cancer Research. 63 (2): 298–303. PMID 12543778.
12. Pendergast AM, Muller AJ, Havlik MH, Maru Y, Witte ON (July 1991). "BCR sequences essential for transformation by the BCR-ABL oncogene bind to the ABL SH2 regulatory domain in a non-phosphotyrosine-dependent manner". Cell. 66 (1): 161–171. doi:10.1016/0092-8674(91)90148-R. PMID 1712671. S2CID 9933891.
13. Hallek M, Danhauser-Riedl S, Herbst R, Warmuth M, Winkler A, Kolb HJ, et al. (July 1996). "Interaction of the receptor tyrosine kinase p145c-kit with the p210bcr/abl kinase in myeloid cells". British Journal of Haematology. 94 (1): 5–16. doi:10.1046/j.1365-2141.1996.6102053.x. PMID 8757502. S2CID 30033345.
14. Bai RY, Jahn T, Schrem S, Munzert G, Weidner KM, Wang JY, et al. (August 1998). "The SH2-containing adapter protein GRB10 interacts with BCR-ABL". Oncogene. 17 (8): 941–948. doi:10.1038/sj.onc.1202024. PMID 9747873. S2CID 20866214.
15. Million RP, Harakawa N, Roumiantsev S, Varticovski L, Van Etten RA (June 2004). "A direct binding site for Grb2 contributes to transformation and leukemogenesis by the Tel-Abl (ETV6-Abl) tyrosine kinase". Molecular and Cellular Biology. 24 (11): 4685–4695. doi:10.1128/MCB.24.11.4685-4695.2004. PMC 416425. PMID 15143164.
16. Heaney C, Kolibaba K, Bhat A, Oda T, Ohno S, Fanning S, et al. (January 1997). "Direct binding of CRKL to BCR-ABL is not required for BCR-ABL transformation". Blood. 89 (1): 297–306. doi:10.1182/blood.V89.1.297. PMID 8978305.
17. Kolibaba KS, Bhat A, Heaney C, Oda T, Druker BJ (March 1999). "CRKL binding to BCR-ABL and BCR-ABL transformation". Leukemia & Lymphoma. 33 (1–2): 119–126. doi:10.3109/10428199909093732. PMID 10194128.
18. Lionberger JM, Smithgall TE (February 2000). "The c-Fes protein-tyrosine kinase suppresses cytokine-independent outgrowth of myeloid leukemia cells induced by Bcr-Abl". Cancer Research. 60 (4): 1097–1103. PMID 10706130.
19. Maru Y, Peters KL, Afar DE, Shibuya M, Witte ON, Smithgall TE (February 1995). "Tyrosine phosphorylation of BCR by FPS/FES protein-tyrosine kinases induces association of BCR with GRB-2/SOS". Molecular and Cellular Biology. 15 (2): 835–842. doi:10.1128/MCB.15.2.835. PMC 231961. PMID 7529874.
20. Million RP, Van Etten RA (July 2000). "The Grb2 binding site is required for the induction of chronic myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase". Blood. 96 (2): 664–670. doi:10.1182/blood.V96.2.664. PMID 10887132.
21. Ma G, Lu D, Wu Y, Liu J, Arlinghaus RB (May 1997). "Bcr phosphorylated on tyrosine 177 binds Grb2". Oncogene. 14 (19): 2367–2372. doi:10.1038/sj.onc.1201053. PMID 9178913. S2CID 9249479.
22. Stanglmaier M, Warmuth M, Kleinlein I, Reis S, Hallek M (February 2003). "The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains". Leukemia. 17 (2): 283–289. doi:10.1038/sj.leu.2402778. PMID 12592324. S2CID 8695384.
23. Lionberger JM, Wilson MB, Smithgall TE (June 2000). "Transformation of myeloid leukemia cells to cytokine independence by Bcr-Abl is suppressed by kinase-defective Hck". The Journal of Biological Chemistry. 275 (24): 18581–18585. doi:10.1074/jbc.C000126200. PMID 10849448.
24. Radziwill G, Erdmann RA, Margelisch U, Moelling K (July 2003). "The Bcr kinase downregulates Ras signaling by phosphorylating AF-6 and binding to its PDZ domain". Molecular and Cellular Biology. 23 (13): 4663–4672. doi:10.1128/MCB.23.13.4663-4672.2003. PMC 164848. PMID 12808105.
25. Salgia R, Sattler M, Pisick E, Li JL, Griffin JD (February 1996). "p210BCR/ABL induces formation of complexes containing focal adhesion proteins and the protooncogene product p120c-Cbl". Experimental Hematology. 24 (2): 310–313. PMID 8641358.
26. Salgia R, Li JL, Lo SH, Brunkhorst B, Kansas GS, Sobhany ES, et al. (March 1995). "Molecular cloning of human paxillin, a focal adhesion protein phosphorylated by P210BCR/ABL". The Journal of Biological Chemistry. 270 (10): 5039–5047. doi:10.1074/jbc.270.10.5039. PMID 7534286.
27. Skorski T, Kanakaraj P, Nieborowska-Skorska M, Ratajczak MZ, Wen SC, Zon G, et al. (July 1995). "Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells". Blood. 86 (2): 726–736. doi:10.1182/blood.V86.2.726.bloodjournal862726. PMID 7606002.
28. Liedtke M, Pandey P, Kumar S, Kharbanda S, Kufe D (October 1998). "Regulation of Bcr-Abl-induced SAP kinase activity and transformation by the SHPTP1 protein tyrosine phosphatase". Oncogene. 17 (15): 1889–1892. doi:10.1038/sj.onc.1202117. PMID 9788431. S2CID 42228230.
29. Park AR, Oh D, Lim SH, Choi J, Moon J, Yu DY, et al. (October 2012). "Regulation of dendritic arborization by BCR Rac1 GTPase-activating protein, a substrate of PTPRT". Journal of Cell Science. 125 (Pt 19): 4518–4531. doi:10.1242/jcs.105502. PMID 22767509. S2CID 22422544.
30. Takeda N, Shibuya M, Maru Y (January 1999). "The BCR-ABL oncoprotein potentially interacts with the xeroderma pigmentosum group B protein". Proceedings of the National Academy of Sciences of the United States of America. 96 (1): 203–207. Bibcode:1999PNAS...96..203T. doi:10.1073/pnas.96.1.203. PMC 15117. PMID 9874796.

Further reading

• Wang L, Seale J, Woodcock BE, Clark RE (August 2002). "e19a2-positive chronic myeloid leukaemia with BCR exon e16-deleted transcripts". Leukemia. 16 (8): 1562–1563. doi:10.1038/sj.leu.2402600. PMID 12145699. S2CID 24651759.

External links

• BCR+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human BCR genome location and BCR gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: P11274 (Human Breakpoint cluster region protein) at the PDBe-KB.

This article incorporates text from the public domain Pfam and InterPro: IPR015123