BCR (gene)

Breakpoint cluster region
PDB rendering based on 1k1f.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1K1F​, 2AIN​
Identifiers
Symbols	BCR ; ALL; BCR1; CML; D22S11; D22S662; PHL
External IDs	OMIM: 151410 MGI: 88141 HomoloGene: 3192 ChEMBL: 5146 GeneCards: BCR Gene
EC number	2.7.11.1
Gene ontology Molecular function • protein serine/threonine kinase activity • protein tyrosine kinase activity • Rho guanyl-nucleotide exchange factor activity • GTPase activator activity • protein binding • ATP binding • kinase activity • enzyme binding Cellular component • cytosol • postsynaptic density • membrane • cell junction • protein complex • postsynaptic membrane • extracellular exosome Biological process • negative regulation of cellular extravasation • protein phosphorylation • signal transduction • small GTPase mediated signal transduction • brain development • peptidyl-tyrosine phosphorylation • actin cytoskeleton organization • response to lipopolysaccharide • regulation of Rho protein signal transduction • inner ear morphogenesis • regulation of vascular permeability • negative regulation of neutrophil degranulation • positive regulation of GTPase activity • protein autophosphorylation • platelet-derived growth factor receptor signaling pathway • negative regulation of inflammatory response • positive regulation of phagocytosis • neuromuscular process controlling balance • regulation of small GTPase mediated signal transduction • regulation of cell cycle • negative regulation of blood vessel remodeling Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	613	110279
Ensembl	ENSG00000186716	ENSMUSG00000009681
UniProt	P11274	Q6PAJ1
RefSeq (mRNA)	NM_004327	NM_001081412
RefSeq (protein)	NP_004318	NP_001074881
Location (UCSC)	Chr 22: 23.18 – 23.32 Mb	Chr 10: 75.06 – 75.18 Mb
PubMed search

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 PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

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 complex, which is associated with the Philadelphia chromosome. Two transcript variants encoding different isoforms have been found for this gene.

Function

Although the BCR-ABL fusion protein has been extensively studied, the function of the normal BCR gene product is not clear. The protein has serine/threonine kinase activity and is a GTPase-activating protein for RAC1 and CDC42.^[1]

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.^[2]

Structure

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.^[3]

Interactions

BCR gene has been shown to interact with:

• Abl gene,^[4][5][6]
• CD117,^[7]
• CRKL^{[8][9][10][11]}
• FES,^[12][13]
• Grb2,^{[4][8][9][13][14][15]}
• GRB10,^[8]
• HCK,^[16][17]
• MLLT4,^[18]
• PXN,^[19][20]
• PIK3CG,^[8][19][21]
• PTPN6,^[22]
• PTPRT(PTPrho)^[23]
• SOS1,^[4][13] and
• XPB.^[24]

See also

• Abl gene

References

1. "Entrez Gene: Breakpoint cluster region".
2. "Entrez Gene: BCR breakpoint cluster region".
3. Zhao X, Ghaffari S, Lodish H, Malashkevich VN, Kim PS (February 2002). "Structure of the Bcr-Abl oncoprotein oligomerization domain". Nat. Struct. Biol. 9 (2): 117–20. doi:10.1038/nsb747. PMID 11780146.
4. Puil L, Liu J, Gish G, Mbamalu G, Bowtell D, Pelicci PG, Arlinghaus R, Pawson T (February 1994). "Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway". EMBO J. 13 (4): 764–73. PMC 394874. PMID 8112292.
5. 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 Res. 63 (2): 298–303. PMID 12543778.
6. 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): 161–71. doi:10.1016/0092-8674(91)90148-R. PMID 1712671.
7. Hallek M, Danhauser-Riedl S, Herbst R, Warmuth M, Winkler A, Kolb HJ, Druker B, Griffin JD, Emmerich B, Ullrich A (July 1996). "Interaction of the receptor tyrosine kinase p145c-kit with the p210bcr/abl kinase in myeloid cells". Br. J. Haematol. 94 (1): 5–16. doi:10.1046/j.1365-2141.1996.6102053.x. PMID 8757502.
8. Bai RY, Jahn T, Schrem S, Munzert G, Weidner KM, Wang JY, Duyster J (August 1998). "The SH2-containing adapter protein GRB10 interacts with BCR-ABL". Oncogene 17 (8): 941–8. doi:10.1038/sj.onc.1202024. PMID 9747873.
9. 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". Mol. Cell. Biol. 24 (11): 4685–95. doi:10.1128/MCB.24.11.4685-4695.2004. PMC 416425. PMID 15143164.
10. Heaney C, Kolibaba K, Bhat A, Oda T, Ohno S, Fanning S, Druker BJ (January 1997). "Direct binding of CRKL to BCR-ABL is not required for BCR-ABL transformation". Blood 89 (1): 297–306. PMID 8978305.
11. Kolibaba KS, Bhat A, Heaney C, Oda T, Druker BJ (March 1999). "CRKL binding to BCR-ABL and BCR-ABL transformation". Leuk. Lymphoma 33 (1-2): 119–26. doi:10.3109/10428199909093732. PMID 10194128.
12. 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 Res. 60 (4): 1097–103. PMID 10706130.
13. 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". Mol. Cell. Biol. 15 (2): 835–42. PMC 231961. PMID 7529874.
14. 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): 664–70. PMID 10887132.
15. Ma G, Lu D, Wu Y, Liu J, Arlinghaus RB (May 1997). "Bcr phosphorylated on tyrosine 177 binds Grb2". Oncogene 14 (19): 2367–72. doi:10.1038/sj.onc.1201053. PMID 9178913.
16. 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): 283–9. doi:10.1038/sj.leu.2402778. PMID 12592324.
17. 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". J. Biol. Chem. 275 (24): 18581–5. doi:10.1074/jbc.C000126200. PMID 10849448.
18. 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". Mol. Cell. Biol. 23 (13): 4663–72. doi:10.1128/MCB.23.13.4663-4672.2003. PMC 164848. PMID 12808105.
19. 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". Exp. Hematol. 24 (2): 310–3. PMID 8641358.
20. Salgia R, Li JL, Lo SH, Brunkhorst B, Kansas GS, Sobhany ES, Sun Y, Pisick E, Hallek M, Ernst T (March 1995). "Molecular cloning of human paxillin, a focal adhesion protein phosphorylated by P210BCR/ABL". J. Biol. Chem. 270 (10): 5039–47. doi:10.1074/jbc.270.10.5039. PMID 7534286.
21. Skorski T, Kanakaraj P, Nieborowska-Skorska M, Ratajczak MZ, Wen SC, Zon G, Gewirtz AM, Perussia B, Calabretta B (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): 726–36. PMID 7606002.
22. 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): 1889–92. doi:10.1038/sj.onc.1202117. PMID 9788431.
23. Park AR, Oh D, Lim SH, Choi J, Moon J, Yu DY, Park SG, Heisterkamp N, Kim E, Myung PK, Lee JR (2012). "Regulation of dendritic arborization by BCR Rac1 GTPase-activating protein, a substrate of PTPRT". J. Cell. Sci. 125 (Pt 19): 4518–31. doi:10.1242/jcs.105502. PMID 22767509.
24. Takeda N, Shibuya M, Maru Y (January 1999). "The BCR-ABL oncoprotein potentially interacts with the xeroderma pigmentosum group B protein". Proc. Natl. Acad. Sci. U.S.A. 96 (1): 203–7. doi:10.1073/pnas.96.1.203. PMC 15117. PMID 9874796.

Further reading

• Wang L, Seale J, Woodcock BE, Clark RE (2002). "e19a2-positive chronic myeloid leukaemia with BCR exon e16-deleted transcripts". Leukemia 16 (8): 1562–3. doi:10.1038/sj.leu.2402600. PMID 12145699.

External links

• BCR protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

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