BCR (gene)

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Breakpoint cluster region
PBB Protein BCR image.jpg
PDB rendering based on 1k1f.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols BCR ; ALL; BCR1; CML; D22S11; D22S662; PHL
External IDs OMIM151410 MGI88141 HomoloGene3192 ChEMBL: 5146 GeneCards: BCR Gene
EC number 2.7.11.1
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:
23.52 – 23.66 Mb
Chr 10:
75.06 – 75.18 Mb
PubMed search [1] [2]
Bcr-Abl oncoprotein oligomerisation domain
PDB 1k1f EBI.jpg
structure of the bcr-abl oncoprotein oligomerization domain
Identifiers
Symbol Bcr-Abl_Oligo
Pfam PF09036
InterPro IPR015123

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[edit]

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[edit]

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[edit]

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[edit]

BCR gene has been shown to interact with:

See also[edit]

References[edit]

  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. ^ a b c Puil L, Liu J, Gish G, Mbamalu G, Bowtell D, Pelicci P G, 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 Guozhen, Sun Tong, Liu Jiaxin, Arlinghaus Ralph B (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 A J, Havlik M H, Maru Y, Witte O N (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 H J, Druker B, Griffin J D, 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. ^ a b c d Bai RY, Jahn T, Schrem S, Munzert G, Weidner K M, Wang J Y, 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. ^ a b Million RP, Harakawa Nari, Roumiantsev Sergei, Varticovski Lyuba, Van Etten Richard A (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 B J (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 B J (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 T E (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. ^ a b c Maru Y, Peters K L, Afar D E, Shibuya M, Witte O N, Smithgall T E (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 R A (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 R B (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 M B, Smithgall T E (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 R A, 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. ^ a b Salgia R, Sattler M, Pisick E, Li J L, Griffin J D (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 J L, Lo S H, Brunkhorst B, Kansas G S, Sobhany E S, 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 M Z, Wen S C, Zon G, Gewirtz A M, 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 et al. (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". PNAS 96 (1): 203–7. doi:10.1073/pnas.96.1.203. PMC 15117. PMID 9874796. 

Further reading[edit]

  • 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[edit]

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