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.
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.
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 antiparallelcoiled 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.
^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. PMID11780146.
^ abcPuil 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. PMC394874. PMID8112292.
^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. PMID12543778.
^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". Cell66 (1): 161–71. doi:10.1016/0092-8674(91)90148-R. PMID1712671.
^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. PMID8757502.
^ abcdBai 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". Oncogene17 (8): 941–8. doi:10.1038/sj.onc.1202024. PMID9747873.
^ abMillion 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. PMC416425. PMID15143164.
^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". Blood89 (1): 297–306. PMID8978305.
^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. PMID10706130.
^ abcMaru 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. PMC231961. PMID7529874.
^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". Blood96 (2): 664–70. PMID10887132.
^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". Leukemia17 (2): 283–9. doi:10.1038/sj.leu.2402778. PMID12592324.
^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. PMID10849448.
^ abSalgia 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. PMID8641358.
^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. PMID7534286.
^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". Blood86 (2): 726–36. PMID7606002.
^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". Oncogene17 (15): 1889–92. doi:10.1038/sj.onc.1202117. PMID9788431.