BCR (gene) explained

Symbol:	Bcr-Abl_Oligo
Bcr-Abl oncoprotein oligomerisation domain
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 fusion protein, 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 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.^{[1] [2]}

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.^[3]

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.^[4] 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.^[5]

Interactions

The BCR protein has been shown to interact with:

• Abl gene,^{[6] [7]}
• CD117,^[8]
• CRKL^{[9] [10]}
• FES,^{[11] [12]}
• Grb2,^{[13] [14] [12] [15] [16]}
• GRB10,^[17]
• HCK,^{[18] [19]}
• MLLT4,^[20]
• PXN,^[21]
• PIK3CG,^{[17] [22] [23]}
• PTPN6,^[24]
• PTPRT(PTPrho)^[25]
• SOS1,^{[13] [12]} and
• XPB.^[26]

See also

• Abl gene

Further reading

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

Notes and References

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