Breakpoint cluster region protein

BCR
Identifiers
AliasesBCR, 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 IDsOMIM: 151410; MGI: 88141; GeneCards: BCR
Available structures
PDBOrtholog search: PDBe RCSB
Enzyme activity
EC #BRENDAExPASyKEGGMetaCyc
2.7.11.1↗↗↗↗
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
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 MbChr 10: 74.9 – 75.02 Mb
PubMed search
Wikidata
View/Edit HumanView/Edit Mouse
Bcr-Abl oncoprotein oligomerisation domain
structure of the bcr-abl oncoprotein oligomerization domain
Identifiers
SymbolBcr-Abl_Oligo
PfamPF09036
InterProIPR015123
Available protein structures:
PDB  IPR015123 PF09036 (ECOD; PDBsum)  
AlphaFold

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.

Structure

Native protein

From the N-terminal to the C-terminal, BCR has a largely disordered kinase region (1-426), a DH domain (498-691), a PH domain (708-866), a C2 domain (893-1020), and a Rho-GAP (1054-1248) domain. The Protein Data Bank includes experimental structures for residues 1–72 (oncoprotein oligomerisation domain, see below), 1277–1271 (a C-terminal tail), 487-702 (DH), and 704-893 (PH).

Oncoprotein

Schematic of the BCR-ABL formation through chromosomal translocation

In the BCR-ABL oncoprotein, the N-terminal part of BCR is fused to the C-terminal part of ABL. The approximately 75 residues on the N-terminus functions as an oligomerisation domain essential for the oncogenicity of the BCR-ABL fusion protein. This 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. 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.

The kinase also includes a region that binds the ABL SH2 domain.

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.

BCR is a paralog of ABR, RhoGEF and GTPase activating protein. Both are GTPase-activating proteins selective for Rac. Despite their "GTPase-activating" domain they actually reduce the activity of Rac. They keep mature innate immune system cells from becoming overactive.

BCR knockout mice are viable, fertile, and free of obvious behavioral or physical abnormalities. They are however much more sensitive to lipopolysaccharide in blood, reacting with neutrophilia and septic shock. Their neutrophils are more active than those of normal mice. BCR knockout also disrupts gut movement and brain development in mice.

Interactions

The BCR protein has been shown to interact with:

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.

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000186716 – Ensembl, May 2017
  2. 1 2 3 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. 1 2 P11274
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ "Entrez Gene: Breakpoint cluster region".
  10. ↑ Cho YJ, Cunnick JM, Yi SJ, Kaartinen V, Groffen J, Heisterkamp N (February 2007). "Abr and Bcr, two homologous Rac GTPase-activating proteins, control multiple cellular functions of murine macrophages". Molecular and Cellular Biology. 27 (3): 899–911. doi:10.1128/MCB.00756-06. PMC 1800684. PMID 17116687.
  11. ↑ Cunnick JM, Schmidhuber S, Chen G, Yu M, Yi SJ, Cho YJ, et al. (November 2009). "Bcr and Abr cooperate in negatively regulating acute inflammatory responses". Molecular and Cellular Biology. 29 (21): 5742–5750. doi:10.1128/MCB.00357-09. PMC 2772743. PMID 19703997.
  12. ↑ "003803 - bcr- Strain Details". www.jax.org.
  13. ↑ Xiao Y, Sun Y, Lu Y, Du J, Tian X, Cai W, et al. (December 2021). "Loss function of Bcr mutation causes gastrointestinal dysmotility and brain developmental defects". Neurogastroenterology and Motility. 33 (12) e14190. doi:10.1111/nmo.14190. PMID 34190380.
  14. 1 2 3 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. 1 2 3 4 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.
  19. 1 2 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. 1 2 3 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 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.
  29. 1 2 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ "Entrez Gene: BCR breakpoint cluster region".

Further reading

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