Biology:BCR (gene)
 Generic protein structure example |
| Bcr-Abl oncoprotein oligomerisation domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 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 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][8]
- CD117,[9]
- CRKL[10][11][12][13]
- FES,[14][15]
- Grb2,[6][10][11][15][16][17]
- GRB10,[10]
- HCK,[18][19]
- MLLT4,[20]
- PXN,[21][22]
- PIK3CG,[10][21][23]
- PTPN6,[24]
- PTPRT(PTPrho)[25]
- SOS1,[6][15] and
- XPB.[26]
See also
- Abl gene
References
- ↑ "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. doi:10.1083/jcb.201304133. PMID 23940119.
- ↑ "Entrez Gene: Breakpoint cluster region". https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=613.
- ↑ "Entrez Gene: BCR breakpoint cluster region". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=613.
- ↑ "Structure of the Bcr-Abl oncoprotein oligomerization domain". Nature Structural Biology 9 (2): 117–120. February 2002. doi:10.1038/nsb747. PMID 11780146.
- ↑ Nagarkar, Radhika P.; Fichman, Galit; Schneider, Joel P. (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. http://dx.doi.org/10.1002/pep2.24180.
- ↑ 6.0 6.1 6.2 "Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway". The EMBO Journal 13 (4): 764–773. February 1994. doi:10.1002/j.1460-2075.1994.tb06319.x. PMID 8112292.
- ↑ "Bcr and Abl interaction: oncogenic activation of c-Abl by sequestering Bcr". Cancer Research 63 (2): 298–303. January 2003. PMID 12543778.
- ↑ "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. doi:10.1016/0092-8674(91)90148-R. PMID 1712671.
- ↑ "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. doi:10.1046/j.1365-2141.1996.6102053.x. PMID 8757502.
- ↑ 10.0 10.1 10.2 10.3 "The SH2-containing adapter protein GRB10 interacts with BCR-ABL". Oncogene 17 (8): 941–948. August 1998. doi:10.1038/sj.onc.1202024. PMID 9747873.
- ↑ 11.0 11.1 "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. doi:10.1128/MCB.24.11.4685-4695.2004. PMID 15143164.
- ↑ "Direct binding of CRKL to BCR-ABL is not required for BCR-ABL transformation". Blood 89 (1): 297–306. January 1997. doi:10.1182/blood.V89.1.297. PMID 8978305.
- ↑ "CRKL binding to BCR-ABL and BCR-ABL transformation". Leukemia & Lymphoma 33 (1–2): 119–126. March 1999. doi:10.3109/10428199909093732. PMID 10194128.
- ↑ "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. PMID 10706130.
- ↑ 15.0 15.1 15.2 "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. doi:10.1128/MCB.15.2.835. PMID 7529874.
- ↑ "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. doi:10.1182/blood.V96.2.664. PMID 10887132. https://escholarship.org/uc/item/2pv2423x.
- ↑ "Bcr phosphorylated on tyrosine 177 binds Grb2". Oncogene 14 (19): 2367–2372. May 1997. doi:10.1038/sj.onc.1201053. PMID 9178913.
- ↑ "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. doi:10.1038/sj.leu.2402778. PMID 12592324.
- ↑ "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. doi:10.1074/jbc.C000126200. PMID 10849448.
- ↑ "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. doi:10.1128/MCB.23.13.4663-4672.2003. PMID 12808105.
- ↑ 21.0 21.1 "p210BCR/ABL induces formation of complexes containing focal adhesion proteins and the protooncogene product p120c-Cbl". Experimental Hematology 24 (2): 310–313. February 1996. PMID 8641358.
- ↑ "Molecular cloning of human paxillin, a focal adhesion protein phosphorylated by P210BCR/ABL". The Journal of Biological Chemistry 270 (10): 5039–5047. March 1995. doi:10.1074/jbc.270.10.5039. PMID 7534286.
- ↑ "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. doi:10.1182/blood.V86.2.726.bloodjournal862726. PMID 7606002.
- ↑ "Regulation of Bcr-Abl-induced SAP kinase activity and transformation by the SHPTP1 protein tyrosine phosphatase". Oncogene 17 (15): 1889–1892. October 1998. doi:10.1038/sj.onc.1202117. PMID 9788431.
- ↑ "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. doi:10.1242/jcs.105502. PMID 22767509. https://zenodo.org/record/895735.
- ↑ "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. doi:10.1073/pnas.96.1.203. PMID 9874796. Bibcode: 1999PNAS...96..203T.
Further reading
- "e19a2-positive chronic myeloid leukaemia with BCR exon e16-deleted transcripts". Leukemia 16 (8): 1562–1563. August 2002. doi:10.1038/sj.leu.2402600. PMID 12145699.
External links
- BCR+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
- Human BCR genome location and BCR gene details page in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: P11274 (Human Breakpoint cluster region protein) at the PDBe-KB.
PDB gallery | |
|---|---|
|
 |  |
