BCR (gene)

Last updated
BCR
PBB Protein BCR image.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases BCR , 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 IDs OMIM: 151410 MGI: 88141 HomoloGene: 3192 GeneCards: BCR
Orthologs
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 Mb Chr 10: 74.9 – 75.02 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Bcr-Abl oncoprotein oligomerisation domain
PDB 1k1f EBI.jpg
structure of the bcr-abl oncoprotein oligomerization domain
Identifiers
SymbolBcr-Abl_Oligo
Pfam PF09036
InterPro IPR015123
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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.

Contents

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. [5] [6]

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. [7]

Structure

Schematic of the BCR-ABL formation through chromosomal translocation Schematic of the Philadelphia Chromosome.svg
Schematic of the BCR-ABL formation through chromosomal translocation

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. [8] 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. [9]

Interactions

The BCR protein has been shown to interact with:

See also

Related Research Articles

<span class="mw-page-title-main">Tyrosine kinase</span> Class hi residues

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.

<span class="mw-page-title-main">Philadelphia chromosome</span> Genetic abnormality in leukemia cancer cells

The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells. This chromosome is defective and unusually short because of reciprocal translocation, t(9;22)(q34;q11), of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the breakpoint cluster region BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signaling protein that is "always on", causing the cell to divide uncontrollably by interrupting the stability of the genome and impairing various signaling pathways governing the cell cycle.

<span class="mw-page-title-main">Chronic myelogenous leukemia</span> Medical condition

Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes and their precursors is found; characteristic increase in basophils is clinically relevant. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.

<span class="mw-page-title-main">ABL (gene)</span> Human protein-coding gene on chromosome 9

Tyrosine-protein kinase ABL1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian genome, while v-Abl refers to the viral gene, which was initially isolated from the Abelson murine leukemia virus.

<span class="mw-page-title-main">GRB2</span> Protein-coding gene in the species Homo sapiens

Growth factor receptor-bound protein 2, also known as Grb2, is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene.

<span class="mw-page-title-main">STAT5</span> Protein family

Signal transducer and activator of transcription 5 (STAT5) refers to two highly related proteins, STAT5A and STAT5B, which are part of the seven-membered STAT family of proteins. Though STAT5A and STAT5B are encoded by separate genes, the proteins are 90% identical at the amino acid level. STAT5 proteins are involved in cytosolic signalling and in mediating the expression of specific genes. Aberrant STAT5 activity has been shown to be closely connected to a wide range of human cancers, and silencing this aberrant activity is an area of active research in medicinal chemistry.

<span class="mw-page-title-main">Acute myeloblastic leukemia with maturation</span> Medical condition

Acute myeloblastic leukemia with maturation (M2) is a subtype of acute myeloid leukemia (AML).

<span class="mw-page-title-main">GAB2</span> Protein-coding gene in the species Homo sapiens

GRB2-associated-binding protein 2 also known as GAB2 is a protein that in humans is encoded by the GAB2 gene.

<span class="mw-page-title-main">ETV6</span> Protein-coding gene in the species Homo sapiens

ETV6 protein is a transcription factor that in humans is encoded by the ETV6 gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However, ETV6 is also an anti-oncogene or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers.

<span class="mw-page-title-main">CBL (gene)</span> Mammalian gene

Cbl is a mammalian gene family. CBL gene, a part of the Cbl family, encodes the protein CBL which is an E3 ubiquitin-protein ligase involved in cell signalling and protein ubiquitination. Mutations to this gene have been implicated in a number of human cancers, particularly acute myeloid leukaemia.

<span class="mw-page-title-main">PDGFRB</span> Protein-coding gene in the species Homo sapiens

Platelet-derived growth factor receptor beta is a protein that in humans is encoded by the PDGFRB gene. Mutations in PDGFRB are mainly associated with the clonal eosinophilia class of malignancies.

<span class="mw-page-title-main">HCK</span> Protein-coding gene in the species Homo sapiens

Tyrosine-protein kinase HCK is an enzyme that in humans is encoded by the HCK gene.

<span class="mw-page-title-main">CRKL</span> Protein-coding gene in the species Homo sapiens

Crk-like protein is a protein that in humans is encoded by the CRKL gene.

<span class="mw-page-title-main">GRB2-associated-binding protein 1</span> Protein-coding gene in the species Homo sapiens

GRB2-associated-binding protein 1 is a protein that in humans is encoded by the GAB1 gene.

<span class="mw-page-title-main">RAPGEF1</span> Protein-coding gene in the species Homo sapiens

Rap guanine nucleotide exchange factor 1 is a protein that in humans is encoded by the RAPGEF1 gene.

<span class="mw-page-title-main">VAV1</span> Human protein and coding gene

Proto-oncogene vav is a protein that in humans is encoded by the VAV1 gene.

<span class="mw-page-title-main">Tyrosine-protein kinase Fes/Fps</span> Human protein and coding gene

Tyrosine-protein kinase Fes/Fps also known as proto-oncogene c-Fes/Fps is an enzyme that in humans is encoded by the FES gene. FES was originally cloned as a retroviral oncogene from feline (v-FES) and avian (v-FPS) sarcomas. This triggered the subsequent identification and cloning of the cellular FES (c-FES) genes in birds and mammals.

<span class="mw-page-title-main">MECOM</span> Protein-coding gene in the species Homo sapiens

MDS1 and EVI1 complex locus protein EVI1 (MECOM) also known as ecotropic virus integration site 1 protein homolog (EVI-1) or positive regulatory domain zinc finger protein 3 (PRDM3) is a protein that in humans is encoded by the MECOM gene. EVI1 was first identified as a common retroviral integration site in AKXD murine myeloid tumors. It has since been identified in a plethora of other organisms, and seems to play a relatively conserved developmental role in embryogenesis. EVI1 is a nuclear transcription factor involved in many signaling pathways for both coexpression and coactivation of cell cycle genes.

Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called Philadelphia chromosome. This abnormality was discovered by Peter Nowell in 1960 and is a consequence of fusion between the Abelson (Abl) tyrosine kinase gene at chromosome 9 and the break point cluster (Bcr) gene at chromosome 22, resulting in a chimeric oncogene (Bcr-Abl) and a constitutively active Bcr-Abl tyrosine kinase that has been implicated in the pathogenesis of CML. Compounds have been developed to selectively inhibit the tyrosine kinase.

Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.

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. ↑ 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.
  6. ↑ "Entrez Gene: Breakpoint cluster region".
  7. ↑ "Entrez Gene: BCR breakpoint cluster region".
  8. ↑ 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.
  9. ↑ 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.
  10. 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. 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.
  15. 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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.

Further reading

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