Kinase Family BCR

Kinase Classification: Group Atypical: Family BCR

BCR is a putative atypical protein kinase which is fused to the Abl tyrosine kinase in most cases of chronic myelogenous leukemia. BCR does not have a typical kinase domain, and though it shows biochemical kinase activity, it may be due to a co-purifying kinase.

Domain Structure

BCR is a multi-domain protein. The first exon (in vertebrates) encodes an oligomerization domain that also contains the kinase catalytic activity. This is followed by a RhoGEF domain, a PH-like domain, a C2 domain and a RhoGAP domain, implicating it in Rho small GTPase activation and inactivation, as well as membrane association. The structure of the oligomerization domain has been solved [1]. This comprises the first 72 AA of the 428 AA first exon in human. It has a largely helical structure and its oligomerization ability has been modeled. This is followed in exon 1 by a poorly conserved linked and a second region that is conserved in vertebrate BCR, but not well conserved in other paralogs or invertebrate orthologs.

Evolution

Homologs of human BCR can be found in all animals other than nematodes. The exon1 domain has been reported to be specific to vertebrate BCR, but can be seen to be weakly conserved in several other homologs, including insect RhoGAP1A and homologs as divergent as Hydra. ABR is a vertebrate paralog of BCR, whose published sequences lack the first exon. However, our analysis of ESTs and genomic sequences from throughout the vertebrates shows that ABR can be extended, with a single conserved upstream exon also encoding similarity to BCR exon 1. Another BCR-like gene has been found in fish, but not yet annotated. We call this ABRf for now. ABRf does not appear to have the exon1 domain. Fish also have a duplication of the BCR gene.

Multiple homologs also exist in some invertebrates. Drosophila RhoGAP1A includes homology to BCR exon 1, while RhoGAP100F has no recognizable similarity in this region.

Function

Highly-purified BCR has auto- and trans-phosphorylation activities, and later mapped cysteines and tyrosines that were critical for kinase activity [2]. This region is also required for interaction with the SH2 domain of the Abl tyrosine kinase (independent of the cancer-assocaited fusion protein), however the kinase activity was on Ser/Thr rather than tyrosine, indicating that this is not due to contaminating Abl. A number of subsequent paper have shown kinase activity associated with immunoprecipitated BCR, but the kinase activity has not been further validated or explored. A reciprocal translocation between chromosmes 9 and 22 ('Philadelphia chromosome') is found in most cases of chronic myelogenous leukemia. It creates a fusion protein containing at least the first exon of BCR and the C-terminal regions of Abl, resulting in constitutive activation of the Abl tyrosine kinase activity. The normal BCR protein is also known to interact with Abl, through a site on exon 1 binding to the Abl SH2 domain [3], suggesting that the fusion protein intensifies this native interaction. Oncogenic BCR fusions to the tyrosine kinases Jak2 and PDGFA have also been reported [4, 5].

References

1. Zhao X, Ghaffari S, Lodish H, Malashkevich VN, and Kim PS. Structure of the Bcr-Abl oncoprotein oligomerization domain. Nat Struct Biol. 2002 Feb;9(2):117-20. DOI:10.1038/nsb747 |
2. Maru Y and Witte ON. The BCR gene encodes a novel serine/threonine kinase activity within a single exon. Cell. 1991 Nov 1;67(3):459-68. DOI:10.1016/0092-8674(91)90521-y |
3. Pendergast AM, Muller AJ, Havlik MH, Maru Y, and 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. 1991 Jul 12;66(1):161-71. DOI:10.1016/0092-8674(91)90148-r |
5. Wang HY, Thorson JA, Broome HE, Rashidi HH, Curtin PT, and Dell'Aquila ML. t(4;22)(q12;q11.2) involving presumptive platelet-derived growth factor receptor A and break cluster region in a patient with mixed phenotype acute leukemia. Hum Pathol. 2011 Dec;42(12):2029-36. DOI:10.1016/j.humpath.2010.07.028 |

Unlinked References

1. Griesinger pmid=16001431