Current understanding of tyrosine kinase BMX in inflammation and its inhibitors
© Author 2014
Received: 14 April 2014
Accepted: 11 June 2014
Published: 28 July 2014
Tec family kinases, which include tyrosine kinase expressed in hepatocellular carcinoma (TEC), Bruton’s tyrosine kinase (BTK), interleukin (IL)-2-inducible T-cell kinase (ITK), tyrosine-protein kinase (TXK), and bone marrow tyrosine kinase on chromosome X (BMX), are the second largest group of non-receptor tyrosine kinases and have a highly conserved carboxyl-terminal kinase domain. BMX was identified in human bone marrow cells, and was demonstrated to have been expressed in myeloid hematopoietic lineages cells, endothelial cells, and several types of cancers. Significant progress in this area during the last decade revealed an important role for BMX in inflammation and oncologic disorders. This review focuses on BMX biology, its role in inflammation and possible signaling pathways, and the potential of selective BMX inhibitors.
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While BTK, ITK and TXK show selective expression in cells of bone marrow origin, the expression patterns of BMX and TEC are broader and extends to certain normal somatic cells — such as the cardiac endothelium as a response to ischemia and pressure overload. Specifically, BMX is expressed in hematopoietic cells of the myeloid lineage like granulocytes and monocytes.[5,6] Besides, BMX expression has also been demonstrated in glioblastoma cancer stem cells and several solid tumors, such as prostate and breast cancer. BMX has been suggested to have a role in differentiation, motility and cell survival. The endothelial cells, granulocytes and monocytes play critical roles in the inflammation. This review will examine BMX biology, its role in inflammation and possible signaling pathway, and the potential of selective BMX inhibitors.
Structure and function of BMX
BMX was the latest identified one among the 5 human TEC kinases. In 1994, the human BMX gene was first identified and cloned in bone marrow cells by Tamagnone et al. The BMX gene is located in chromosomal band X p22.2 between the DXS197 and DXS207 loci. The BTK gene, the closest relative of BMX, is also located in chromosome X. The BMX gene encodes a protein with 675 amino acids, of which 70% are identical with BTK. Mutations in BTK gene are responsible for X-linked agammaglobulinemia (XLA) in humans or X-linked immunodeficiency (XID) in mice. However, diseases-associated BMX gene mutations have not been described yet.
BMX in inflammation
Inflammation is a necessary and rapid, yet coordinated response that is induced by microbial infection or tissue injury. Triggers capable of inducing an inflammatory response include tissue damage and infection by pathogenic and nonpathogenic microbes. Undue prolongation of inflammation can be very destructive or even initiate the systemic inflammatory response syndrome, multiple organ failure and death. The inflammatory cytokines, which affect various and numerous physiologic activities, play a significant role in the pathogenesis of inflammation. In the previous studies, tumor necrosis factor (TNF)-α, IL-1β and IL-6 have been demonstrated to be the core of the cytokine-network and play a critical role in the inflammatory response.[15,16] During the immune response, the cytokine IL-8 functions as a potent neutrophil attractant and activator leads to the recruitment of neutrophils from blood, penetration of these cells through the vessel wall, and their directed migration to inflammatory sites and contributes to the advance of inflammation by releasing superoxide anion, matrix metalloproteinase, leukotriene B(4) and platelet-activating factor.[17–19]
There is emerging evidence that non-receptor tyrosine kinase BMX is involved in the pathogenesis of inflammatory disorders, such as rheumatoid arthritis (RA).[7,20,21] An siRNA against BMX-inhibited lipopolysaccharide (LPS)-induced IL-6 secretion in synovial fibroblasts. In macrophages and synovial fibroblasts from RA patients, overexpression of BMX mediates an increase in LPS-induced stabilization of the IL-6 mRNA.[20,21] In the absence of LPS, overexpression of BMX failed to induce IL-6 mRNA expression. Further study revealed that transient depletion of BMX strongly reduced secretion of IL-8 in human fibroblasts stimulated by TNF-α and IL-1β. In neuronal injury induced by H2O2 or ischemia, BMX is activated and suppressing BMX activity protects against neurodegeneration. Altogether, an essential role for the tyrosine kinase BMX in cytokine signaling and inflammation has been established.
The stimulation of Toll-like receptor (TLR)4 by LPS induces the release of critical pro-inflammatory cytokines that result in systemic inflammation and sepsis.[16,24] TLR4 signaling has been divided into MyD88-dependent and MyD88-independent pathways. Signaling through the MyD88-dependent pathway leads to the activation of p38 mitogen-activated protein kinase (MAPK), c-Jun NH(2)-terminal kinase (JNK), and nuclear factor-κB (NF-κB).[25,26] Such signaling activation consequently lead to the release of pro-inflammatory cytokines including TNF-α and IL-1β.[27,28]
BMX kinase inhibitors
As shown in the previously mentioned data, BMX is an important molecule involved in the inflammatory processes. Modulating BMX activity might control the excessive inflammatory response. Prerequisite for the treatment of inflammation by modifying BMX activity is to use a specific, non-toxic inhibitor.
Ibrutinib (PCI-32765), a reported irreversible inhibitor of BTK, is also a potent inhibitor of BMX and other TEC family kinases.[35,36] Primary data showed that ibrutanib is beneficial in models of arthritis and patients with relapsed or refractory chronic lymphocytic leukemia.[36,37]
Whether these inhibitors could provide significant beneficial effects in inflammatory diseases remains to be established.
This study was supported by the National Natural Science Foundation of China (Grant No. 81372050 and 81000836) and the Natural Science Foundation of Anhui Province (Grant No. 1208085MH135).
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