The Role of Tec Family Kinases in Myeloid Cells
Members of the Tec kinase family (Bmx, Btk, Itk, Rlk and Tec) are primarily expressed in the hematopoietic system and form, after the Src kinase family, the second largest class of non-receptor protein tyrosine kinases. During lymphocyte development and activation Tec kinases have important functions in signaling pathways downstream of the antigen receptors. Tec family kinases are also expressed in cells of the myeloid lineage. However, with the exception of mast cells and platelets, their biological role in the myeloid system is only poorly understood. This review summarizes the current knowledge about the function of Tec family kinases in hematopoietic cells of the myeloid lineage.
Available from: Lesley A Mathews Griner
- "The appearance of Bmx (also referred to as Etk) as a differentially methylated target was also interesting, yet not surprising, since this protein is a well-known regulator of prostate cancer. BMX is a family member of the Tec family of non-receptor tyrosine kinases that are predominately expressed in cells of hematopoietic origin, yet recently has also been shown to be expressed in arterial endothelium and a variety of epithelial cells [21,39,47,48]. Although BMX has a role in the formation of leukemia [21,49], our research is the first to demonstrate that BMX may play a significant role in the regulation of prostate cancer invasion and TICs. "
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ABSTRACT: Recently, much attention has been focused on gaining a better understanding of the different populations of cells within a tumor and their contribution to cancer progression. One of the most commonly used methods to isolate a more aggressive sub-population of cells utilizes cell sorting based on expression of certain cell adhesion molecules. A recently established method we developed is to isolate these more aggressive cells based on their properties of increased invasive ability. These more invasive cells have been previously characterized as tumor initiating cells (TICs) that have a stem-like genomic signature and express a number of stem cell genes including Oct3/4 and Nanog and are more tumorigenic compared to their 'non-invasive' counterpart. They also have a profile reminiscent of cells undergoing a classic pattern of epithelial to mesenchymal transition or EMT. Using this model of invasion, we sought to investigate which genes are under epigenetic control in this rare population of cells. Epigenetic modifications, specifically DNA methylation, are key events regulating the process of normal human development. To determine the specific methylation pattern in these invasive prostate cells, and if any developmental genes were being differentially regulated, we analyzed differences in global CpG promoter methylation.
Differentially methylated genes were determined and select genes were chosen for additional analyses. The non-receptor tyrosine kinase BMX and transcription factor SOX1 were found to play a significant role in invasion. Ingenuity pathway analysis revealed the methylated gene list frequently displayed genes from the IL-6/STAT3 pathway. Cells which have decreased levels of the targets BMX and SOX1 also display loss of STAT3 activity. Finally, using Oncomine, it was determined that more aggressive metastatic prostate cancers in humans also have higher levels of both Stat3 and Sox1.
Using this method we can begin to understand which genes are epigenetically regulated in the invasive population compared to the bulk tumor cells. These aggressive sub-populations of cells may be linked to the cancer stem cell hypothesis, making their patterns of epigenetic regulation very attractive for biomarker analysis.
Available from: Christine D Palmer
- "Studies from this group and others have shown a role for Tec family kinase Bruton's tyrosine kinase (Btk) in the regulation of cytokines by TLRs in myeloid cells and cell lines    . Cytokines such as IL-6 and VEGF can be produced by RA fibroblasts; Btk expression is restricted to haematopoietic cells . "
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ABSTRACT: Discordant cytokine production is characteristic of chronic inflammatory conditions like rheumatoid arthritis (RA), and anti-cytokine therapeutics are becoming routinely used to treat RA in the clinic. Fibroblasts from rheumatoid synovium have been shown to contribute to cytokine production in inflamed joints; likewise these cells also produce cytokines in response to inflammatory mediators signalling through Toll like receptors (TLRs). Tyrosine kinase activity is essential to LPS-induced cytokine production, and we have previously implicated a role for the Tec kinase, Bmx, in inflammatory cytokine production. Here we show that Bmx kinase activity in RASF is increased following LPS stimulation and that Bmx is involved in the regulation of LPS-induced IL-6 and VEGF production via mRNA stabilisation. This is an important insight into the regulation of VEGF, which is involved in a wide range of different pathologies, and may lead to more effective design of novel anti-inflammatory/angiogenic therapeutics for conditions such as RA.
Available from: Csaba Ortutay
- "More subtle effects of Tec have been recognized in platelets (Atkinson et al., 2003; Crosby and Poole, 2002; Oda et al., 2000), erythroid (Schmidt et al., 2004a; van Dijk et al., 2000), and phagocytic cells (Jongstra- Bilen et al., 2008; Melcher et al., 2008). In these cells, Tec is important for signaling through various receptors (Atkinson et al., 2003; Crosby and Poole, 2002; Oda et al., 2000; Schmidt et al., 2004b; van Dijk et al., 2000), and lack of Tec resulted in increased levels of caspases (Melcher et al., 2008). Furthermore, Tec showed a unique late effect in the phagocytic process (Jongstra-Bilen et al., 2008). "
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ABSTRACT: It is generally considered mammals and birds have five Tec family kinases (TFKs): Btk, Bmx (also known as Etk), Itk, Tec, and Txk (also known as Rlk). Here, we discuss the domains and their functions and regulation in TFKs. Over the last few years, a large number of genomes from various phyla have been sequenced making it possible to study evolutionary relationships at the molecular and sequence level. Using bioinformatics tools, we for the first time demonstrate that a TFK ancestor exists in the unicellular choanoflagellate Monosiga brevicollis, which is the closest known relative to metazoans with a sequenced genome. The analysis of the genomes for sponges, insects, hagfish, and frogs suggests that these species encode a single TFK. The insect form has a divergent and unique N-terminal region. Duplications generating the five members took place prior to the emergence of vertebrates. Fishes have two or three forms and the platypus, Ornithorhynchus anatinus, has four (lacks Txk). Thus, not all mammals have all five TFKs. The single identified TFK in frogs is an ortholog of Tec. Bmx seems to be unique to mammals and birds. SH3BP5 is a negative regulator of Btk. It is conserved in choanoflagellates and interestingly exists also in nematodes, which do not express TFKs, suggesting a broader function in addition to Btk regulation. The related SH3BP5-like protein is not found in Nematodes.
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