Deceiving appearances: signaling by “dead” and “fractured” receptor protein-tyrosine kinases
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Abstract:
The mechanisms by which most receptor protein-tyrosine kinases (RTKs) transmit signals are now well established. Binding of ligand results in the dimerization of receptor monomers followed by transphosphorylation of tyrosine residues within the cytoplasmic domains of the receptors. This tidy picture has, however, some strange characters lurking around the edges. Cases have now been identified in which RTKs lack kinase activity, but, despite being “dead” appear to have roles in signal transduction. Even stranger are the cases in which genes encoding RTKs produce protein products consisting of only a portion of the kinase domain. At least one such “fractured” RTK appears to be involved in signal transduction. Here we describe how these strange molecules might function and discuss the questions associated with their evolution. BioEssays 23:69–76, 2001. © 2001 John Wiley & Sons, Inc.Keywords:
Receptor Protein-Tyrosine Kinases
Protein kinase domain
Extract: Tyrosine kinases are a large and diverse family of proteins found only in Metazoans. The ERBB receptor tyrosine kinases (RTK), the main focus of this article, belong to the sub-group encompassing the cell surface proteins. All receptor tyrosine kinases have an extracellular domain that binds peptide ligands, span the membrane once, and have an intracellular portion with protein tyrosine kinase activity. Ligand binding to receptor tyrosine kinases induces the formation of receptor dimers and activates the kinase domain of the receptor, which transfers a phosphate group from the bound ATP to specific tyrosine side chains on the receptor proteins and on intracellular signaling proteins that bind the active receptor tyrosine kinases. In many types of human tumors, ERBB (erythroblastosis group B) receptor tyrosine kinases are aberrantly activated and contribute to cancer development. Accordingly, these receptors have been intensely studied both to understand their roles in cancer biology and to employ them as therapeutic targets. Many ERBB targeted inhibitors are now in clinical use.
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The epidermal growth factor receptor (EGFR) and gp185erbB-2 are closely related tyrosine kinases. Despite extensive sequence and structural homology, these two receptors display quantitative and qualitative differences in their ability to couple with mitogenic signalling pathways. By using chimeric molecules between EGFR and erbB-2, we found that the determinants responsible for the specificity of mitogenic signal transduction are located in the amino-terminal half of the tyrosine kinase domain of either receptor. In the EGFR, mutational analysis within this subdomain revealed that deletion of residues 660 to 667 impaired receptor mitogenic activity without affecting its tyrosine kinase properties. This sequence is therefore likely to contribute to the specificity of substrate recognition by the EGFR kinase.
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The Ron receptor tyrosine kinase (RTK) has been implicated in the progression of a number of carcinomas, thus understanding the regulatory mechanisms governing its activity is of potential therapeutic significance. A critical role for the juxtamembrane domain in regulating RTK activity is emerging, however the mechanism by which this regulation occurs varies considerably from receptor to receptor.Unlike other RTKs described to date, tyrosines in the juxtamembrane domain of Ron are inconsequential for receptor activation. Rather, we have identified an acidic region in the juxtamembrane domain of Ron that plays a central role in promoting receptor autoinhibition. Furthermore, our studies demonstrate that phosphorylation of Y1198 in the kinase domain promotes Ron activation, likely by relieving the inhibitory constraints imposed by the juxtamembrane domain.Taken together, our experimental data and molecular modeling provide a better understanding of the mechanisms governing Ron activation, which will lay the groundwork for the development of novel therapeutic approaches for targeting Ron in human malignancies.
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A chimeric expression vector which encoded for a molecule encompassing the extracellular domain of the epidermal growth factor (EGF) receptor (EGFR) and the intracellular domain of the ret kinase (EGFR/ret chimera) was generated. Upon ectopic expression in mammalian cells, the EGFR/ret chimera was correctly synthesized and transported to the cell surface, where it was shown capable of binding EGF and transducing an EGF-dependent signal intracellularly. Thus, the EGFR/ret chimera allows us to study the biological effects and biochemical activities of the ret kinase under controlled conditions of activation. Comparative analysis of the growth-promoting activity of the EGFR/ret chimera expressed in fibroblastic or hematopoietic cells revealed a biological phenotype clearly distinguishable from that of the EGFR, indicating that the two kinases couple with mitogenic pathways which are different to some extent. Analysis of biochemical pathways implicated in the transduction of mitogenic signals also evidenced significant differences between the ret kinase and other receptor tyrosine kinases. Thus, the sum of our results indicates the existence of a ret-specific pathway of mitogenic signaling.
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Does Generic Cyclic Kinase Insert Domain of Receptor Tyrosine Kinase KIT Clone Its Native Homologue?
Receptor tyrosine kinases (RTKs) are modular membrane proteins possessing both well-folded and disordered domains acting together in ligand-induced activation and regulation of post-transduction processes that tightly couple extracellular and cytoplasmic events. They ensure the fine-turning control of signal transmission by signal transduction. Deregulation of RTK KIT, including overexpression and gain of function mutations, has been detected in several human cancers. In this paper, we analysed by in silico techniques the Kinase Insert Domain (KID), a key platform of KIT transduction processes, as a generic macrocycle (KIDGC), a cleaved isolated polypeptide (KIDC), and a natively fused TKD domain (KIDD). We assumed that these KID species have similar structural and dynamic characteristics indicating the intrinsically disordered nature of this domain. This finding means that both polypeptides, cyclic KIDGC and linear KIDC, are valid models of KID integrated into the RTK KIT and will be helpful for further computational and empirical studies of post-transduction KIT events.
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A chimeric expression vector which encoded for a molecule encompassing the extracellular domain of the epidermal growth factor (EGF) receptor (EGFR) and the intracellular domain of the ret kinase (EGFR/ret chimera) was generated. Upon ectopic expression in mammalian cells, the EGFR/ret chimera was correctly synthesized and transported to the cell surface, where it was shown capable of binding EGF and transducing an EGF-dependent signal intracellularly. Thus, the EGFR/ret chimera allows us to study the biological effects and biochemical activities of the ret kinase under controlled conditions of activation. Comparative analysis of the growth-promoting activity of the EGFR/ret chimera expressed in fibroblastic or hematopoietic cells revealed a biological phenotype clearly distinguishable from that of the EGFR, indicating that the two kinases couple with mitogenic pathways which are different to some extent. Analysis of biochemical pathways implicated in the transduction of mitogenic signals also evidenced significant differences between the ret kinase and other receptor tyrosine kinases. Thus, the sum of our results indicates the existence of a ret-specific pathway of mitogenic signaling.
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The discoidin domain receptor tyrosine kinases DDR1 and DDR2 are distinguished from other kinase enzymes by their extracellular domains, which interact with collagen rather than with peptidic growth factors, before initiating signaling via tyrosine phosphorylation. They share significant sequence and structural homology with both the c-Kit and Bcr-Abl kinases, and so many inhibitors of those kinases are also effective. Nevertheless, there has been an extensive research effort to develop potent and specific DDR inhibitors. A key interaction for many of these compounds is H-bonding to Met-704 in a hydrophobic pocket of the DDR enzyme. The most widespread use of DDR inhibitors has been for cancer therapy, but they have also shown effectiveness in animal models of inflammatory conditions such as Alzheimer’s and Parkinson’s diseases, and in chronic renal failure and glomerulonephritis.
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The identification of additional therapeutic targets by clinical molecular profiling is necessary to expand the range of molecular-targeted cancer therapeutics. This study aimed to identify novel functional tumor-specific single nucleotide variants (SNVs) in the kinase domain of receptor tyrosine kinases (RTKs), from whole-exome sequencing (WES) data.SNVs were selected from WES data of multiple cancer types using both cancer-related databases and the index reflecting molecular evolution. Immunoblotting and luciferase assay were performed to assess the function of selected SNVs.Among the seven selected SNVs, two, namely neurotrophic receptor tyrosine kinase 1 (NTRK1) V710A and fms related tyrosine kinase 3 (FLT3) K868N, detected in kinase subdomain IX, were investigated. These SNVs inhibited the autophosphorylation of the respective RTKs, thereby reducing the activity of extracellular signal-regulated kinases.RTK subdomain IX is a promising target for the molecular design of kinase inhibitors.
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Recently several oncogenic mutations were reported in tyrosine kinases in hematological malignancies as well as in solid tumors that can be targeted by kinase inhibitors. The aim of this study is to establish cellular systems for studying biochemical and signaling aspects of oncogenic tyrosine kinases, and to use these systems to test the effectiveness of small molecule inhibitors that target them. We have successfully established cell models to study the biochemical properties and drug sensitivity of oncogenic mutations in EGFR, HER2 and FLT3.
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