Figure S5 from Heparan Sulfate Synthesized by <i>Ext1</i> Regulates Receptor Tyrosine Kinase Signaling and Promotes Resistance to EGFR Inhibitors in GBM
Yuki OhkawaAnna WadeOlle R. LindbergKatharine Y. ChenVy M. TranSpencer J. BrownAnupam KumarMausam KalitaC. David JamesJoanna J. Phillips
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Tyrosine kinase receptors are expressed on the surface of tumor and/or endothelial cells and represent attractive targets for new anti-cancer treatment strategies. The so-called "small molecule" tyrosine kinase inhibitors have been designed to interact with the intracellular ATP binding site of these receptors, subsequently causing arrest of tumor cell proliferation, as well as induction of apoptosis and tumor migration. Furthermore, these molecules can impact on tumor angiogenesis. Tyrosine kinase inhibitors have been evaluated in several clinical trials for various adult malignant tumor entities and are currently being studied in pediatric solid malignancies. In this review, we will address the data available supporting the potential use of tyrosine kinase inhibitors in solid malignancies of childhood. Keywords: Tyrosine kinase, tyrosine kinase inhibitors, imatinib, gefitinib, erlotinib, embryonic tumors, sarcomas, pediatric oncology
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Epidermal growth factor receptor (EGFR) tyrosine kinase is over-expressed in numerous human tumors, which plays pivotal roles in cellular signal transduction, and it is involved in a variety of tumor cellular behaviors such as proliferation, metastasis, angiogenesis and so on. Many investigations have indicated that tumor growth can be suppressed by inhibiting EGFR tyrosine kinase activity. Currently, several EGFR tyrosine kinase inhibitors are in clinical trial stage.
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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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Among the intracellular milieu of proteins are molecules with defined biochemical functions that serve as substrates for ligand-activated tyrosine kinase receptors. It seems likely that some of these substrate molecules are elements of a critical signaling pathway used by growth factors to control cell proliferation and subverted by oncogenes to deregulate this process. Although the process of cell growth and division is relatively slow compared with other hormonally regulated responses, homeostasis in a human being requires approximately 20 x 10(6) cell divisions per second for the renewal of various cell populations. This review summarizes the present understanding of tyrosine kinase substrates that seem likely to have key roles in the signal transduction pathway that regulates cell proliferation. This includes structural features of these molecules, the influence of tyrosine phosphorylation on their functions, the biological roles of these proteins, and the capacity of these substrates to associate with activated receptor tyrosine kinases.
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Abstract: The tyrosine kinase (TK) family is considered one of the important family members of the kinase family due to its important role in various cellular processes like cell growth, cell differentiation, apoptosis, etc. Mutation, overexpression, and dysfunction of tyrosine kinase receptors lead to the development of malignancy; thus, they are considered as one of the important targets for the development of anti-cancer molecules. The tyrosine kinase family is majorly divided into two classes; receptor and non-receptor tyrosine kinase. Both of the classes have an important role in the development of tumour cells. Currently, there are more than 40 FDA-approved tyrosine kinase inhibitors, which are used in the treatment of various types of cancers. Tyrosine kinase inhibitors mainly block the phosphorylation of tyrosine residue of the corresponding kinase substrate and so activation of downstream signalling pathways can be inhibited. The promising results of tyrosine kinase inhibitors in solid tumours provide a revolution in oncology research. In this article, we had summarized the role of some important members of the tyrosine kinase family in the development and progression of tumour cells and the significance of tyrosine kinase inhibitors in the treatment of various types of cancer.
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The signal transduction system induced by epidermal growth factor receptor(EGFR) regulates cell cycle ,modulates cell growth and differentiation and improves damage repair.The overexpression of EGFR in several epithelial tumors including non small cell lung cancer(NSCLC) forecasts low survival rate, poor prognosis and metastasis. Thereby EGFR can be a potential target for gene therapy. Tyrosine kinase inhibitors(TKIs) selectively inhibit tyrosine kinase activity,supress tumor growth ,and increase the sensitivity of radio chemotherapy. [
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