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>Receptor Tyrosine Kinase
Receptor Tyrosine Kinase
Receptor tyrosine kinases are a diverse group of transmembrane proteins that act as receptors for cytokines, growth factors, hormones and other signaling molecules. Receptor tyrosine kinases are expressed in many cell types and play important roles in a wide variety of cellular processes, including growth, differentiation and angiogenesis.
Receptor tyrosine kinases have been shown to play critical roles in a variety of cellular processes including growth, differentiation and angiogenesis, and in the development and progression of many types of cancer. Inhibition of receptor tyrosine kinases seems to be effective strategies in cancer therapy. The EGFR inhibitors Erlotinib, Gefitinib, and Cetuximab have undergone extensive clinical testing and have established clinical activity in non small cell lung cancer (NSCLS) and other types of solid tumors.
The receptors for many polypeptide growth factors and hormones are proteins with a single transmembrane domain and an intrinsic tyrosine kinase activity. Those receptors include epidermal growth factor receptor (EGFR. See EGFR Signaling), vascular endothelial growth factor receptor (VEGFR. See VEGF Signaling), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). Insulin-like growth factor receptor (IGFR), a dimeric receptor, is also another tyrosine kinase receptor. Human epidermal growth factor receptor (HER) is one member of a family of four related proteins, termed the ErbB/HER receptors (because of their similarity to the v-ErbB oncogene of avian erythroblastosis virus that induces erythroid leukemia in birds). The link of ErbB2/HER2 with cancer is also observed in human, as overexpression of the human ErbB2 gene, which encodes the human EGFR (also known as HER2), is related with cancer.
When a growth factor binds to the extracellular domain of tyrosine kinase receptor, it triggers dimerization with another tyrosine kinase receptor, which phosphorylates the neighbour receptor (autophosphorylation) on several tyrosine residues . Cytoplasmic proteins of the growth factor signalling pathway typically contain similar domains as the protein SRC (pronounced "sarc," as it is the short for "sarcoma"). These domains are called SH2 (SRC homology 2 domain), which binds to phosphorylated tyrosine, and SH3 (SCR homology 3 domain), which binds to a region in a protein that has polyproline helix secondary structure. GRB2 is a protein that contains SH2 and SH3 domains and can form a bridge between the receptor and a guanine exchange factor (GEF), which is able to exchange GDP for GTP in a GTP activating protein (GAP). SOS (son of sevenless) is the main Ras GTPase-activating protein (RasGAP). Thus, SOS activates Ras.
The majority of growth factor receptors are composed of extracellular, transmembrane, and cytoplasmic tyrosine kinase (TK) domains. Receptor tyrosine kinase (RTK) activation regulates many key processes including cell growth and survival. However, dysregulation of receptor tyrosine kinase has been found in a wide range of cancers, and it has been shown to correlate with the development and progression of numerous cancers. Therefore, receptor tyrosine kinase has become an attractive therapeutic target. One way to effectively block signaling from receptor tyrosine kinase is inhibition of its catalytic activity with small-molecule inhibitors. Low-molecular-weight TK inhibitors (TKIs), such as imatinib, targeting tumors with mutant c-Kit, and gefitinib, targeting non-small cell lung cancer with mutant epidermal growth factor receptor (EGFR), have received marketing approval in Japan. MET, fibroblast growth factor receptor (FGFR), and insulin-like growth factor-I receptor (IGF-IR) are frequently genetically altered in advanced cancers. TKIs of these receptors have not yet appeared on the market, but many anticancer drug candidates are currently undergoing clinical trials. Most of these TKIs were designed to compete with ATP at the ATP-binding site within the TK domain.
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