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 kinase (RTK) is part of the larger family of protein tyrosine kinase. Receptor tyrosine kinase consists of epidermal growth factor receptor family (EGFRs), platelet-derived growth factor receptor family (PDGFRs), macrophage colony stimulating factor receptor family (MCSFRs), insulin-like growth factor-1 receptor family (IGF1Rs), insulin receptor family (INSR), nerve growth factor receptors family (NGFRs), fibroblast growth factor receptor family (FGFRs), vascular endothelial growth factor receptor family (VEGFRs) and hepatocyte growth factor receptor family (HGFRs).
The receptor kinase protein usually contains a transmembrane domain. However, the non receptor tyrosine kinase does not possess transmembrane domain. This is the visible difference between them. Receptor tyrosine kinases are activated by the ligands that bind to their extracellular domain. Ligands can induce the receptor dimerization, which are extracellular signal molecules. The C-terminal region in the cell has the highest level of conservation and contains catalytic domains. These catalytic domains are responsible for the kinase activity of these receptors, which catalyse receptor autophosphorylation and tyrosine substrate phosphorylation.
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. It seems that Inhibition of receptor tyrosine kinases are effective measures in cancer treatment. Researchers have undergone multiple clinical trials and have established clinical activity in non small cell lung cancer and other types of solid tumors on EGFR inhibitors, such as Erlotinib, Gefitinib, and Cetuximab.
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), vascular endothelial growth factor receptor (VEGFR), 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 cell 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.