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Receptor Tyrosine Kinase

The Introduction of Receptor Tyrosine Kinase

Receptor Tyrosine Kinase

Protein tyrosine kinase (PTK) was first discovered in 1990 by Hunter et al. in the sarcoma virus. It specifically transfers the phosphate group to tyrosine (Tyr) and has no effect on Ser/Thr. Subsequently, various PTKs and their substrates were found. According to the structure of PTK and its position in the cell, it can be divided into three categories. Among them, receptor tyrosine kinases (RTKs) are the largest class of enzyme-linked receptors, which are both receptors and enzymes, and they can bind to ligands and phosphorylate tyrosine residues of target proteins. These RTKs are receptors for growth factors, cytokines or hormones. It is mainly composed of three functional regions; the extracellular region binds to the ligand to accept the foreign signal; the transmembrane region connects the intracellular and extracellular signals transmembrane; the tyrosine kinase region is the enzymatically active region, which is located intracellularly and mediates the biological reaction. In addition, there are also one or two regulatory regions, consisting of a C-terminal tail or a kinase insertion region and multiple autophosphorylation sites, which regulate kinase activity; the core region is separated from the cell membrane.

RTK Family and Classification

More than 50 different RTKs have been discovered, the main types of which include epidermal growth factor (EGF) receptors; Platelet-derived growth factor (PDGF) receptor and macrophage colony stimulating factor (M-CSF); insulin and insulin-like growth factor-1 (IGF-1) receptor; nerve growth factor (NGF) receptor; fibroblast growth factor (FGF) receptor; vascular endothelial growth factor (VEGF) receptor and hepatocyte growth factor (HGF) receptor. According to the structural characteristics, RTK can be divided into four sub-categories. The first subclass is represented by EGF-R, including HER /NEU, HER3/c-erb-3, and Xmkr. There are two or three semi-proline-rich repeat regions extracellularly, which are single-stranded structures. The second subclass is α2β2 structure, including Insulin-R, and IG F-1-R. IRR is a disulfide-linked heterotetrametric, and extracellular cysteine-rich region; the third sub-class includes PDGF-RAB, CSF-1; the last subclasses include FGF-R and bek; these two types have 5 or 3 Ig-like regions. In addition, a series of new RTKs were discovered and their structures were also diversified.

Research Progress on RTK Activation and Inhibitors

The receptor tyrosine kinase is present as a monomer when it is not bound to a signal molecule and has no activity; once a signal molecule binds to the extracellular domain of the receptor, two monomeric receptor molecules form on the membrane. The tails of the intracellular domains of the two receptors are in contact with one another, activating the function of their protein kinases, resulting in phosphorylation of the tyrosine residues in the tail. Phosphorylation results in the assembly of the tail of the receptor's intracellular domain into a signaling complex. The newly phosphorylated tyrosine site immediately becomes the binding site for intracellular signaling proteins, and there may be 10 to 20 different intracellular signaling proteins that are activated after binding to the receptor phosphorylation site. Signal complexes expand information through several different signal transduction pathways, activate a series of biochemical reactions in cells, or combine different information to cause a comprehensive response (such as cell proliferation). The receptor tyrosine kinase translocates the membrane receptor signal downstream by G protein coupling. The protein kinase is a phosphotransferase, which acts to transfer the γ phosphate of ATP to the specific amino acid of the substrate. Phosphorylation of the protein on the residue is a conversion unit of the membrane receptor signal. Six types of enzyme-coupled receptors are known, receptor tyrosine kinase, receptor serine/threonine kinase, receptor tyrosine phospholipase, receptor linked to tyrosine kinase, guanosine A receptor and a histidine kinase. Signals transduced by enzyme-coupled receptors are usually associated with cell growth, proliferation, differentiation, and survival. There are currently 58 receptor tyrosine kinases in humans, covering genes including ddr1, tp53, egfr, erbb2, tgfb1, atks, atk1, braf, and pten. The development of closely related genes, some gene mutations and abnormal signaling pathways, and abnormal activation of signaling pathways promote tumor growth, proliferation and maintenance of malignant features of the tumor. Common receptor tyrosine kinase structures include the extracellular domain (binding to the ligand), the hydrophobic alpha helix region of the single transmembrane and the intracellular domain. The site of action of small molecule tyrosine kinase inhibitors is the intracellular domain. In the case of non-small cell lung cancer (NSCLC) EGFR receptor tyrosine kinase inhibitors, EGFR activation involves binding of the EGFR receptor to the ligand; EGFR ligand dimerization after receptor activation, and intracellular tyrosine acidity phosphorylation of the kinase, phosphorylation of the tyrosine moiety binds to intracellular signaling proteins to form a signaling protein complex, while the signaling protein is activated. The sustained activation of the EGFR pathway will transmit growth, proliferation and anti-apoptotic signals to tumor cells. In recent years, the development of receptor tyrosine kinase inhibitors has progressed rapidly, with EGFR RTK inhibition as an example of non-small cell lung cancer EGFR pathway inhibitors. EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor), which directly acts on EGFR intracellular protein tyrosine kinase, competes with ATP for binding to tyrosine kinase domain, and reversibly or irreversibly inhibits tyrosine phosphorylation. The first generation of EGFR-TKI currently in clinical use includes erlotinib (trade name Tarceva), gefitinib (trade name Iressa), and ectinib (trade name Kamena). Other small molecule RTK inhibitors of non-small cell lung cancer currently include crizotinib, Alectinib, and LDK378.


  1. Fey D, Aksamitiene E, Kiyatkin A, et al. Modeling of Receptor Tyrosine Kinase Signaling: Computational and Experimental Protocols. Methods Mol Biol. 2017, 1636:417-453.
  2. Serizawa M, Kusuhara M, Ohnami S, et al. Novel Tumor-specific Mutations in Receptor Tyrosine Kinase Subdomain IX Significantly Reduce Extracellular Signal-regulated Kinase Activity. Anticancer Research. 2016, 36(6):2733.
  3. Ophélie C, Maeva D, Arnaud J, et al. All tyrosine kinase inhibitor-resistant chronic myelogenous cells are highly sensitive to Ponatinib. Oncotarget. 2012, 3(12):1557-1565.

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