Protein tyrosine kinase

The protein tyrosine kinase inhibitor PTK is a group of enzymes that catalyze the transfer of a phosphate group on ATP to many important protein tyrosine residues, phosphorylating their residues, and activating various substrate enzymes. A series of reactions affect cell growth, proliferation and differentiation. To date, many PTK inhibitors have been shown to have anticancer activity, some of which can induce leukemia cell differentiation; PTK inhibitors have also achieved some promising results in combination with other anticancer drugs for the treatment of cancer. (1) Receptor tyrosine kinase (RTK) is a major family of receptors on the cell surface. All RTKs consist of three components: (1) an extracellular domain containing a ligand binding site, (2) a single transmembrane hydrophobic alpha helix region, and (3) a tyrosine kinase-containing cell. Internal domain. More than 50 different RTKs have been discovered, which can be divided into 6 subfamilies according to their structure (Fig. 32-15). Its extracellular ligand is a soluble or membrane-bound polypeptide or protein hormone, including insulin and various growth factors, mainly epidermal growth factor (EGF), platelet growth factor (PDGF), macrophage colony-stimulating factor ( M-CSF), insulin, insulin-like growth factor-1 (IGF-1), hepatocyte growth factor (HGF), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF). (2) Activation of the receptor tyrosine kinase is a rather complex process, first requiring ligand-mediated dimerization to form homologous or heterologous dimers by dimerization. The dimers phosphorylate tyrosine residues in the intracellular region of the receptor, ie, autophosphorylation of the receptor. Ligand-mediated receptor dimerization (oligomerization) has been found to be a common mechanism for activating transmembrane enzyme-coupled receptors. For different types of ligands, the specific mechanism of action can be slightly different: some ligands are themselves dimers (such as PDGF, etc.), they contain two receptor-binding surfaces that allow the two receptors to crosslink. Together; some ligands are haplotypes (such as hGH), but they have two different sites on their surface that can be contacted with two receptor molecules to form a 1:2 ratio of ligand-receptor complexes. In addition, fibroblast growth factor itself is a monomer that does not induce dimerization of its receptor, and it is required to form a multivalent complex with heparin sulfate proteoglycan to bind two or more receptors. (3) Imatinib mesylate is a novel tyrosine kinase inhibitor and a derivative of phenylpyrimidine. About 95% of patients with chronic myeloid leukemia (CML) are positive for Ph1 chromosome, that is, the proto-oncogene ABL of chromosome 9 is ectopic to the oncogene of chromosome 22 called the breakpoint clustering region (BCR). The two genes are recombined to produce the fusion protein p-210. Compared with the normal C-ABL protein p-150, p-210 has high tyrosine kinase activity, which can stimulate leukocyte proliferation and lead to leukemia. The drug can strongly inhibit the activity of ABL tyrosine kinase in vitro and in vivo, specifically inhibit the expression of ABL and the proliferation of BCR-ABL cells, and thus can be used for the treatment of CML. In addition, the drug inhibits tyrosine kinases of platelet-derived growth factor (PDGF) and stem cell factor (SCF) receptors, and inhibits PDGF and SCF-mediated biochemical reactions, but does not affect other stimulating factors such as epidermal growth factor. Signaling. (4) Tyrosine kinase receptor pathway: The tyrosine kinase receptor pathway is one of the most important pathways in cell signaling networks. Most growth factor signals perform regulatory functions through this pathway. The growth factor receptor itself has tyrosine kinase activity or acts by binding to a membrane tyrosine protein kinase. The tyrosine protein kinase consists of four major components: the outer side of the cell is the ligand recognition binding site, followed by a transmembrane structure, the intracellular is the catalytic site of tyrosine protein kinase, and the regulatory site is located at the carboxy terminus. Peptide chain tail. When the agonist binds to the extracellular recognition site, the membrane tyrosine protein kinase is activated, autophosphorylated, and then alters the activation of the effector. Various structural changes, some of which are only a few amino acid residues in key regions, can lead to the production of uncontrolled tyrosine protein kinase oncogenes. (5) Receptor tyrosine protein kinase: Tyrosine protein kinase (TPK) functions by phosphorylating a tyrosine residue in a substrate protein, and has both a receptor type and a non-receptor type. The receptors themselves have tyrosine protein kinase activity, and their ligands are mostly cell growth factors such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (EGF), fibroblast growth factor (FGF) and the like. Upon binding of the ligand to the receptor, cell growth, differentiation and metabolism are regulated by phosphorylation of the receptor itself and substrate protein tyrosine residues and the enzymatic cascade initiated thereby. Such receptor molecules can be divided into three structural regions, namely an extracellular ligand binding region, a tyrosine kinase active region in the cell, and a transmembrane region connecting the two structural regions. Such receptors not only have tyrosine protein activating properties, but also the receptor itself has a phosphorylation site of a tyrosine residue, that is, tyrosine phosphorylation can occur by itself. When a ligand binds to a receptor, receptor dimerization can occur, activating the tyrosinase activity of the receptor, and phosphorylating its own tyrosine residue, which in turn causes phosphorylation of its own tyrosine. Its conformation changes to become the recognition site of the tyrosine protein kinase substrate, which is recognized by the downstream signaling molecules, thereby promoting the signal transmission and amplification step by step through the cascade phosphorylation reaction. (6) Protein tyrosine kinase-associated receptors: These receptors do not themselves have tyrosine kinase activity, but their cytoplasmic side contains a site for protein tyrosine kinase activity when the receptor binds to a ligand. The JAK-like protein tyrosine kinase can be combined and activated to initiate intracellular signal transduction.