Тирозинкиназы: структура, функции и роль в развитии рака

Class hi residues

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger class of enzymes known as protein kinases which also attach phosphates to other amino acids such as serine and threonine. Phosphorylation of proteins by kinases is an important mechanism for communicating signals within a cell (signal transduction) and regulating cellular activity, such as cell division. Protein kinases can become mutated, stuck in the "on" position, and cause unregulated growth of the cell, which is a necessary step for the development of cancer. Therefore, kinase inhibitors, such as imatinib and osimertinib, are often effective cancer treatments. Most tyrosine kinases have an associated protein tyrosine phosphatase, which removes the phosphate group.

Protein kinases are a group of enzymes that possess a catalytic subunit that transfers the gamma (terminal) phosphate from nucleoside triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. The enzymes fall into two broad classes, characterised with respect to substrate specificity: serine/threonine specific, and tyrosine specific (the subject of this article).

Kinase is a large family of enzymes that are responsible for catalyzing the transfer of a phosphoryl group from a nucleoside triphosphate donor, such as ATP, to an acceptor molecule. The phosphorylation of tyrosine residues in turn causes a change in the function of the protein that they are contained in. Finally mutations can cause some tyrosine kinases to become constitutively active, a nonstop functional state that may contribute to initiation or progression of cancer. Tyrosine kinases function in a variety of processes, pathways, and actions, and are responsible for key events in the body. The receptor tyrosine kinases function in transmembrane signaling, whereas tyrosine kinases within the cell function in signal transduction to the nucleus. Tyrosine kinase activity in the nucleus involves cell cycle control and properties of transcription factors. Cellular proliferation, as explained in some detail above, may rely in some part on tyrosine kinase.

Major changes are sometimes induced when the tyrosine kinase enzyme is affected by other factors. One of the factors is a molecule that is bound reversibly by a protein, called a ligand. A number of receptor tyrosine kinases, though certainly not all, do not perform protein kinase activity until they are occupied, or activated, by one of these ligands. In addition, ligands participate in reversible binding, with inhibitors binding non covalently (inhibition of different types are effected depending on whether these inhibitors bind the enzyme, the enzyme substrate complex, or both). Multivalency, which is an attribute that bears particular interest to some people involved in related scientific research, is a phenomenon characterized by the concurrent binding of several ligands positioned on one unit to several coinciding receptors on another. In any case, the binding of the ligand to its partner is apparent owing to the effects that it can have on the functionality of many proteins. In erythrocyte regulation, erythropoietin is a protein containing 165 amino acids that plays a role in activating the cytoplasmic protein kinase JAK. There are over 1800 3D structures of tyrosine kinases available in the Protein Data Bank. An example is , the crystal structure of the tyrosine kinase domain of the human insulin receptor.

There are 90 human genes that contain a total of 94 protein tyrosine kinase domains (PTKs). Four genes contain both a catalytically active kinase domain and a pseudokinase domain (a kinase domain with no catalytic activity: JAK1, JAK2, JAK3, and TYK2). Including these four genes, there are 82 human genes that contain a catalytically active tyrosine kinase domain They are divided into two classes, receptor and non receptor tyrosine kinases.

By 2004, 58 human receptor tyrosine kinases (RTKs) were known, grouped into 20 subfamilies. Eight of these membrane proteins which contain tyrosine protein kinase domains are actually pseudokinases, without catalytic activity (EPHA10, EPHB6, ERBB3, PTK7, ROR1, ROR2, RYK, and STYK1). Receptor tyrosine kinases play pivotal roles in diverse cellular activities including growth (by signaling neurotrophins), differentiation, metabolism, adhesion, motility, and death. RTKs are composed of an extracellular domain, which is able to bind a specific ligand, a transmembrane domain, and an intracellular catalytic domain, which is able to bind and phosphorylate selected substrates. Binding of a ligand to the extracellular region causes a series of structural rearrangements in the RTK that lead to its enzymatic activation. In particular, movement of some parts of the kinase domain gives free access to adenosine triphosphate (ATP) and the substrate to the active site. This triggers a cascade of events through phosphorylation of intracellular proteins that ultimately transmit ("transduce") the extracellular signal to the nucleus, causing changes in gene expression. Many RTKs are involved in oncogenesis, either by gene mutation, or chromosome translocation, or simply by over expression. In every case, the result is a hyper active kinase, that confers an aberrant, ligand independent, non regulated growth stimulus to the cancer cells.

In humans, there are 32 cytoplasmic protein tyrosine kinases
The first non receptor tyrosine kinase identified was the v src oncogenic protein. Most animal cells contain one or more members of the Src family of tyrosine kinases. A chicken sarcoma virus, the Rous sarcoma virus mentioned above, was found to carry mutated versions of the normal cellular Src gene. The mutated v src gene has lost the normal built in inhibition of enzyme activity that is characteristic of cellular SRC (c src) genes. SRC family members have been found to regulate many cellular processes. For example, the T cell antigen receptor leads to intracellular signalling by activation of Lck and Fyn, two proteins that are structurally similar to Src.

Tyrosine kinases are particularly important today because of their implications in the treatment of cancer. A mutation that causes certain tyrosine kinases to be constitutively active has been associated with several cancers. Imatinib (brand names Gleevec and Glivec) is a drug able to bind the catalytic cleft of these tyrosine kinases, inhibiting its activity. Tyrosine kinase activity is also significantly involved in other events that are sometimes considered highly unfavorable. For instance, enhanced activity of the enzyme has been implicated in the derangement of the function of certain systems, such as cell division. Also included are numerous diseases related to local inflammation such as atherosclerosis and psoriasis, or systemic inflammation such as sepsis and septic shock. A common, widespread cancer, non small cell lung cancer is the cause of death in more people than the total number in breast, colorectal, and prostate cancer together. Gefitinib is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor, inducing favorable outcomes in patients with non small cell lung cancers. A common, widespread cancer, non small cell lung cancer is the cause of death in more people than breast, colorectal, and prostate cancer together. By 2010 Two monoclonal antibodies and another small molecule tyrosine kinase inhibitor called Erlotinib had also been developed to treat cancer. Tyrosine kinase activity is crucial for the transformation of BCR ABL. Therefore, inhibiting it improves cancer symptoms. Among currently available inhibitors to treat CML are imatinib, dasatinib, nilotinib, bosutinib and ponatinib.

Gastrointestinal stromal tumors (GIST) are known to withstand cancer chemotherapy treatment and do not respond to any kind of therapy (in 2001) in advanced cases. However, tyrosine kinase inhibitor STI571 (imatinib) is effective in the treatment of patients with metastatic gastrointestinal stromal tumors. Gastrointestinal stromal tumors consist of a cluster of mesenchymal neoplasms that are formed from precursors to cells that make up the connective tissue in the gastrointestinal tract. Treatment options have been limited. This inhibitor is a highly selective Bcr Abl tyrosine kinase inhibitor. Dasatinib is a Src tyrosine kinase inhibitor that is effective both as a senolytic and as therapy for chronic myelogenous leukemia.