Tyrosine kinase
Protein tyrosine kinase | |||||||||
---|---|---|---|---|---|---|---|---|---|
OPM superfamily | 186 | ||||||||
OPM protein | 2k1k | ||||||||
CDD | cd00192 | ||||||||
Membranome | 3 | ||||||||
|
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.
Reaction
Protein kinases are a group of enzymes that possess a catalytic subunit that transfers the gamma (terminal) phosphate from
Function
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.[2] Tyrosine kinases catalyze the phosphorylation of tyrosine residues in proteins.[2] The phosphorylation of tyrosine residues in turn causes a change in the function of the protein that they are contained in.[2]
Phosphorylation at tyrosine residues controls a wide range of properties in proteins such as enzyme activity, subcellular localization, and interaction between molecules.
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.
The transmission of mechanical force and regulatory signals are quite fundamental in the normal survival of a living organism. Protein tyrosine kinase plays a role in this task, too. A protein tyrosine kinase called pp125, also referred to as focal adhesion kinase (FAK) is likely at hand in the influence of cellular focal adhesions, as indicated by an immunofluorescent localization of FAK. Focal adhesions are macromolecular structures that function in the transmission of mechanical force and regulatory signals.[5]
Cellular proliferation, as explained in some detail above, may rely in some part on tyrosine kinase.[3] Tyrosine kinase function has been observed in the nuclear matrix. Lyn, the type of kinase that was the first to be discovered in the nuclear matrix, is part of Src family of tyrosine kinases, which can be contained in the nucleus of differentiating, calcium-provoked kertinocytes. Lyn, in the nuclear matrix, among the nuclear envelope and the “fibrous web” that physically stabilizes DNA, was found functioning in association with the matrix. Also, it appeared to be conditional to cell cycle.[3] The contribution of the Lyn protein to the total tyrosine kinase activity within the nuclear matrix is unknown, however; because the Lyn was extracted only partially, an accurate measurement of its activity could not be managed.[3] Indications, as such, are that, according to Vegesna et al. (1996), Lyn polypeptides are associated with tyrosine kinase activity in the nuclear matrix. The extracted Lyn was enzymatically active, offering support for this notion.
Yet another possible and probable role of protein tyrosine kinase is that in the event of circulatory failure and organ dysfunction caused by endotoxin in rats, where the effects of inhibitors
Regulation
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.[2] Although more research indicates that receptors remain active within endosomes, it was once thought that endocytosis caused by ligands was the event responsible for the process in which receptors are inactivated. Activated receptor tyrosine kinase receptors are internalized (recycled back into the system) in short time and are ultimately delivered to lysosomes, where they become work-adjacent to the catabolic acid hydrolases that partake in digestion. Internalized signaling complexes are involved in different roles in different receptor tyrosine kinase systems, the specifics of which were researched.[7] 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.[8] 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.[2] Ligand-activated receptor tyrosine kinases, as they are sometimes referred to, demonstrate a unique attribute. Once a tyrosine receptor kinase is bonded to its ligand, it is able to bind to tyrosine kinase residing in the cytosol of the cell.[2]
Erythrocytes
An example of this trigger-system in action is the process by which the formation of
Other examples
Additional instances of factor-influenced protein tyrosine kinase activity, similar to this one, exist. An adapter protein such as
Furthermore, to illustrate an extra circumstance, insulin-associated factors have been determined to influence tyrosine kinase.
The epidermal growth factor receptor system, as such, has been used as an intermediate example.[7] Some signals are produced from the actual cell surface in this case but other signals seem to emanate from within the endosomes. This variety of function may be a means to create ligand-specific signals.[7] This supports the notion that trafficking, a term for the modification of proteins subsequent to mRNA translation, may be vital to the function of receptor signaling.
Structure
Protein tyrosine kinase proteins contain a
There are over 1800 3D structures of tyrosine kinases available in the Protein Data Bank. An example is PDB: 1IRK, the crystal structure of the tyrosine kinase domain of the human insulin receptor.
Families
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:
Receptor
By 2004, 58 human
Cytoplasmic/non-receptor
In humans, there are 32 cytoplasmic protein tyrosine kinases (EC 2.7.10.2).
The first non-receptor tyrosine kinase identified was the
Clinical significance
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.[14]
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.[4] A number of viruses target tyrosine kinase function during infection. The polyoma virus affects tyrosine kinase activity inside the nuclear matrix.[3] Fibroblasts are cells involved in wound healing and cell structure formation in mammalian cells. When these cells are transformed by the polyoma virus, higher tyrosine activity is observed in the cellular matrix, which is also correlated to cellular proliferation.[3] Another virus that targets tyrosine kinase is the Rous sarcoma virus, a retrovirus that causes sarcoma in chickens. Infected cells display obvious structure modifications and cell growth regulation that is extremely unusual.[5] Protein tyrosine kinases that are encoded by the Rous sarcoma virus cause cellular transformation, and are termed oncoproteins.[5] In addition, tyrosine kinase can sometimes function incorrectly in such a way that leads to non-small cell lung cancer.[15] 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.[15]
Research has shown that protein phosphorylation occurs on residues of tyrosine by both transmembrane receptor- and membrane-associated protein tyrosine kinases in normal cells. Phosphorylation plays a significant role in cellular signalling that regulates the number and variety of growth factors. This is evidenced by the observation that cells affected by the Rous sarcoma virus display obvious structural modifications and a total lack of normal cell growth regulation.
A tyrosine kinase can become an unregulated enzyme within an organism due to influences discussed, such as mutations and more. This behavior causes havoc; essential processes become disorganized. Systems on which the organism relies malfunction, resulting often in cancers. Preventing this type of circumstance is highly desirable. Much research has already noted the significant effect that inhibitors of the radically functioning protein tyrosine kinase enzymes have on related ailments.[
Non-small cell lung cancer
Cancer's response to an inhibitor of tyrosine kinase was assessed in a clinical trial.
Gefitinib is well endured by humans, and treatment resulted in a symptom improvement rate of 43% (with 95% confidence in a 33%–53% interval) for patients that received 250 mg of Gefitinib and 35% (with 95% confidence in a 26%–45% interval) for those that received 500 mg.[15] In the trial, epidermal growth factor receptor showed a rapid response to the inhibitor, as demonstrated by the improvement of the cancer symptoms. In each group, improvements were noted after a single week of epidermal growth factor receptor tyrosine kinase inhibitor treatment.[15] Gefitinib application once per day caused “rapid” symptom improvement and tumor regressions in non-small cell lung cancer patients.[15] In the field of medical research, this is an especially significant example of the use of an inhibitor to treat tyrosine kinase-associated cancer. Chemotherapy, surgery, and radiotherapy were the only major options available prior to the discoveries made in this trial. The side-effects of Gefitinib oral treatment once per day were considered significant. Diarrhea was reported in 57% of patients in the 250 mg group and in 75% of the 500 mg group.[15] One patient had diarrhea more severe than Grade 2, with up to six bowel movements in only one day.[15] Also, a death occurred possibly due to epidermal growth factor receptor tyrosine kinase inhibitor treatment; however, the correlation is not exactly clear.[15] In addition, skin toxicity was observed in 62% of patients in the 250 mg group. Nevertheless, the side-effects of Gefitinib were only “generally mild, manageable, noncumulative, and reversible.”[15] Unfortunately, ceasing to take the inhibitor may be the only reversal strategy of the unfavorable symptoms.[15] Gefitinib still represents a reasonably safe and effective treatment compared to other cancer therapies.
Furthermore, epidermal growth factor receptor plays a crucial role in
July 12, 2013 FDA approved afatinib "multiple receptor, irreversible TKI" for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) mutation
Chronic myeloid leukemia
BCR-ABL is a constitutively activated tyrosine kinase that is associated with chronic myeloid leukemia. It is formed from a fusion gene when pieces of chromosomes 9 and 22 break off and trade places. The ABL gene from chromosome 9 joins to the BCR gene on chromosome 22, to form the BCR-ABL fusion gene.
Gastrointestinal stromal tumors
This section needs to be updated.(February 2016) |
Inhibitors
To reduce enzyme activity, inhibitor molecules bind to enzymes. Reducing enzyme activity can disable a pathogen or correct an incorrectly function system; as such, many enzyme inhibitors are developed to be used as drugs by the general public.
GIST and Imatinib
Chronic myelogenous leukemia and nilotinib
If imatinib does not work, patients with advanced
Others
Gefitinib and erlotinib inhibit the tyrosine kinase domain of epidermal growth factor receptor (EGFR), and can be used to treat lung and pancreatic cancer where there is often over-expression of this cell-surface receptor tyrosine kinase.
Kinase inhibitors can also be mediated.
Dasatinib is a Src tyrosine kinase inhibitor that is effective both as a senolytic and as therapy for chronic myelogenous leukemia.[24]
Examples
Human proteins containing this domain include:
See also
- Tyrphostins
- Bcr-Abl tyrosine kinase inhibitors
- BYKdb
References
- PMID 3291115.
- ^ ISBN 978-1-4292-2416-1.
- ^ PMID 8612602.
- ^ PMID 9298529.
- ^ PMID 1594631.
- PMID 19756300.
- ^ S2CID 7329602.
- PMID 18654566.
- ^ S2CID 21902484.
- PMID 30867294.
- PMID 22900354.
- PMID 18045055.
- ^ Tontonoz, Matthew (December 27, 2017). "How a Chicken Helped Solve the Mystery of Cancer". Memorial Sloan Kettering Cancer Center. Retrieved 27 October 2022.
- ISBN 978-0-8153-4076-8.
- ^ PMID 14570950.
- ^ S2CID 34389318.
- ^ PMID 19922468.
- S2CID 8399298. Archived from the original(PDF) on 2019-02-19.
- PMID 35818053.
- ^ PMID 11287975.
- ^ PMID 18235121.
- ^ PMID 18048643.
- PMID 18472966.
- PMID 31619990.
External links
- Eukaryotic Linear Motif resource motif class MOD_TYR_CSK
- Tyrosine Kinases on KinCore: the Kinase Conformation Resource: A web resource for protein kinase sequence, structure and phylogeny
- The Tyrosine Kinase group
- Overview of all the structural information available in the PDB for UniProt: P08631 (Tyrosine-protein kinase HCK) at the PDBe-KB.
- Overview of all the structural information available in the PDB for UniProt: P00520 (Tyrosine-protein kinase ABL1) at the PDBe-KB.
- Overview of all the structural information available in the PDB for UniProt: O60674 (Tyrosine-protein kinase JAK2) at the PDBe-KB.