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Tyrosine kinase
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Protein tyrosine kinase
pdb 2HCK, rendered in PyMOL
Identifiers
Symbol
Pkinase_Tyr
Pfam
PF07714
InterPro
IPR001245
SMART
TyrKc
PROSITE
PDOC00629
SCOP
1apm
SUPERFAMILY
1apm
OPM superfamily
207
OPM protein
2k1k
CDD
cd00192
[show]Available protein structures:
Pfam
structures
PDB
RCSB PDB; PDBe; PDBj
PDBsum
structure summary
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases are a subclass of protein kinase.
The phosphate group is attached to the amino acid tyrosine on the protein. Tyrosine kinases are a subgroup of the larger class of protein kinases that attach phosphate groups to other amino acids (serine and threonine). Phosphorylation of proteins by kinases is an important mechanism in 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, are often effective cancer treatments.
Most tyrosine kinases have an associated protein tyrosine phosphatase, which removes the phosphate group.
Contents
[hide]
1 Reaction
2 Function
3 Regulation
3.1 Erythrocytes as an example
3.2 Other examples
4 Structure
5 Families
5.1 Receptor
5.2 Cytoplasmic/non-receptor
6 Clinical significance
6.1 Non-small cell lung cancer
6.2 Chronic myeloid leukemia
6.3 Gastrointestinal stromal tumors
7 Inhibitors
7.1 GIST and Imatinib
7.2 Chronic myelogenous leukemia and nilotinib
7.3 Others
8 Examples
9 See also
10 References
11 External links
Reaction[edit]
Protein kinases are a group of enzymes that possess a catalytic subunit that transfers the gamma (terminal) phosphate from nucleotide 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).[1]
Function[edit]
The term kinase describes 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.[3] Furthermore, tyrosine kinases function in many signal transduction cascades wherein extracellular signals are transmitted through the cell membrane to the cytoplasm and often to the nucleus, where gene expression may be modified.[3] 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.[4] Tyrosine kinase activity in the nucleus involves cell-cycle control and properties of transcription factors.[3] In this way, in fact, tyrosine kinase activity is involved in mitogenesis, or the induction of mitosis in a cell; proteins in the cytosol and proteins in the nucleus are phosphorylated at tyrosine residues during this process.[3] Cellular growth and reproduction may rely to some degree on tyrosine kinase. Tyrosine kinase function has been observed in the nuclear matrix, which comprises not the chromatin but rather the nuclear envelope and a “fibrous web” that serves to physically stabilize DNA.[3] To be specific, Lyn, a type of kinase in the Src family that was identified in the nuclear matrix, appears to control the cell cycle. Src family tyrosine kinases are closely related but demonstrate a wide variety of functionality. Roles or expressions of Src family tyrosine kinases vary significantly according to cell type, as well as during cell growth and differentiation.[3] Lyn and Src family tyrosine kinases in general have been known to function in signal transduction pathways.[3] There is evidence that Lyn is localized at the cell membrane; Lyn is associated both physically and functionally with a variety of receptor molecules.[3]
Fibroblasts – a type of cell that synthesizes the extracellular matrix and collagen and is involved in wound healing – that have been transformed by the polyomavirus possess higher tyrosine activity in the cellular matrix. Furthermore, tyrosine kinase activity has been determined to be correlated to cellular transformation.[3] It has also been demonstrated that phosphorylation of a middle-T antigen on tyrosine is also associated with cell transformation, a change that is similar to cellular growth or reproduction.[3]
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 is likely at hand in the influence of cellular focal adhesions, as indicated by an immunofluorescent localization of the said kinase. Focal adhesions are macromolecular structures that function in the transmission of mechanical force and regulatory signals.[5] Among the scientific community, pp125 is also referred to as FAK (focal adhesion kinase), due to its aforementioned presence in cellular focal adhesions. The protein tyrosine kinase pp125 is one of the major phosphotyrosine–containing proteins in unaffected (untransformed) avian and rodent fibroblast cells (fibroblast cells are explained above in some detail).[5] Fibroblasts are a cell type responsible for wound healing and cell structure in animals, among a number of other relatively minor but important jobs that take place often or occasionally. The sequence and structure of pp125, when compared to National Biomedical Research Foundation and GenBank data bases,[5] may be quite unique, meaning that it could be a new member of the protein tyrosine kinase family. This protein tyrosine kinase is up to about 70% unique compared to some other protein tyrosine kinases, a figure that is unlike those between actual members of an established protein tyrosine kinase family.[5] Also, the amino acid sequence that was observed indirectly signifies that it is associated with the cytoplasm, dubbing it one in a large group of cytoplasmic protein tyrosine kinases.[5] It was discovered when monoclonal antibodies were observed to recognize it.[5] Monoclonal antibodies, from chicken embryo cells transformed by pp60v-src, recognize seven different phosphotyrosine-containing proteins.[5] One of these monoclonal antibodies, named 2A7, recognizes pp125, support for the idea that pp125 is, in fact, a protein tyrosine kinase.[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 tyrphostin and genistein are involved with protein tyrosine kinase.[4] Signals in the surroundings received by receptors in the membranes of cells are transmitted into the cell cytoplasm. Transmembrane signaling due to receptor tyrosine kinases, according to Bae et al. (2009), relies heavily on interactions, for example, mediated by the SH2 protein domain; it has been determined via experimentation that the SH2 protein domain selectivity is functional in mediating cellular processes involving tyrosine kinase. Receptor tyrosine kinases may, by this method, influence growth factor receptor signaling. This is one of the more fundamental cellular communication functions metazoans.[6]
Regulation[edit]
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] It is interesting to note that, although many more recent cases of research indicate 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, a term that describes those inhibitors that bind 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 as an example[edit]
An example of this trigger-system in action is the process by which the formation of erythrocytes is regulated. Mammals possess this system, which begins in the kidneys where the developmental signal is manufactured.[2] The developmental signal, also called a cytokine, is erythropoietin in this case. (Cytokines are key regulators of hematopoietic cell proliferation and differentiation.) Erythropoietin's activity is initiated when hematopoietic cytokine receptors become activated.[9] In erythrocyte regulation, erythropoietin is a protein containing 165 amino acids that plays a role in activating the cytoplasmic protein kinase JAK.[2] The results of some newer research have also indicated that the aforementioned cytokine receptors function with members of the JAK tyrosine kinase family. The cytokine receptors activate the JAK kinases. This then results in the phosphorylation of several signaling proteins located in the cell membrane. This subsequently affects both the stimulation of ligand-mediated receptors and intracellular signaling pathway activation.[9] Substrates for JAK kinases mediate some gene responses and more.[9] The process is also responsible for mediating the production of blood cells.[2] In this case, erythropoietin binds to the corresponding plasma membrane receptor, dimerizing the receptor.[2] The dimer is responsible for activating the kinase JAK via binding.[2] Tyrosine residues located in the cytoplasmic domain of the erythropoietin receptor are consequently phosphorylated by the activated protein kinase JAK.[2] Overall, this is also how a receptor tyrosine kinase might be activated by a ligand to regulate erythrocyte formation.
Other examples[edit]
Additional instances of factor-influenced protein tyrosine kinase activity, similar to this one, exist. An adapter protein such as Grb2 will bind to phosphate-tyrosine residues under the influence of receptor protein kinases. This mechanism is an ordinary one that provokes protein-protein interactions.[2]
Furthermore, to illustrate an extra circumstance, insulin-associated factors have been determined to influence tyrosine kinase. Insulin receptor substrates are molecules that function in signaling by regulating the effects of insulin.[2] Many receptor enzymes have closely related structure and receptor tyrosine kinase activity, and it is said by Lehninger (2008) that the foundational or prototypical receptor enzyme, is insulin. It is interesting to note that insulin receptor substrates IRS2 and IRS3 each have unique characteristic tissue function and distribution that serves to enhance signaling capabilities in pathways that are initiated by receptor tyrosine kinases.[2] Activated IRS-1 molecules enhance the signal created by insulin.[2] The insulin receptor system, in contrast, appears to diminish the efficacy of endosomal signaling.[7]
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.
Tyrosine
Phosphate
ATP
Structure[edit]
Included in a number of the structural features that can be recognized in all protein tyrosine kinases are an ATP binding site, three residues that are thought to be associated with the function of the third phosphate group (often called the gamma-phosphate group) of an ATP molecule bound to the enzyme, and a possible catalytic site of the enzyme that is an amino acid.[5] Also very common among protein tyrosine kinases are two peptide sequences.[5]
There are over 100 3D structures of tyrosine kinases available at the Protein Data Bank. An example is PDB: 1IRK, the crystal structure of the tyrosine kinase domain of the human insulin receptor.
Families[edit]
The tyrosine kinases are divided into two main families:
the transmembrane receptor-linked kinases
those that are cytoplasmic proteins
Approximately 2000 kinases are known[citation needed], and more than 90 Protein Tyrosine Kinases (PTKs) have been found in the human genome. They are divided into two classes, receptor and non-receptor PTKs.
Receptor[edit]
For more details on this topic, see receptor tyrosine kinase.
By 2004, 58 receptor tyrosine kinases (RTKs) were known, grouped into 20 subfamilies. They play pivotal roles in diverse cellular activities including growth (by signaling neurotrophins), differentiation, metabolism, adhesion, motility, death.[10] 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,[11] 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.
Cytoplasmic/non-receptor[edit]
For more details on this topic, see Non-receptor tyrosine kinase.
In humans, there are 32 cytoplasmic protein tyrosine kinases (EC 2.7.10.2).
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 was found to carry mutated versions of the normal cellular Src gene.[citation needed] 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.[citation needed]
Clinical significance[edit]
Main article: Protein kinase inhibitor
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.[12]
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.[13] 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.[13]
Research has shown that protein phosphorylation occurs on residues of tyrosine by both transmembrane receptor- and membrane-associated protein tyrosine kinases in normal cells.[5] Phosphorylation plays a significant role in cellular signalling that regulates the number and variety of growth factors.[5] 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.[5] Rous sarcoma virus-encoded oncoproteins are protein tyrosine kinases that are the cause of, and are required for, this cellular transformation.[5] Tyrosine phosphorylation activity also increases or decreases in conjunction with changes in cell composition and growth regulation.[5] In this way, a certain transformation exhibited by cells is dependent on a role that tyrosine kinase demonstrates.[5] Protein tyrosine kinases, have a major role in the activation of lymphocytes.[5] In addition, they are functional in mediating communication pathways in cell types such as adrenal chromaffin, platelets, and neural cells.[5]
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.[citation needed] (See Tyrosine-kinase inhibitor )
Non-small cell lung cancer[edit]
Cancer’s response to an inhibitor of tyrosine kinase was assessed in a clinical trial.[13] In this case, Gefitinib is the inhibitor of tyrosine kinase. Incorrect tyrosine kinase function can lead to non-small cell lung cancer.[14] 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.[13] This is strong motivation to perform research on tyrosine kinase inhibitors as potential targets in cancer treatment. Gefitinib, functioning as an epidermal growth factor receptor tyrosine kinase inhibitor, improved symptoms related to non-small cell lung cancer and resulted in radiographic tumor regressions.[13] This is an example of the efficacy of such an inhibitor. The process of inhibition shows how the cancer sustains. Mutations in the epidermal growth factor receptor activate signalling pathways that promote cell survival. Non-small cell lung cancer cells become dependent on these survival signals. Gefitinib’s inhibition of the survival signals may be a contributing factor to its efficacy as a drug for non-small cell cancer treatment.[14]
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.[13] 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.[13] Gefitinib application once per day caused “rapid” symptom improvement and tumor regressions in non-small cell lung cancer patients.[13] 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.[13] One patient had diarrhea more severe than Grade 2, with up to six bowel movements in only one day.[13] Also, a death occurred possibly due to epidermal growth factor receptor tyrosine kinase inhibitor treatment; however, the correlation is not exactly clear.[13] 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.”[13] Unfortunately, ceasing to take the inhibitor may be the only reversal strategy of the unfavorable symptoms.[13] Gefitinib still represents a reasonably safe and effective treatment compared to other cancer therapies.
Furthermore, epidermal growth factor receptor plays a crucial role in tumorigenesis, which is the production of a new tumor.[15] By 2010 Two monoclonal antibodies and another small-molecule tyrosine kinase inhibitor called Erlotinib had also been developed to treat cancer.[15]
July 12, 2013 FDA approved afatinib "multiple recepptor, 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[edit]
BCR-ABL is a constitutively activated tyrosine kinase that is associated with chronic myeloid leukemia.[16] 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[edit]
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.[17] 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.[17] Most of these tumors are found in the stomach, though they can also be located in the small intestine or elsewhere in the intestinal tract. The cells of these tumors have a growth factor receptor associated with tyrosine kinase activity.[17] This growth factor receptor is called c-kit and is produced by a proto-oncogene (c-kit). Mutation of c-kit causes the constitutive activity of tyrosine kinase, which results in cancerous gastrointestinal stromal tumors. Results of c-kit mutation include unrestricted tyrosine kinase activity and cell proliferation, unregulated phosphorylation of c-kit, and disruption of some communication pathways.[17] Therapy with imatinib can inhibit the non-normal cell signaling mechanisms in gastrointestinal stromal tumors. This results in significant responses in patients and sustained disease control. By 2001 it was no longer doubted that this inhibitor can be effective and safe in humans.[7] In similar manner, protein tyrosine kinase inhibitor STI571 was found to significantly reduce the physical size of tumors; they decreased roughly 65% in size in 4 months of trialing, and continued to diminish. New lesions did not appear, and a number of the liver metastases completely reduced to non-existence. The single patient in the study remained healthy following treatment.[17] There are no effective means of treatment for advanced gastrointestinal stromal tumors, but that STI571 represents an effective treatment in early stage cancer associated with constitutively active c-kit, by inhibiting unfavourable tyrosine kinase activity.[17]
This section needs to be updated. Please update this article to reflect recent events or newly available information. (February 2016)
Inhibitors[edit]
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 for the general public.
GIST and Imatinib[edit]
Gastrointestinal stromal tumors (GIST) are mesenchymal tumors that affect the gastrointestinal tract.[18] Treatment options have been limited.[18] However Imatinib, as an inhibitor to the malfunctioning enzyme, can be effective.[18]
Chronic myelogenous leukemia and nilotinib[edit]
If imatinib does not work, patients with advanced chronic myelogenous leukemia can use nilotinib, dasatinib, bosutinib, ponatinib, or another inhibitor to the malfunction enzyme that causes the leukemia.[19] This inhibitor is a highly selective Bcr-Abl tyrosine kinase inhibitor.[19]
Others[edit]
Sunitinib is an oral tyrosine kinase inhibitor that acts upon vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor, and colony-stimulating factor-1 receptor (Burstein et al. 2008)
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. Paracrine signalling mediates the response to epidermal growth factor receptor kinase inhibitors. Paracrine activates epidermal growth factor receptor in endothelial cells of the tumor to do this.[20]
Examples[edit]
Human proteins containing this domain include:
AATK; ABL; ABL2; ALK; AXL; BLK; BMX; BTK; CSF1R; CSK; DDR1; DDR2; EGFR; EPHA1; EPHA2; EPHA3; EPHA4; EPHA5; EPHA6; EPHA7; EPHA8; EPHA10; EPHB1; EPHB2; EPHB3; EPHB4; EPHB6; ERBB2; ERBB3; ERBB4; FER; FES; FGFR1; FGFR2; FGFR3; FGFR4; FGR; FLT1; FLT3; FLT4; FRK; FYN; GSG2; HCK; IGF1R; ILK; INSR; INSRR; IRAK4; ITK; JAK1; JAK2; JAK3; KDR; KIT; KSR1; LCK; LMTK2; LMTK3; LTK; LYN; MATK; MERTK; MET; MLTK; MST1R; MUSK; NPR1; NTRK1; NTRK2; NTRK3; PDGFRA; PDGFRB; PLK4; PTK2; PTK2B; PTK6; PTK7; RET; ROR1; ROR2; ROS1; RYK; SGK493; SRC; SRMS; STYK1; SYK; TEC; TEK; TEX14; TIE1; TNK1; TNK2; TNNI3K; TXK; TYK2; TYRO3; YES1; ZAP70
See also[edit]
Tyrphostins
Bcr-Abl tyrosine kinase inhibitors
References[edit]
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^ Jump up to: a b c d e f Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, Silberman S, Capdeville R, Dimitrijevic S, Druker B, Demetri GD (April 2001). "Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor". The New England Journal of Medicine. 344 (14): 1052–6. doi:10.1056/NEJM200104053441404. PMID 11287975.
^ Jump up to: a b c Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA, Corless CL, Fletcher CD, Roberts PJ, Heinz D, Wehre E, Nikolova Z, Joensuu H (February 2008). "Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT". Journal of Clinical Oncology. 26 (4): 620–5. doi:10.1200/JCO.2007.13.4403. PMID 18235121.
^ Jump up to: a b le Coutre P, Ottmann OG, Giles F, Kim DW, Cortes J, Gattermann N, Apperley JF, Larson RA, Abruzzese E, O'Brien SG, Kuliczkowski K, Hochhaus A, Mahon FX, Saglio G, Gobbi M, Kwong YL, Baccarani M, Hughes T, Martinelli G, Radich JP, Zheng M, Shou Y, Kantarjian H (February 2008). "Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia". Blood. 111 (4): 1834–9. doi:10.1182/blood-2007-04-083196. PMID 18048643.
Jump up ^ Kuwai T, Nakamura T, Sasaki T, Kim SJ, Fan D, Villares GJ, Zigler M, Wang H, Bar-Eli M, Kerbel RS, Fidler IJ (May 2008). "Phosphorylated epidermal growth factor receptor on tumor-associated endothelial cells is a primary target for therapy with tyrosine kinase inhibitors". Neoplasia. 10 (5): 489–500. doi:10.1593/neo.08200. PMC 2373870  . PMID 18472966.
External links[edit]
Eukaryotic Linear Motif resource motif class MOD_TYR_CSK
The Tyrosine Kinase group
[show]
v
t
e
Transferases: phosphorus-containing groups (EC 2.7)
2.7.1-2.7.4:
phosphotransferase/kinase
(PO4)
2.7.1: OH acceptor
Hexo-
Gluco-
Fructo-
Hepatic
Galacto-
Phosphofructo-
1
Liver
Muscle
Platelet
2
Riboflavin
Shikimate
Thymidine
ADP-thymidine
NAD+
Glycerol
Pantothenate
Mevalonate
Pyruvate
Deoxycytidine
PFP
Diacylglycerol
Phosphoinositide 3
Class I PI 3
Class II PI 3
Sphingosine
Glucose-1,6-bisphosphate synthase
2.7.2: COOH acceptor
Phosphoglycerate
Aspartate kinase
2.7.3: N acceptor
Creatine
2.7.4: PO4 acceptor
Phosphomevalonate
Adenylate
Nucleoside-diphosphate
Uridylate
Guanylate
Thiamine-diphosphate
2.7.6: diphosphotransferase
(P2O7)
Ribose-phosphate diphosphokinase
Thiamine diphosphokinase
2.7.7: nucleotidyltransferase
(PO4-nucleoside)
Polymerase
DNA polymerase
DNA-directed DNA polymerase
I
II
III
IV
V
RNA-directed DNA polymerase
Reverse transcriptase
Telomerase
DNA nucleotidylexotransferase/Terminal deoxynucleotidyl transferase
RNA nucleotidyltransferase
RNA polymerase/DNA-directed RNA polymerase
RNA polymerase I
RNA polymerase II
RNA polymerase III
RNA polymerase IV
Primase
RNA-dependent RNA polymerase
PNPase
Phosphorolytic
3' to 5' exoribonuclease
RNase PH
PNPase
Nucleotidyltransferase
UTP—glucose-1-phosphate uridylyltransferase
Galactose-1-phosphate uridylyltransferase
Guanylyltransferase
mRNA capping enzyme
Other
Recombinase (Integrase)
Transposase
2.7.8: miscellaneous
Phosphatidyltransferases
CDP-diacylglycerol—glycerol-3-phosphate 3-phosphatidyltransferase
CDP-diacylglycerol—serine O-phosphatidyltransferase
CDP-diacylglycerol—inositol 3-phosphatidyltransferase
CDP-diacylglycerol—choline O-phosphatidyltransferase
Glycosyl-1-phosphotransferase
N-acetylglucosamine-1-phosphate transferase
2.7.10-2.7.13: protein kinase
(PO4; protein acceptor)
2.7.10: protein-tyrosine
see tyrosine kinases
2.7.11: protein-serine/threonine
see serine/threonine-specific protein kinases
2.7.12: protein-dual-specificity
see serine/threonine-specific protein kinases
2.7.13: protein-histidine
Protein-histidine pros-kinase
Protein-histidine tele-kinase
Histidine kinase
[show]
v
t
e
Protein kinases: tyrosine kinases (EC 2.7.10)
[show]
Receptor tyrosine kinases (EC 2.7.10.1)
Growth factor receptors
EGF receptor family
EGFR
ERBB2
ERBB3
ERBB4
Insulin receptor family
IGF1R
INSR
INSRR
PDGF receptor family
CSF1R
FLT3
KIT
PDGFR (PDGFRA
PDGFRB)
FGF receptor family
FGFR1
FGFR2
FGFR3
FGFR4
VEGF receptors family
VEGFR1
VEGFR2
VEGFR3
HGF receptor family
MET
RON
Trk receptor family
NTRK1
NTRK2
NTRK3
EPH receptor family
EPHA1
EPHA2
EPHA3
EPHA4
EPHA5
EPHA6
EPHA7
EPHA8
EPHB1
EPHB2
EPHB3
EPHB4
EPHB5
EPHB6
EPHX
LTK receptor family
LTK
ALK
TIE receptor family
TIE
TEK
ROR receptor family
ROR1
ROR2
DDR receptor family
DDR1
DDR2
PTK7 receptor family
PTK7
RYK receptor family
RYK
MuSK receptor family
MUSK
ROS receptor family
ROS1
AATYK receptor family
AATYK
AATYK2
AXL receptor family
AXL
MER
TYRO3
RET receptor family
RET
uncategorised
STYK1
[show]
Non-receptor tyrosine kinases (EC 2.7.10.2)
ABL family
ABL1
ARG
ACK family
ACK1
TNK1
CSK family
CSK
MATK
FAK family
FAK
PYK2
FES family
FES
FER
FRK family
FRK
BRK
SRMS
JAK family
JAK1
JAK2
JAK3
TYK2
SRC-A family
SRC
FGR
FYN
YES1
SRC-B family
BLK
HCK
LCK
LYN
TEC family
TEC
BMX
BTK
ITK
TXK
SYK family
SYK
ZAP70
[show]
v
t
e
Enzymes
Activity
Active site
Binding site
Catalytic triad
Oxyanion hole
Enzyme promiscuity
Catalytically perfect enzyme
Coenzyme
Cofactor
Enzyme catalysis
Regulation
Allosteric regulation
Cooperativity
Enzyme inhibitor
Classification
EC number
Enzyme superfamily
Enzyme family
List of enzymes
Kinetics
Enzyme kinetics
Eadie–Hofstee diagram
Hanes–Woolf plot
Lineweaver–Burk plot
Michaelis–Menten kinetics
Types
EC1 Oxidoreductases (list)
EC2 Transferases (list)
EC3 Hydrolases (list)
EC4 Lyases (list)
EC5 Isomerases (list)
EC6 Ligases (list)
[show]
v
t
e
Growth factor receptor modulators
Angiopoietin
Agonists: Angiopoietin 1
Angiopoietin 4
Antagonists: Angiopoietin 2
Angiopoietin 3
Kinase inhibitors: Altiratinib
CE-245677
Rebastinib
Antibodies: Evinacumab (against angiopoietin 3)
Nesvacumab (against angiopoietin 2)
CNTF
Agonists: Axokine
CNTF
Dapiclermin
EGF (ErbB)
EGF
(ErbB1/HER1)
Agonists: Amphiregulin
Betacellulin
EGF (urogastrone)
Epigen
Epiregulin
Heparin-binding EGF-like growth factor (HB-EGF)
Murodermin
Nepidermin
Transforming growth factor alpha (TGFα)
Kinase inhibitors: Afatinib
AG-490
Agerafenib
Brigatinib
Canertinib
Dacomitinib
Erlotinib
Gefitinib
Grandinin
Icotinib
Lapatinib
Neratinib
Osimertinib
Vandetanib
WHI-P 154
Antibodies: Cetuximab
Depatuxizumab
Depatuxizumab mafodotin
Futuximab
Imgatuzumab
Matuzumab
Necitumumab
Nimotuzumab
Panitumumab
Zalutumumab
ErbB2/HER2
Agonists: Unknown/none
Antibodies: Ertumaxomab
Pertuzumab
Trastuzumab
Trastuzumab duocarmazine
Trastuzumab emtansine
Kinase inhibitors: Afatinib
AG-490
Lapatinib
Mubritinib
Neratinib
ErbB3/HER3
Agonists: Neuregulins (heregulins) (1, 2, 6 (neuroglycan C))
Antibodies: Duligotumab
Patritumab
Seribantumab
ErbB4/HER4
Agonists: Betacellulin
Epigen
Heparin-binding EGF-like growth factor (HB-EGF)
Neuregulins (heregulins) (1, 2, 3, 4, 5 (tomoregulin, TMEFF))
FGF
FGFR1
Agonists: Ersofermin
FGF (1, 2 (bFGF), 3, 4, 5, 6, 8, 10 (KGF2), 20)
Repifermin
Trafermin
Velafermin
FGFR2
Agonists: Ersofermin
FGF (1, 2 (bFGF), 3, 4, 5, 6, 7 (KGF), 8, 9, 10 (KGF2), 17, 18, 22)
Palifermin
Repifermin
Sprifermin
Trafermin
Antibodies: Aprutumab
Aprutumab ixadotin
FGFR3
Agonists: Ersofermin
FGF (1, 2 (bFGF), 4, 8, 9, 18, 23)
Sprifermin
Trafermin
Antibodies: Burosumab (against FGF23)
FGFR4
Agonists: Ersofermin
FGF (1, 2 (bFGF), 4, 6, 8, 9, 19)
Trafermin
Unsorted
Agonists: FGF15/19
HGF (c-Met)
Agonists: Hepatocyte growth factor
Potentiators: Dihexa (PNB-0408)
Kinase inhibitors: Altiratinib
AM7
AMG-458
Amuvatinib
BMS-777607
Cabozantinib
Crizotinib
Foretinib
Golvatinib
INCB28060
JNJ-38877605
K252a
MK-2461
PF-04217903
PF-2341066
PHA-665752
SU-11274
Tivantinib
Volitinib
Antibodies: Emibetuzumab
Ficlatuzumab
Flanvotumab
Onartuzumab
Rilotumumab
Telisotuzumab
Telisotuzumab vedotin
IGF
IGF-1
Agonists: des(1-3)IGF-1
Insulin-like growth factor-1 (somatomedin C)
IGF-1 LR3
Insulin-like growth factor-2 (somatomedin A)
Insulin
Mecasermin
Mecasermin rinfabate
Kinase inhibitors: BMS-754807
Linsitinib
NVP-ADW742
NVP-AEW541
OSl-906
Antibodies: AVE-1642
Cixutumumab
Dalotuzumab
Figitumumab
Ganitumab
Robatumumab
R1507
Teprotumumab
Xentuzumab (against IGF-1 and IGF-2)
IGF-2
Agonists: Insulin-like growth factor-2 (somatomedin A)
Antibodies: Dusigitumab
Xentuzumab (against IGF-1 and IGF-2)
Others
Binding proteins: IGFBP (1, 2, 3, 4, 5, 6, 7)
Cleavage products/derivatives with unknown target: Glypromate (GPE, (1-3)IGF-1)
Trofinetide
LNGF (p75NTR)
Agonists: BDNF
BNN-20
BNN-27
Cenegermin
DHEA
DHEA-S
NGF
NT-3
NT-4
Antagonists: ALE-0540
Dexamethasone
EVT-901 (SAR-127963)
Testosterone
Antibodies: Against NGF: ABT-110 (PG110)
ASP-6294
Fasinumab
Frunevetmab
Fulranumab
MEDI-578
Ranevetmab
Tanezumab
Aptamers: Against NGF: RBM-004
Decoy receptors: LEVI-04 (p75NTR-Fc)
PDGF
Agonists: Becaplermin
Platelet-derived growth factor (A, B, C, D)
Kinase inhibitors: Agerafenib
Axitinib
Crenolanib
Imatinib
Lenvatinib
Masitinib
Motesanib
Nintedanib
Pazopanib
Radotinib
Quizartinib
Sunitinib
Sorafenib
Toceranib
Antibodies: Olaratumab
Ramucirumab
Tovetumab
RET (GFL)
GFRα1
Agonists: Glial cell line-derived neurotrophic factor (GDNF)
Liatermin
Kinase inhibitors: Vandetanib
GFRα2
Agonists: Neurturin (NRTN)
Kinase inhibitors: Vandetanib
GFRα3
Agonists: Artemin (ARTN)
Kinase inhibitors: Vandetanib
GFRα4
Agonists: Persephin (PSPN)
Kinase inhibitors: Vandetanib
Unsorted
Kinase inhibitors: Agerafenib
SCF (c-Kit)
Agonists: Ancestim
Stem cell factor
Kinase inhibitors: Agerafenib
Axitinib
Dasatinib
Imatinib
Masitinib
Nilotinib
Pazopanib
Quizartinib
Sorafenib
Sunitinib
Toceranib
TGFβ
See here instead.
Trk
TrkA
Agonists: Amitriptyline
BNN-20
BNN-27
Cenegermin
DHEA
DHEA-S
Gambogic amide
NGF
Tavilermide
Antagonists: ALE-0540
Dexamethasone
FX007
Testosterone
Negative allosteric modulators: VM-902A
Kinase inhibitors: Altiratinib
AZD-6918
CE-245677
CH-7057288
DS-6051
Entrectinib
GZ-389988
K252a
Larotrectinib
Lestaurtinib
Milciclib
ONO-4474
ONO-5390556
PLX-7486
Rebastinib
SNA-120 (pegylated K252a))
Antibodies: Against TrkA: GBR-900; Against NGF: ABT-110 (PG110)
ASP-6294
Fasinumab
Frunevetmab
Fulranumab
MEDI-578
Ranevetmab
Tanezumab
Aptamers: Against NGF: RBM-004
Decoy receptors: ReN-1820 (TrkAd5)
TrkB
Agonists: 3,7-DHF
3,7,8,2'-THF
4'-DMA-7,8-DHF
7,3'-DHF
7,8-DHF
7,8,2'-THF
7,8,3'-THF
Amitriptyline
BDNF
BNN-20
Deoxygedunin
Deprenyl
Diosmetin
DMAQ-B1
HIOC
LM22A-4
N-Acetylserotonin
NT-3
NT-4
Norwogonin (5,7,8-THF)
R7
TDP6
Antagonists: ANA-12
Cyclotraxin B
Gossypetin (3,5,7,8,3',4'-HHF)
Ligands: DHEA
Kinase inhibitors: Altiratinib
AZD-6918
CE-245677
CH-7057288
DS-6051
Entrectinib
GZ-389988
K252a
Larotrectinib
Lestaurtinib
ONO-4474
ONO-5390556
PLX-7486
TrkC
Agonists: BNN-20
DHEA
NT-3
Kinase inhibitors: Altiratinib
AZD-6918
CE-245677
CH-7057288
DS-6051
Entrectinib
GZ-389988
K252a
Larotrectinib
Lestaurtinib
ONO-4474
ONO-5390556
PLX-7486
VEGF
Agonists: Placental growth factor (PGF)
Telbermin
VEGF (A, B, C, D (FIGF))
Allosteric modulators: Cyclotraxin B
Kinase inhibitors: Agerafenib
Altiratinib
Axitinib
Cabozantinib
Cediranib
Lapatinib
Lenvatinib
Motesanib
Nintedanib
Pazopanib
Pegaptanib
Rebastinib
Regorafenib
Semaxanib
Sorafenib
Sunitinib
Toceranib
Tivozanib
Vandetanib
WHI-P 154
Antibodies: Alacizumab pegol
Bevacizumab
Icrucumab
Ramucirumab
Ranibizumab
Decoy receptors: Aflibercept
Others
Additional growth factors: Adrenomedullin
Colony-stimulating factors (see here instead)
Connective tissue growth factor (CTGF)
Ephrins (A1, A2, A3, A4, A5, B1, B2, B3)
Erythropoietin (see here instead)
Glucose-6-phosphate isomerase (GPI; PGI, PHI, AMF)
Glia maturation factor (GMF)
Hepatoma-derived growth factor (HDGF)
Interleukins/T-cell growth factors (see here instead)
Leukemia inhibitory factor (LIF)
Macrophage-stimulating protein (MSP; HLP, HGFLP)
Midkine (NEGF2)
Migration-stimulating factor (MSF; PRG4)
Oncomodulin
Pituitary adenylate cyclase-activating peptide (PACAP)
Pleiotrophin
Renalase
Thrombopoietin (see here instead)
Wnt signaling proteins
Additional growth factor receptor modulators: Cerebrolysin (neurotrophin mixture)
See also
Receptor/signaling modulators
Signaling peptide/protein receptor modulators
Cytokine receptor modulators
Molecular and Cellular Biology portal
Retrieved from "https://en.wikipedia.org/w/index.php?title=Tyrosine_kinase&oldid=818622294"
Categories:
EC 2.7.10
Tyrosine kinases
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