Tyrosine kinase - Wikipedia Tyrosine kinase 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 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 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 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 ). Function 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. Tyrosine kinases catalyze the phosphorylation of tyrosine residues in proteins. The phosphorylation of tyrosine residues in turn causes a change in the function of the protein that they are contained in. Phosphorylation at tyrosine residues controls a wide range of properties in proteins such as enzyme activity, subcellular localization, and interaction between molecules. 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. 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. 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. 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. 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. Lyn and Src family tyrosine kinases in general have been known to function in signal transduction pathways. There is evidence that Lyn is localized at the cell membrane ; Lyn is associated both physically and functionally with a variety of receptor molecules. 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. 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. 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. 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 ). 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, 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. 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. It was discovered when monoclonal antibodies were observed to recognize it. Monoclonal antibodies, from chicken embryo cells transformed by pp60v - src, recognize seven different phosphotyrosine - containing proteins. One of these monoclonal antibodies, named 2A7, recognizes pp125, support for the idea that pp125 is, in fact, a protein tyrosine kinase. Cellular proliferation, as explained in some detail above, may rely in some part on tyrosine kinase. 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. 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. 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. 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. 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. 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. 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. 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. 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. Erythrocytes as an example 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. 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. In erythrocyte regulation, erythropoietin is a protein containing 165 amino acids that plays a role in activating the cytoplasmic protein kinase JAK. 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. Substrates for JAK kinases mediate some gene responses and more. The process is also responsible for mediating the production of blood cells. In this case, erythropoietin binds to the corresponding plasma membrane receptor, dimerizing the receptor. The dimer is responsible for activating the kinase JAK via binding. Tyrosine residues located in the cytoplasmic domain of the erythropoietin receptor are consequently phosphorylated by the activated protein kinase JAK. Overall, this is also how a receptor tyrosine kinase might be activated by a ligand to regulate erythrocyte formation. Other examples 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. 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. 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. Activated IRS - 1 molecules enhance the signal created by insulin. The insulin receptor system, in contrast, appears to diminish the efficacy of endosomal signaling. The epidermal growth factor receptor system, as such, has been used as an intermediate example. 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. 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 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. Also very common among protein tyrosine kinases are two peptide sequences. 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 The tyrosine kinases are divided into two main families : the transmembrane receptor - linked kinases those that are cytoplasmic proteins Approximately 2000 kinases are known, 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 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. 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. Cytoplasmic / non-receptor 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. 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. Clinical significance 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. 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 number of viruses target tyrosine kinase function during infection. The polyoma virus affects tyrosine kinase activity inside the nuclear matrix. 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. 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. Protein tyrosine kinases that are encoded by the Rous sarcoma virus cause cellular transformation, and are termed oncoproteins. In addition, tyrosine kinase can sometimes function incorrectly in such a way that leads to non-small cell lung cancer. 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. 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. Rous sarcoma virus - encoded oncoproteins are protein tyrosine kinases that are the cause of, and are required for, this cellular transformation. Tyrosine phosphorylation activity also increases or decreases in conjunction with changes in cell composition and growth regulation. In this way, a certain transformation exhibited by cells is dependent on a role that tyrosine kinase demonstrates. Protein tyrosine kinases, have a major role in the activation of lymphocytes. In addition, they are functional in mediating communication pathways in cell types such as adrenal chromaffin, platelets, and neural cells. 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. ( See Tyrosine - kinase inhibitor ) Non-small cell lung cancer Cancer 's response to an inhibitor of tyrosine kinase was assessed in a clinical trial. In this case, Gefitinib is the inhibitor of tyrosine kinase. Incorrect tyrosine kinase function can lead to non-small cell lung cancer. 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. 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. 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. 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. 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. Gefitinib application once per day caused `` rapid '' symptom improvement and tumor regressions in non-small cell lung cancer patients. 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. One patient had diarrhea more severe than Grade 2, with up to six bowel movements in only one day. Also, a death occurred possibly due to epidermal growth factor receptor tyrosine kinase inhibitor treatment ; however, the correlation is not exactly clear. 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. '' Unfortunately, ceasing to take the inhibitor may be the only reversal strategy of the unfavorable symptoms. 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. By 2010 Two monoclonal antibodies and another small - molecule tyrosine kinase inhibitor called Erlotinib had also been developed to treat cancer. 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 BCR - ABL is a constitutively activated tyrosine kinase that is associated with chronic myeloid leukemia. 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 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. 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. 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. 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. 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. 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. This section needs to be updated. Please update this article to reflect recent events or newly available information. ( 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 for the general public. GIST and imatinib Gastrointestinal stromal tumors ( GIST ) are mesenchymal tumors that affect the gastrointestinal tract. Treatment options have been limited. However Imatinib, as an inhibitor to the malfunctioning enzyme, can be effective. Chronic myelogenous leukemia and nilotinib 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. This inhibitor is a highly selective Bcr - Abl tyrosine kinase inhibitor. Others 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. Examples 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 Tyrphostins Bcr - Abl tyrosine kinase inhibitors References Jump up ^ Hanks SK, Quinn AM, Hunter T ( July 1988 ). `` The protein kinase family : conserved features and deduced phylogeny of the catalytic domains ''. 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PMID 18235121. ^ Jump up to : 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 Eukaryotic Linear Motif resource motif class MOD_TYR_CSK The Tyrosine Kinase group Transferases : phosphorus - containing groups ( EC 2.7 ) 2.7. 1 - 2.7. 4 : phosphotransferase / kinase ( PO ) 2.7. 1 : OH acceptor Hexo - Gluco - Fructo - Hepatic Galacto - Phosphofructo - Liver Muscle Platelet 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 : PO acceptor Phosphomevalonate Adenylate Nucleoside - diphosphate Uridylate Guanylate Thiamine - diphosphate 2.7. 6 : diphosphotransferase ( P O ) Ribose - phosphate diphosphokinase Thiamine diphosphokinase 2.7. 7 : nucleotidyltransferase ( PO - nucleoside ) Polymerase DNA polymerase DNA - directed DNA polymerase 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 ( PO ; 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 Protein kinases : tyrosine kinases ( EC 2.7. 10 ) 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 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 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 ) 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 ( p75 ) 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 ( p75 - 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 Hidden categories : All articles with unsourced statements Articles with unsourced statements from June 2016 Pages containing citation needed template with deprecated parameters Articles with unsourced statements from February 2016 Wikipedia articles in need of updating from February 2016 All Wikipedia articles in need of updating Talk Contents About Wikipedia Català Čeština Deutsch Español فارسی Français Galego Bahasa Indonesia Lietuvių Português Română Русский Српски / srpski Srpskohrvatski / српскохрватски Türkçe 中文 Edit links This page was last edited on 4 January 2018, at 16 : 48. 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Question: why does overexpression of rtks lead to cancer development
Answer: a hyper-active kinase, that confers an aberrant, ligand-independent, non-regulated growth stimulus to the cancer cells