Tyrosine kinase

Protein kinases are a group of enzymes that possess a catalytic subunit that transfers the gamma (terminal) phosphate from nucleoside triphosphates (often ATP) to one or more amino acid residues in a protein substrate side-chain, resulting in a conformational change affecting protein function. The enzymes fall into two broad classes, characterised with respect to substrate specificity: serine/threonine-specific, and tyrosine-specific (the subject of this article). == 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. The phosphorylation of tyrosine residues in turn causes a change in the function of the protein that they are contained in. Finally mutations can cause some tyrosine kinases to become constitutively active, a nonstop functional state that may contribute to initiation or progression of cancer. Tyrosine kinases function in a variety of processes, pathways, and actions, and are responsible for key events in the body. The receptor tyrosine kinases function in transmembrane signaling, whereas tyrosine kinases within the cell function in signal transduction to the nucleus. Tyrosine kinase activity in the nucleus involves cell-cycle control and properties of transcription factors. Cellular proliferation, as explained in some detail above, may rely in some part on tyrosine kinase. == 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. In addition, ligands participate in reversible binding, with inhibitors binding non-covalently (inhibition of different types are effected depending on whether these inhibitors bind the enzyme, the enzyme-substrate complex, or both). Multivalency, which is an attribute that bears particular interest to some people involved in related scientific research, is a phenomenon characterized by the concurrent binding of several ligands positioned on one unit to several coinciding receptors on another. In any case, the binding of the ligand to its partner is apparent owing to the effects that it can have on the functionality of many proteins. In erythrocyte regulation, erythropoietin is a protein containing 165 amino acids that plays a role in activating the cytoplasmic protein kinase JAK. 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 has been determined that the foundational or prototypical receptor enzyme is insulin. 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. Image:L-tyrosine-skeletal.png|Tyrosine Image:Phosphate Group.svg|Phosphate Image:ATP structure revised.svg|ATP == Structure ==

Protein tyrosine kinase proteins contain a Protein kinase domain, which consists of an N-terminal lobe comprising 5 beta sheet strands and an alpha helix called the C-helix, and a C-terminal domain usually comprising 6 alpha helices (helices D, E, F, G, H, and I). Two loops in the center of the kinase domain control catalysis. The catalytic loop contains the HRD motif (usually with sequence His-Arg-Asp). The aspartic acid of this motif forms a hydrogen bond with the substrate OH group on Tyr during catalysis. The other loop is the activation loop, whose position and conformation determine in part whether the kinase is active or inactive. The activation loop begins with the DFG motif (usually with sequence Asp-Phe-Gly). There are over 1800 3D structures of tyrosine kinases available in the Protein Data Bank. An example is , the crystal structure of the tyrosine kinase domain of the human insulin receptor. == 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: JAK1, JAK2, JAK3, and TYK2). Including these four genes, there are 82 human genes that contain a catalytically active tyrosine kinase domain They are divided into two classes, receptor and non-receptor tyrosine kinases. Receptor By 2004, 58 human receptor tyrosine kinases (RTKs) were known, grouped into 20 subfamilies. Eight of these membrane proteins which contain tyrosine protein kinase domains are actually pseudokinases, without catalytic activity (EPHA10, EPHB6, ERBB3, PTK7, ROR1, ROR2, RYK, and STYK1). Receptor tyrosine kinases play pivotal roles in diverse cellular activities including growth (by signaling neurotrophins), differentiation, metabolism, adhesion, motility, and death. RTKs are composed of an extracellular domain, which is able to bind a specific ligand, a transmembrane domain, and an intracellular catalytic domain, which is able to bind and phosphorylate selected substrates. Binding of a ligand to the extracellular region causes a series of structural rearrangements in the RTK that lead to its enzymatic activation. In particular, movement of some parts of the kinase domain gives free access to adenosine triphosphate (ATP) and the substrate to the active site. This triggers a cascade of events through phosphorylation of intracellular proteins that ultimately transmit ("transduce") the extracellular signal to the nucleus, causing changes in gene expression. Many RTKs are involved in oncogenesis, either by gene mutation, or chromosome translocation, or simply by over-expression. In every case, the result is a hyper-active kinase, that confers an aberrant, ligand-independent, non-regulated growth stimulus to the cancer cells. Cytoplasmic/non-receptor In humans, there are 32 cytoplasmic protein tyrosine kinases (). The first non-receptor tyrosine kinase identified was the v-src oncogenic protein. Most animal cells contain one or more members of the Src family of tyrosine kinases. A chicken sarcoma virus, the Rous sarcoma virus mentioned above, was found to carry mutated versions of the normal cellular Src gene. The mutated v-src gene has lost the normal built-in inhibition of enzyme activity that is characteristic of cellular SRC (c-src) genes. SRC family members have been found to regulate many cellular processes. For example, the T-cell antigen receptor leads to intracellular signalling by activation of Lck and Fyn, two proteins that are structurally similar to Src. ==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. Tyrosine kinase activity is also significantly involved in other events that are sometimes considered highly unfavorable. For instance, enhanced activity of the enzyme has been implicated in the derangement of the function of certain systems, such as cell division. Also included are numerous diseases related to local inflammation such as atherosclerosis and psoriasis, or systemic inflammation such as sepsis and septic shock. A common, widespread cancer, non-small cell lung cancer is the cause of death in more people than the total number in breast, colorectal, and prostate cancer together. Gefitinib is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor, inducing favorable outcomes in patients with non-small cell lung cancers. A common, widespread cancer, non-small cell lung cancer is the cause of death in more people than breast, colorectal, and prostate cancer together. By 2010 Two monoclonal antibodies and another small-molecule tyrosine kinase inhibitor called Erlotinib had also been developed to treat cancer. Tyrosine kinase activity is crucial for the transformation of BCR-ABL. Therefore, inhibiting it improves cancer symptoms. Among currently available inhibitors to treat CML are imatinib, dasatinib, nilotinib, bosutinib and ponatinib. Gastrointestinal stromal tumors 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. == 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 Gastrointestinal stromal tumors (GIST) are mesenchymal tumors that affect the gastrointestinal tract. Treatment options have been limited. This inhibitor is a highly selective Bcr-Abl tyrosine kinase inhibitor. Dasatinib is a Src tyrosine kinase inhibitor that is effective both as a senolytic and as therapy for chronic myelogenous leukemia. == 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; PKDCC; PLK4; PTK2; PTK2B; PTK6; PTK7; RET; ROR1; ROR2; ROS1; RYK; SRC; SRMS; STYK1; SYK; TEC; TEK; TEX14; TIE1; TNK1; TNK2; TNNI3K; TXK; TYK2; TYRO3; YES1; ZAP70 == See also ==