|Protein tyrosine kinase|
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.
Enzymes are macromolecular biological catalysts. Enzymes accelerate chemical reactions. The molecules upon which enzymes may act are called substrates and the enzyme converts the substrates into different molecules known as products. Almost all metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps. The study of enzymes is called enzymology and a new field of pseudoenzyme analysis has recently grown up, recognising that during evolution, some enzymes have lost the ability to carry out biological catalysis, which is often reflected in their amino acid sequences and unusual 'pseudocatalytic' properties.
A phosphate is a chemical derivative of phosphoric acid. The phosphate ion is an inorganic chemical, the conjugate base that can form many different salts. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Of the various phosphoric acids and phosphates, organic phosphates are important in biochemistry and biogeochemistry, and inorganic phosphates are mined to obtain phosphorus for use in agriculture and industry. At elevated temperatures in the solid state, phosphates can condense to form pyrophosphates.
Adenosine triphosphate (ATP) is a complex organic chemical that provides energy to drive many processes in living cells, e.g. muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all forms of life, ATP is often referred to as the "molecular unit of currency" of intracellular energy transfer. When consumed in metabolic processes, it converts either to adenosine diphosphate (ADP) or to adenosine monophosphate (AMP). Other processes regenerate ATP so that the human body recycles its own body weight equivalent in ATP each day. It is also a precursor to DNA and RNA, and is used as a coenzyme.
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.
Amino acids are organic compounds containing amine (-NH2) and carboxyl (-COOH) functional groups, along with a side chain (R group) specific to each amino acid. The key elements of an amino acid are carbon (C), hydrogen (H), oxygen (O), and nitrogen (N), although other elements are found in the side chains of certain amino acids. About 500 naturally occurring amino acids are known (though only 20 appear in the genetic code) and can be classified in many ways. They can be classified according to the core structural functional groups' locations as alpha- (α-), beta- (β-), gamma- (γ-) or delta- (δ-) amino acids; other categories relate to polarity, pH level, and side chain group type (aliphatic, acyclic, aromatic, containing hydroxyl or sulfur, etc.). In the form of proteins, amino acid residues form the second-largest component (water is the largest) of human muscles and other tissues. Beyond their role as residues in proteins, amino acids participate in a number of processes such as neurotransmitter transport and biosynthesis.
Tyrosine or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Greek tyros, meaning cheese, as it was first discovered in 1846 by German chemist Justus von Liebig in the protein casein from cheese. It is called tyrosyl when referred to as a functional group or side chain. While tyrosine is generally classified as a hydrophobic amino acid, it is more hydrophilic than phenylalanine. It is encoded by the codons UAC and UAU in messenger RNA.
A protein kinase is a kinase enzyme that modifies other molecules, mostly proteins, by chemically adding phosphate groups to them (phosphorylation). Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 518 protein kinase genes and they constitute about 2% of all human genes. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction. Protein kinases are also found in bacteria and plants, and include the pseudokinase sub-family, which exhibit unusual features including atypical nucleotide binding and weak, or no, catalytic activity and are part of a much larger pseudoenzyme group of 'degraded' enzyme relatives that are found throughout life, where they take an active participation in mechanistic cellular signaling.
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.
Imatinib, sold under the brand names Gleevec among others, is a medication used to treat cancer. Specifically, it is used for chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) that are Philadelphia chromosome-positive (Ph+), certain types of gastrointestinal stromal tumors (GIST), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), systemic mastocytosis, and myelodysplastic syndrome. It is taken by mouth.
Most tyrosine kinases have an associated protein tyrosine phosphatase, which removes the phosphate group.
Protein tyrosine phosphatases are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins. Protein tyrosine (pTyr) phosphorylation is a common post-translational modification that can create novel recognition motifs for protein interactions and cellular localization, affect protein stability, and regulate enzyme activity. As a consequence, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways and cell cycle control, and are important in the control of cell growth, proliferation, differentiation, transformation, and synaptic plasticity.
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).
A serine/threonine protein kinase is a kinase enzyme that phosphorylates the OH group of serine or threonine. At least 125 of the 500+ human protein kinases are serine/threonine kinases (STK).
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.
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.Although more research indicates that receptors remain active within endosomes, it was once thought that endocytosis caused by ligands was the event responsible for the process in which receptors are inactivated. Activated receptor tyrosine kinase receptors are internalized (recycled back into the system) in short time and are ultimately delivered to lysosomes, where they become work-adjacent to the catabolic acid hydrolases that partake in digestion. Internalized signaling complexes are involved in different roles in different receptor tyrosine kinase systems, the specifics of which were researched. 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.
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.
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. 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.
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 , the crystal structure of the tyrosine kinase domain of the human insulin receptor.
The tyrosine kinases are divided into two main families:
More than 90 protein tyrosine kinases (PTKs) have been found in the human genome. They are divided into two classes, receptor and non-receptor tyrosine kinases.
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.
In humans, there are 32 cytoplasmic protein tyrosine kinases (EC 22.214.171.124).
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 ]
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.[ citation needed ] (See Tyrosine-kinase inhibitor )
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
BCR-ABL is a constitutively activated tyrosine kinase that is associated with chronic myeloid leukemia. It is formed from a fusion gene when when pieces of chromosomes 9 and 22 break off and trade places. The ABL gene from chromosome 9 joins to the BCR gene on chromosome 22, to form the BCR-ABL fusion gene.Tyrosine kinase activity is crucial for the transformation of BCR-ABL. Therefore, inhibiting it improves cancer symptoms. Among currently available inhibitors to treat CML are imatinib, dasatinib, nilotinib, bosutinib and ponatinib.
Gastrointestinal stromal tumors (GIST) are known to withstand cancer chemotherapy treatment and do not respond to any kind of therapy (in 2001) in advanced cases. However, tyrosine kinase inhibitor STI571 (imatinib) is effective in the treatment of patients with metastatic gastrointestinal stromal tumors.Gastrointestinal stromal tumors consist of a cluster of mesenchymal neoplasms that are formed from precursors to cells that make up the connective-tissue in the gastrointestinal tract. 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.February 2016)(
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.
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.
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.
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.
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
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.
The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells. This chromosome is defective and unusually short because of reciprocal translocation, t(9;22)(q34;q11), of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the breakpoint cluster region BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signalling protein that is "always on", causing the cell to divide uncontrollably by interrupting the stability of the genome and impairing various signaling pathways governing the cell cycle.
Paracrine signaling is a form of cell-to-cell communication in which a cell produces a signal to induce changes in nearby cells, altering the behavior of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to endocrine factors, juxtacrine interactions, and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.
Gefitinib (ZD1839) is a drug used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR. It is marketed by AstraZeneca and Teva.
The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.
Quinazoline is an organic compound with the formula C8H6N2. It is an aromatic heterocycle with a bicyclic structure consisting of two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. It is a light yellow crystalline solid that is soluble in water. Also known as 1,3-diazanaphthalene, quinazoline received its name from being an aza derivative of quinoline. Though the parent quinazoline molecule is rarely mentioned by itself in technical literature, substituted derivatives have been synthesized for medicinal purposes such as antimalarial and anticancer agents. Quinazoline is a planar molecule. It is isomeric with the other diazanaphthalenes of the benzodiazine subgroup: cinnoline, quinoxaline, and phthalazine.
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non receptor tyrosine kinases which do not possess transmembrane domains.
Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. There are two forms of the PDGF-R, alpha and beta each encoded by a different gene. Depending on which growth factor is bound, PDGF-R homo- or heterodimerizes.
Zalutumumab is a fully human IgG1 monoclonal antibody (mAb) directed towards the epidermal growth factor receptor (EGFR). It is a product developed by Genmab in Utrecht, the Netherlands. Specifically, zalutumumab is designed for the treatment of squamous cell carcinoma of the head and neck (SCCHN), a type of cancer.
Signal transducer and activator of transcription 5 (STAT5) refers to two highly related proteins, STAT5A and STAT5B, which are part of the seven-membered STAT family of proteins. Though STAT5A and STAT5B are encoded by separate genes, the proteins are 90% identical at the amino acid level. STAT5 proteins are involved in cytosolic signalling and in mediating the expression of specific genes. Aberrant STAT5 activity has been shown to be closely connected to a wide range of human cancers, and silencing this aberrant activity is an area of active research in medicinal chemistry.
The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2, Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's Disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.
Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.
Receptor tyrosine-protein kinase erbB-3, also known as HER3, is a membrane bound protein that in humans is encoded by the ERBB3 gene.
Proto-oncogene tyrosine-protein kinase Src, also known as proto-oncogene c-Src or simply c-Src , is a non-receptor tyrosine kinase protein that in humans is encoded by the SRC gene. This protein phosphorylates specific tyrosine residues in other proteins.
Non-receptor tyrosine kinases (nRTKs) are cytosolic enzymes that are responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases are a subgroup of protein family tyrosine kinases, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell.
Cell surface receptors are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving extracellular molecules. They are specialized integral membrane proteins that allow communication between the cell and the extracellular space. The extracellular molecules may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, or nutrients; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction, ligand binding affects a cascading chemical change through the cell membrane.
A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation), a step that TKIs inhibit. TKIs are typically used as anticancer drugs. For example, they have substantially improved outcomes in chronic myelogenous leukemia.
Tyrosine-protein kinase CSK also known as C-terminal Src kinase is an enzyme that, in humans, is encoded by the CSK gene. This enzyme phosphorylates tyrosine residues located in the C-terminal end of Src-family kinases (SFKs) including SRC, HCK, FYN, LCK, LYN and YES1.