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Wikipedia - Tyrosine kinase

Tyrosine kinases are a subclass of protein kinase, see there for the principles of protein phosphorylation
Protein tyrosine kinase
PDB 1m61 EBI.jpg
Tyrosine-protein kinase zap-70
Identifiers
Symbol Pkinase_Tyr
Pfam PF07714
InterPro IPR001245
SMART TyrKc
SCOP 1apm

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein. Tyrosine kinases are a subgroup of the larger class of protein kinases. Phosphorylation of proteins by kinases is an important mechanism in signal transduction for regulation of cellular activity.

Most tyrosine kinases have an associated protein tyrosine phosphatase.

Contents

[edit] Reaction

Protein kinases are a group of enzymes that possess a catalytic subunit that transfers the gamma 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 (this domain).[1]

[edit] 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.[2] Tyrosine kinases catalyze the phosphorylation of tyrosine residues in proteins.[2] The phosphorylation of tyrosine residues in turn cause a change in the function of the protein that they are contained in.[2]

Phosphorylation at tyrosine residues controls a wide range of properties in proteins such as enzyme activity, subcellular localization, and interaction between molecules.[3] Furthermore tyrosine kinases function in many signal transduction cascades wherein extracellular signals are transmitted through the cell membrane to the cytoplasm and often to the nucleus where gene expression may be modified.[3] Finally mutations can cause some tyrosine kinases to become constitutively active, a nonstop functional state that may contribute to initiation or progression of cancer.

Tyrosine kinases function in a variety of processes, pathways, and actions, and is responsible for key events in the body. The receptor tyrosine kinases function in transmembrane signaling, whereas tyrosine kinases within the cell function in signal transduction to the nucleus.[4] Tyrosine kinase activity in the nucleus involves cell-cycle control and properties of transcription factors.[3] In this way, in fact, tyrosine kinase activity is involved in mitogenesis, or the induction of mitosis in a cell; proteins in the cytosol and proteins in the nucleus are phosphorylated at tyrosine residues during this process.[3] Cellular growth and reproduction may rely in some part on tyrosine kinase. Tyrosine kinase function has been observed in the nuclear matrix, which is comprised not of chromatin, but of the nuclear envelope and a “fibrous web” that serves to physically stabilize DNA.[3] More specifically, Lyn, a type of kinase in the Src family that was identified in the nuclear matrix, appears to control the cell cycle. Src family tyrosine kinases are closely related, but demonstrate a wide variety of functionality. Roles or expressions of Src family tyrosine kinases vary significantly according to cell type, as well as during cell growth and differentiation.[3] Lyn and Src family tyrosine kinases in general have been known to function in signal transduction pathways.[3] There is evidence that Lyn is localized at the cell membrane; Lyn is associated both physically and functionally with a variety of receptor molecules.[3]

Fibroblasts – a type of cell that synthesizes the extracellular matrix and collagen and is involved in wound healing – that have been transformed by the polyomavirus possess higher tyrosine activity in the cellular matrix. Furthermore, tyrosine kinase activity has been determined to be correlated to cellular transformation.[3] It has been also been demonstrated that phosphorylation of a middle-T antigen on tyrosine is also associated with cell transformation, a change that is similar to cellular growth or reproduction.[3]

The transmission of mechanical force and regulatory signals are quite fundamental in the normal survival of a living organism. Protein tyrosine kinase plays a role in this task, too. A protein tyrosine kinase called pp125 is likely at hand in the influence of cellular focal adhesions, as indicated by an immunofluorescent localization of the said kinase. Focal adhesions are macromolecular structures that function in the transmission of mechanical force and regulatory signals.[5] Among the scientific community, pp125 is also referred to as FAK (focal adhesion kinase), due to its aforementioned presence in cellular focal adhesions. The protein tyrosine kinase pp125 is one of the major phosphotyrosine–containing proteins in unaffected (untransformed) avian and rodent fibroblast cells (fibroblast cells are explained above in some detail).[5] Fibroblasts are a cell type responsible for wound healing and cell structure in animals, among a number of other relatively minor but important jobs that take place often or occasionally. The sequence and structure of pp125, when compared to National Biomedical Research Foundation and GenBank data bases,[5] may be quite unique, meaning it could be a new member of the protein tyrosine kinase family. This protein tyrosine kinase is up to about 70% unique compared to some other protein tyrosine kinases, a figure that is unlike those between actual members of an established protein tyrosine kinase family.[5] Also, the amino acid sequence that was observed indirectly signifies that it is associated with the cytoplasm, dubbing it one in a large group of cytoplasmic protein tyrosine kinases.[5] It was discovered when monoclonal antibodies were observed to recognize it.[5] Monoclonal antibodies, from chicken embryo cells transformed by pp60v-src, recognize seven different phosphotyrosine-containing proteins.[5] One of these monoclonal antibodies, named 2A7, recognizes pp125, support for the idea that pp125 is, in fact, a protein tyrosine kinase.[5]

Cellular proliferation, as explained in some detail above, may rely in some part on tyrosine kinase.[3] Tyrosine kinase function has been observed in the nuclear matrix. Lyn, the type of kinase that was the first to be discovered in the nuclear matrix, is part of Src family of tyrosine kinases, which can be contained in the nucleus of differentiating, calcium-provoked kertinocytes. Lyn, in the nuclear matrix, among the nuclear envelope and the “fibrous web” that physically stabilizes DNA, was found functioning in association with the matrix. Also, it appeared to be conditional to cell cycle.[3] The contribution of the Lyn protein to the total tyrosine kinase activity within the nuclear matrix is unknown, however; because the Lyn was extracted only partially, an accurate measurement of its activity could not be managed.[3] Indications, as such, are that, according to Vegesna et al (1996), Lyn polypeptides are associated with tyrosine kinase activity in the nuclear matrix. The extracted Lyn was enzymatically active, offering support for this notion.

Yet another possible and probable role of protein tyrosine kinase is that in the event of circulatory failure and organ dysfunction caused by endotoxin in rats, where the effects of inhibitors tyrphostin and genistein are involved with protein tyrosine kinase.[4] As has become clear among many people, tyrosine kinase can be involved in some unfortunate things.

Tyrosine kinase is also involved in signaling. Signals in the surroundings received by receptors in the membranes of cells are transmitted into the cell cytoplasm. Transmembrane signaling due to receptor tyrosine kinases, according to Bae et al (2009), relies heavily on interactions, for example, mediated by the SH2 protein domain; it has been determined via experimentation that the SH2 protein domain selectivity is functional in mediating cellular processes involving tyrosine kinase. Receptor tyrosine kinases may, by this method, influence growth factor receptor signaling. This is one of the more fundamental cellular communication functions metazoans.[6]

[edit] 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 by scientists to be used as drugs for the general public. One ailment, gastrointestinal stromal tumors, as explained in further detail below, are mesenchymal tumors that affect the gastrointestinal tract. They are a problem especially because they are the most common mesenchymal tumors Blanke et al (2008). Few treatments that target the root cause of the tumors are significantly affective against gastrointestinal stromal tumor proliferation. Surgical options, as well, have not exhibited particular success in patients Blanke et al (2008). However, it has been scientifically confirmed that Imatinib as an inhibitor to the malfunctioning enzyme is quite a viable solution to the problem Blanke et al (2008). If this inhibitor doesn’t work – if Imatinib is resisted in or intolerable to the subject – patients with advanced chronic myelogenous leukemia, who would otherwise face dire circumstances, can use nilotinib, another inhibitor to the malfunction enzyme that causes the leukemia.[7] This inhibitor is a highly selective BCR-ABL tyrosine kinase inhibitor.[7] Another example of an inhibitor of tyrosine kinase is sunitinib, an oral tyrosine kinase inhibitor that acts upon vascular endothelial growth factor receptor, platelet-derived growth factor receptor, stem cell factor receptor, and colony-stimulating factor-1 receptor (Burstein et al 2008) Other inhibitors that are discussed in greater detail include Gefitinib and STI571. 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 tumor to do this.[8]

[edit] Regulation

Major changes are sometimes induced when the tyrosine kinase enzyme is affected by another factor. One of the factors is a molecule that is bound reversibly by a protein, called a ligand. A number of receptor tyrosine kinases, though certainly not all, do not perform protein-kinase activity until they are occupied, or activated, by one of these ligands.[2] It is interesting to note that, although many more recent cases of research indicate that receptors remain active within endosomes, it was once thought that endocytosis caused by ligands was the event responsible for the process in which receptors are inactivated. Activated receptor tyrosine kinase receptors are internalized (recycled back into the system) in short time and are ultimately delivered to lysosomes, where they become work adjacent to the catabolic acid hydrolases that partake in digestion. Internalized signaling complexes are involved in different roles in different receptor tyrosine kinase systems, the specifics of which was researched.[9] Additionally, 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.[10] In any case, the binding of the ligand to its partner is apparent owing to the effects that it can have on the functionality of many proteins.[2] Ligand-activated receptor tyrosine kinases, as they are sometimes referred to, demonstrate a unique attribute. Once a tyrosine receptor kinase is bonded to its ligand, it is able to bind to tyrosine kinase residing in the cytosol of the cell.[2] An example of this trigger-system in action is the process by which the formation of erythrocytes is regulated. Mammals possess this system, which begins in the kidneys where the developmental signal is manufactured.[2] The developmental signal, also called a cytokine, is erythropoietin in this case. Cytokines are key regulators of hematopoietic cell proliferation and differentiation. Its activity is initiated when hematopoietic cytokine receptors become activated.[11] In erythrocyte regulation, erythropoietin is a protein containing 165 amino acids that plays a role in activating the cytoplasmic protein kinase JAK.[2] The results of some newer research have also indicated that the aforementioned cytokine receptors function with members of the JAK tyrosine kinase family. The cytokine receptors activate the JAK kinases. This then results in the phosphorylation of several signaling proteins located in the cell membrane. This subsequently affects both the stimulation of ligand-mediated receptors and intracellular signaling pathway activation.[11] Substrates for JAK kinases mediate some gene responses and more.[11] The process is also responsible for mediating the production of blood cells.[2] In this case, erythropoietin binds to the corresponding plasma membrane receptor, dimerizing the receptor.[2] The dimer is responsible for activating the kinase JAK via binding.[2] Tyrosine residues located in the cytoplasmic domain of the erythropoietin receptor are consequently phosphorylated by the activated protein kinase JAK.[2] Overall, this is also how a receptor tyrosine kinase might be activated by a ligand to regulate erythrocyte formation.

Additional instances of factor-influenced protein tyrosine kinase activity, similar to this one, exist. An adapter protein such as Grb2 will bind to phosphate-tyrosine residues under the influence of receptor protein kinases. This mechanism is an ordinary one that provokes protein-protein interactions.[2] Furthermore, to illustrate an extra circumstance, insulin-associated factors have been determined to influence tyrosine kinase. Insulin receptor substrates are molecules that function in signaling, with responsibility in the task that is to regulate the effects of insulin.[2] Many receptor enzymes have closely related structure and receptor tyrosine kinase activity, and it is said by Lehninger (2008) that the foundational receptor enzyme, or prototypical receptor enzyme, is insulin. It is interesting to note that insulin receptor substrates IRS-2 and IRS-3 each have unique characteristic tissue function and distribution that serves to enhance signaling capabilities in pathways, such as those in human body, that are initiated by receptor tyrosine kinases.[2] Activated IRS-1 molecules enhance the signal created by insulin.[2] The insulin receptor system, in contrast, appears to diminish the efficacy of endosomal signaling.[9] The epidermal growth factor receptor system, as such, has been used as an intermediate example.[9] Some signals are produced from the actual cell surface in this case but data suggests that other signals seem to emanate from within the endosomes. There is a purpose for this in the organism, of course, but it is not known for sure what that reason is exactly. This variety of function may be a means to create ligand-specific signals.[9] 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

[edit] 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.[5] Also very common among protein tyrosine kinases are two peptide sequences.[5]

There are over 100 3D structures of tyrosine kinases available at the Protein Data Bank. An example is PDB 1IRK, the crystal structure of the tyrosine kinase domain of the human insulin receptor.

[edit] Families

The tyrosine kinases are divided into two main families:

[edit] Receptor

For more details on this topic, see receptor tyrosine kinase.

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. At present, 58 receptor tyrosine kinases (RTKs) are known, grouped into 20 subfamilies. They play pivotal roles in diverse cellular activities including growth, differentiation, metabolism, adhesion, motility, death.[12] 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,[13] 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.

[edit] 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.

[edit] 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.[14]

However, tyrosine kinase activity is also significantly involved in events that are sometimes considered highly unfavorable. Enhanced activity, for instance, of the enzyme has been implicated in the derangement of the function certain systems, such as cell division. Also included are numerous diseases regarding local inflammation such as atherosclerosis and psoriasis, or systemic inflammation such as sepsis and septic shock.[4] In fact, the polyoma virus affects tyrosine kinase activity in the nuclear matrix.[3] The polyoma virus attacks fibroblasts, which are a cell type involved in wound healing and cell structure formation in mammalian animals. Fibroblasts that are transformed by the polyoma virus involve higher tyrosine activity in the cellular matrix. In this way, it has been determined that tyrosine kinase activity is correlated to cellular proliferation.[3] Another instance of an ailment related to 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 wildly unusual.[5] Oncoproteins ? protein tyrosine kinases ? that are encoded by the Rous sarcoma virus cause cellular transformation.[5] Moreover, tyrosine kinase can sometimes function incorrectly in such a way that leads to non-small cell lung cancer.[15] A common, widespread cancer, non-small cell lung cancer is the cause of death in more people than the total number in breast, colorectal, and prostate cancer altogether.[15]

Several additional functions of tyrosine kinase. It is known among certain members of the scientific community that protein phosphorylation occurs on residues of tyrosine by both transmembrane receptor- and membrane-associated protein tyrosine kinases in normal cells.[5] This occurrence is likely quite significant to the activity of communications that are originally broadcasted a number and variety of growth factors.[5] This is evidenced by the observation that cells affected by the Rous sarcoma virus, a retrovirus that causes sarcoma in chickens, display obvious structure modifications and a total lack of normal cell growth regulation.[5] Rous sarcoma virus-encoded oncoproteins are protein tyrosine kinases that are the cause of and are required for this unfortunate cellular transformation.[5] This is the case, that is, when the Rous sarcoma virus-encoded oncoproteins are expressed. Also, tyrosine phosphorylation activity increases or decreases in conjunction with changes in cell composition and growth regulation.[5] In this way, a certain transformation exhibited by cells is dependent on a role that tyrosine kinase demonstrates.[5] Protein tyrosine kinases, have a major role in the activation of lymphocytes.[5] In addition, they are functional in mediating communication pathways in cells types such as adrenal chromaffin, platelets, and neural cells.[5]

Tyrosine kinase can become a radically functioning 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. Of course, the possibility of preventing this type of circumstance is a highly desirable notion to those that are able to conduct related research. Much research has already noted the significant effect that inhibitors of the radically functioning protein tyrosine kinase enzymes have on related ailments. Encouragingly, research has been seen as quite prolific in a number of different cases.

[edit] Non-small cell lung cancer

Dancer’s response to an inhibitor of tyrosine kinase was assessed in a clinical trial.[15] In this case, Gefitinib is the inhibitor of tyrosine kinase. Tyrosine kinase, sometimes, when functioning incorrectly, leads to non-small cell lung cancer.[16] Gefitinib is a tyrosine kinase inhibitor that affects the epidermal growth factor receptor, provoking favorable outcomes in patients with non-small cell lung cancers. These outcomes were seen as quite successful by the authors of the trial. A common, widespread cancer, non-small cell lung cancer is the cause of death in more people than breast, colorectal, and prostate cancer altogether.[15] Of course, this is sufficient grounds to conduct research regarding tyrosine kinase inhibitors in order to perhaps reduce the unfortunate results of the cancer. Gefitinib, as an epidermal growth factor receptor tyrosine kinase inhibitor improved symptoms related to non-small cell lung cancer and resulted in radiographic tumor regressions.[15] This is an example of the efficacy of such an inhibitor. The process shows how the cancer sustains. The epidermal growth factor receptor mutations communicate “survival signals” that non-small cell lung cancer cells become accustomed to and develop a dependency for. Gefitinib’s inhibition of these survivor signals may be a contributing factor to its efficacy as a drug for non-small cell cancer treatment.[16]

Though differences were negligible between the treatment groups that received 250 mg versus 500 mg of Gefitinib in the trial, the enzyme, which is well-endured by the bodies of human beings, resulted in a symptom improvement rate of 43% (with 95% confidence in a 33%-53% interval) for patients that received 250 mg of Gefitinib and 35% (with 95% confidence in a 26%-45% interval) for those that received 500 mg.[15] The enzyme also reacted to the inhibitor fairly quickly, as demonstrated by the improvement of the cancer symptoms. In each group, improvements were noted after a single week of epidermal growth factor receptor tyrosine kinase inhibitor treatment.[15] The results of the Gefitinib inhibitor trials were considered a success by the authors of the treatment;[15] they wrote that their trial demonstrated that Gefitinib application once per day caused “rapid” symptom improvement and tumor regressions non-small cell lung cancer patients.[15] In the medical research spotlight, this is an especially significant example of tyrosine kinase and an associated inhibitor. Chemotherapy, surgery, and radiotherapy were the only major options available prior to the discoveries made in this trial. However, the effects of Gefitinib oral treatment once per day were not completely practical. Interestingly, diarrhea was an issue in 57% of patients in the 250 mg group and in 75% of the 500 mg group.[15] One patient had diarrhea more severe than Grade 2, with up to six bowel movements in only one day.[15] Also, a death occurred possibly due to epidermal growth factor receptor tyrosine kinase inhibitor treatment; however, the correlation is not exactly clear.[15] In addition, skin toxicity transpired in 62% of patients in the 250-milligram group. Nevertheless the effects of Gefitinib were only “generally mild, manageable, noncumulative, and reversible.”[15] However, ceasing to take the inhibitor may be the only reversal strategy of the unfavorable symptoms.[15] Regardless, in comparison to the well-established aforementioned methods of solving cancer infliction, Gefitinib inhibitor treatment such as this is actually quite safe and effective, demonstrating an example of the large-scale effect of a tyrosine kinase inhibitor on the human body.

Furthermore, epidermal growth factor receptor plays is crucial in tumorigenesis, which is, as the name implies, the production of a new tumor.[17] In the case of non-small cell lung cancer, these tumors are cancerous and dangerous to the health of a human being. Two types of epidermal growth factor receptor-targeted “therapeutic agents.” Gefitinib, as well as two monoclonal antibodies and another small-molecule tyrosine kinase inhibitor called Erlotinib, were used due to their capability of interacting with the intracellular tyrosine kinase region of the epidermal growth factor receptor.[17]

[edit] Chronic myeloid leukemia

Tyrosine kinase inhibitors have the potential to reduce the spread of chronic myeloid leukemia. BCR-ABL is a constitutively activated tyrosine kinase, meaning its activity is constantly “on”.[18] This constitutive nature of BCR-ABL is widely recognized by the scientific community and others as an unfavorable characteristic because it results in chronic myeloid leukemia in this case. However, it is possible that an inhibitor of tyrosine kinase could be a viable option for the treatment of BCR-ABL-caused chronic myeloid leukemia.[18] In fact, tyrosine kinase activity is crucial to the role of transformation of BCR-ABL, so inhibiting it would be likely method to improve cancer symptoms. STI571, otherwise known as CGP 57148B, is an inhibitor specific to the BCR-ABL tyrosine kinase. STI571’s efficacy was tested in 83 patients with chromic myeloid leukemia, who were administered the dose orally during the chronic phase of their ailment. It should be noted that these patients were selected based on a failed response to a previous treatment of interferon alfa. Adverse effects of STI571 existed, but these effects were tolerable.[18] Nausea, myalgias, edema, and diarrhea were all negative side-effects of using STI571 to inhibit the BCR-ABL constitutively activated tyrosine kinase.[18] Complete hematologic reactions (reactions involving blood) resulted in all but one of the study subjects that received more or equal to 300 mg of the inhibitor within a month of the start of the treatment.[18] Cytogenetic reactions (reactions affecting cell structure and function) were present in 29 of these subjects, while 17 of them demonstrated significant reactions (it was determined that a certain percentage of cells in metaphase with the Philadelphia chromosome represented significant reactions). It is interesting to note that seven of these patients had complete recoveries from BCR-ABL-induced chronic myeloid leukemia.[18] Indeed, it was concluded that the well-tolerated inhibitor has a significant favorable affect on chromic myeloid leukemia activity in patients after failure of interferon alfa treatment.[18] One can also infer, using the evidence in the report of the potential of tyrosine kinase inhibitor STI571 to reduce the spread of chronic myeloid leukemia, that the role of BCR-ABL tyrosine kinase activity in the cancer’s progression is vital. Also, the report offers more reason for the creation of anticancer drugs that function according to their ability to act on the abnormalities of cancerous cells in humans.[18]

[edit] Gastrointestinal stromal tumors

Gastrointestinal stromal tumors are known by certain members of the scientific community to withstand cancer chemotherapy treatment. Also, they are not known to respond to any kind of therapy in advanced cases. Tyrosine kinase inhibitor STI571 has been found to be effective in patients with metastatic gastrointestinal stromal tumors.[19] Gastrointestinal stromal tumors comprise of a cluster of mesenchymal neoplasms that were formed from precursors to cells that make up the connective-tissue in the gastrointestinal tract.[19] Most of these tumors are found in the stomach, though they can also be located in the small intestine or somewhere else in the intestinal tract. The cells of these tumors, which are more likely to be found in middle-age and older people than younger people, have been observed in related research to comprise of a growth factor receptor associated with tyrosine kinase activity.[19] This growth factor receptor is called c-kit and is produced by the proto-oncogene called c-kit (note italics). Among scientists in the field, it is, in general, well known that a mutation can cause some tyrosine kinases to become constitutively active, a nonstop function state that is known to cause cancer. In fact, mutations of c-kit cause the functionality of the tyrosine kinase enzyme to become constitutive, which results in the cancerous gastrointestinal stromal tumors. Occurrences that are triggered by the means of the c-kit mutations include unrestricted tyrosine kinase activity and cell proliferation, unregulated phosphorylation of c-kit, and disruption of some communication pathways.[19] 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. It is no longer doubted that this inhibitor can be effective and safe in humans.[9] In similar manner, protein tyrosine kinase inhibitor STI571 was found to quite significantly reduce the physical size of tumors; they decreased roughly 65 percent in size in 4 months of trialing, and continued to diminish from there. The inhibitor was observed to be successful all around. 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.[19] There are no effective means of treatment for advanced gastrointestinal stromal tumors, but that STI571-orchestrated inhibition of the constitutively active mutant c-kit tyrosine kinase is, in fact, an effective method of treatment. In this way, it is implied that the best way to cure this cancer is to inhibit unfavorable tyrosine kinase activity.[19]

[edit] Examples

Human proteins containing this domain include:

AATK; ABL1; 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

[edit] References

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  5. ^ a b c d e f g h i j k l m n o p q r s t Schaller MD, Borgman CA, Cobb BS, Vines RR, Reynolds AB, Parsons JT (June 1992). "pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions". Proc. Natl. Acad. Sci. U.S.A. 89 (11): 5192–6. doi:10.1073/pnas.89.11.5192. PMID 1594631. 
  6. ^ Dengjel J, Kratchmarova I, Blagoev B (October 2009). "Receptor tyrosine kinase signaling: a view from quantitative proteomics". Mol Biosyst 5 (10): 1112–21. doi:10.1039/b909534a. PMID 19756300. 
  7. ^ a b le Coutre P, Ottmann OG, Giles F, Kim DW, Cortes J, Gattermann N, Apperley JF, Larson RA, Abruzzese E, O'Brien SG, Kuliczkowski K, Hochhaus A, Mahon FX, Saglio G, Gobbi M, Kwong YL, Baccarani M, Hughes T, Martinelli G, Radich JP, Zheng M, Shou Y, Kantarjian H (February 2008). "Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia". Blood 111 (4): 1834–9. doi:10.1182/blood-2007-04-083196. PMID 18048643. 
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  9. ^ a b c d e Wiley HS, Burke PM (January 2001). "Regulation of receptor tyrosine kinase signaling by endocytic trafficking". Traffic 2 (1): 12–8. doi:10.1034/j.1600-0854.2001.020103.x. PMID 11208164. 
  10. ^ Rinker S, Ke Y, Liu Y, Chhabra R, Yan H (July 2008). "Self-assembled DNA nanostructures for distance-dependent multivalent ligand-protein binding". Nat Nanotechnol 3 (7): 418–22. doi:10.1038/nnano.2008.164. PMID 18654566. 
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[edit] External links

v • d • e
Transferases: phosphorus-containing groups (EC 2.7)
2.7.1-2.7.4: phosphotransferase/kinase
(phosphorus-containing group: PO4)
2.7.1: OH acceptor
2.7.2: COOH acceptor
2.7.3: N acceptor
2.7.4: PO4 acceptor
2.7.6: diphosphotransferase
(phosphorus-containing group: P2O7)
2.7.7: nucleotidyltransferase
(phosphorus-containing group: PO4-nucleoside)
RNA nucleotidyltransferase
Other
2.7.8: miscellaneous phosphate-containing groups
Phosphatidyltransferases
Glycosyl-1-phosphotransferase
2.7.10-2.7.13: protein kinase
(phosphorus-containing group: PO4; protein acceptor)
2.7.10: protein-tyrosine
2.7.12: protein-dual-specificity
2.7.13: protein-histidine
Retrieved from "http://en.wikipedia.org/wiki/Tyrosine_kinase"

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Tyrosine kinase".

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