receptor protein-tyrosine kinase

• レセプター型チロシンキナーゼ、チロシンキナーゼ共役型受容体

関

receptor tyrosine kinase、tyrosine kinase receptor

WordNet

1. any of a large group of nitrogenous organic compounds that are essential constituents of living cells; consist of polymers of amino acids; essential in the diet of animals for growth and for repair of tissues; can be obtained from meat and eggs and milk and legumes; "a diet high in protein"
2. a cellular structure that is postulated to exist in order to mediate between a chemical agent that acts on nervous tissue and the physiological response
3. an enzyme that catalyzes the conversion of a proenzyme to an active enzyme
4. an amino acid found in most proteins; a precursor of several hormones
5. the basic unit of money in Papua New Guinea

PrepTutorEJDIC

1. 蛋白(たんばく)質
2. =sense organ / 受信装置

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/10/05 15:53:30」(JST)

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receptor protein-tyrosine kinase
Identifiers
EC number	2.7.10.1
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search PMC articles PubMed articles NCBI proteins

Identifiers
Symbol	Pkinase_Tyr
Pfam	PF07714
OPM superfamily	207
OPM protein	2k1k
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

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. 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.

Nomenclature

Receptor tyrosine kinase (RTK) in this article is also known as tyrosine receptor kinase (TRK) or tyrosine kinase receptor (TKR) depending on the permutation.

Receptor tyrosine kinase classes

Approximately 20 different RTK classes have been identified.

1. RTK class I (EGF receptor family) (ErbB family)
2. RTK class II (Insulin receptor family)
3. RTK class III (PDGF receptor family)
4. RTK class IV (FGF receptor family)
5. RTK class V (VEGF receptors family)
6. RTK class VI (HGF receptor family)
7. RTK class VII (Trk receptor family)
8. RTK class VIII (Eph receptor family)
9. RTK class IX (AXL receptor family)
10. RTK class X (LTK receptor family)
11. RTK class XI (TIE receptor family)
12. RTK class XII (ROR receptor family)
13. RTK class XIII (DDR receptor family)
14. RTK class XIV (RET receptor family)
15. RTK class XV (KLG receptor family)
16. RTK class XVI (RYK receptor family)
17. RTK class XVII (MuSK receptor family)

Structure

Most RTKs are single subunit receptors but some exist as multimeric complexes, e.g., the insulin receptor that forms disulfide linked dimers in the presence of hormone (insulin); moreover, ligand binding to the extracellular domain induces formation of receptor dimers. Each monomer has a single hydrophobic transmembrane-spanning domain composed of 25 to 38 amino acids, an extracellular N terminal region, and an intracellular C terminal region. The extracellular N terminal region exhibits a variety of conserved elements including immunoglobulin (Ig)-like or epidermal growth factor (EGF)-like domains, fibronectin type III repeats, or cysteine-rich regions that are characteristic for each subfamily of RTKs; these domains contain primarily a ligand-binding site, which binds extracellular ligands, e.g., a particular growth factor or hormone. The intracellular C terminal region displays the highest level of conservation and comprises catalytic domains responsible for the kinase activity of these receptors, which catalyses receptor autophosphorylation and tyrosine phosphorylation of RTK substrates.

Kinase activity

In biochemistry, a kinase is a type of enzyme that transfers phosphate groups (see below) from high-energy donor molecules, such as ATP (see below) to specific target molecules (substrates); the process is termed phosphorylation. The opposite, an enzyme that removes phosphate groups from targets, is known as a phosphatase. Kinase enzymes that specifically phosphorylate tyrosine amino acids are termed tyrosine kinases.

• Phosphate
• ATP
• Tyrosine

When a growth factor binds to the extracellular domain of an RTK, its dimerization is triggered with other adjacent RTKs. Dimerization leads to a rapid activation of the protein's cytoplasmic kinase domains, the first substrate for these domains being the receptor itself. The activated receptor as a result then becomes autophosphorylated on multiple specific intracellular tyrosine residues.

Signal transduction

Through diverse means, extracellular ligand binding will typically cause or stabilize receptor dimerization. This allows a tyrosine in the cytoplasmic portion of each receptor monomer to be trans-phosphorylated by its partner receptor, propagating a signal through the plasma membrane. The phosphorylation of specific tyrosine residues within the activated receptor creates binding sites for Src homology 2 (SH2) domain- and phosphotyrosine binding (PTB) domain-containing proteins. Specific proteins containing these domains include Src and phospholipase Cγ. Phosphorylation and activation of these two proteins on receptor binding lead to the initiation of signal transduction pathways. Other proteins that interact with the activated receptor act as adaptor proteins and have no intrinsic enzymatic activity of their own. These adaptor proteins link RTK activation to downstream signal transduction pathways, such as the MAP kinase signalling cascade. An example of a vital signal transduction pathway involves the tyrosine kinase receptor, c-met, which is required for the survival and proliferation of migrating myoblasts during myogenesis. A lack of c-met disrupts secondary myogenesis and—as in LBX1—prevents the formation of limb musculature. This local action of FGFs (Fibroblast Growth Factors) with their RTK receptors is classified as paracrine signalling.

Families

Epidermal growth factor receptor family

For more details on this topic, see ErbB.

The ErbB protein family or epidermal growth factor receptor (EGFR) family is a family of four structurally related receptor tyrosine kinases. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's Disease. In mice, loss of signaling by any member of the ErbB family results in embryonic lethality with defects in organs including the lungs, skin, heart, and brain. Excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor. ErbB-1 and ErbB-2 are found in many human cancers and their excessive signaling may be critical factors in the development and malignancy of these tumors.

Fibroblast growth factor receptor (FGFR) family

For more details on this topic, see fibroblast growth factor receptor.

Fibroblast growth factors comprise the largest family of growth factor ligands at 23 members. The natural alternate splicing of four fibroblast growth factor receptor (FGFR) genes results in the production of over 48 different isoforms of FGFR. These isoforms vary in their ligand binding properties and kinase domains; however, all share a common extracellular region composed of three immunoglobulin (Ig)-like domains (D1-D3), and thus belong to the immunoglobulin superfamily. Interactions with FGFs occur via FGFR domains D2 and D3. Each receptor can be activated by several FGFs. In many cases, the FGFs themselves can also activate more than one receptor. This is not the case with FGF-7, however, which can activate only FGFR2b. A gene for a fifth FGFR protein, FGFR5, has also been identified. In contrast to FGFRs 1-4, it lacks a cytoplasmic tyrosine kinase domain, and one isoform, FGFR5γ, only contains the extracellular domains D1 and D2.

Vascular endothelial growth factor receptor (VEGFR) family

For more details on this topic, see Vascular endothelial growth factor.

Vascular endothelial growth factor (VEGF) is one of the main inducers of endothelial cell proliferation and permeability of blood vessels. Two RTKs bind to VEGF at the cell surface, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1).

The VEGF receptors have an extracellular portion consisting of seven Ig-like domains so, like FGFRs, belong to the immunoglobulin superfamily. They also possess a single transmembrane spanning region and an intracellular portion containing a split tyrosine-kinase domain. VEGF-A binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in the embryo). A third receptor has been discovered (VEGFR-3); however, VEGF-A is not a ligand for this receptor. VEGFR-3 mediates lymphangiogenesis in response to VEGF-C and VEGF-D.

RET receptor family

For more details on this topic, see RET proto-oncogene.

The natural alternate splicing of the RET gene results in the production of 3 different isoforms of the protein RET. RET51, RET43, and RET9 contain 51, 43, and 9 amino acids in their C-terminal tail, respectively. The biological roles of isoforms RET51 and RET9 are the most well studied in-vivo, as these are the most common isoforms in which RET occurs.

RET is the receptor for members of the glial cell line-derived neurotrophic factor (GDNF) family of extracellular signalling molecules or ligands (GFLs).

In order to activate RET, first GFLs must form a complex with a glycosylphosphatidylinositol (GPI)-anchored co-receptor. The co-receptors themselves are classified as members of the GDNF receptor-α (GFRα) protein family. Different members of the GFRα family (GFRα1-GFRα4) exhibit a specific binding activity for a specific GFLs. Upon GFL-GFRα complex formation, the complex then brings together two molecules of RET, triggering trans-autophosphorylation of specific tyrosine residues within the tyrosine kinase domain of each RET molecule. Phosphorylation of these tyrosines then initiates intracellular signal transduction processes.

Eph receptor family

For more details on this topic, see Eph_receptor.

Ephrin and Eph receptors are the largest subfamily of RTKs.

Discoidin domain receptor (DDR) family

For more details on this topic, see DDR1.

The DDRs are unique RTKs in that they bind to collagens rather than soluble growth factors.

See also

• Tyrosine kinase
• Insulin receptor
• Enzyme-linked receptor
• Tyrphostins
• Bcr-Abl tyrosine kinase inhibitors

References

External links

• Tyrosine Kinase Receptors at the US National Library of Medicine Medical Subject Headings (MeSH)
• EC 2.7.10.1

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English Journal

• Imatinib mesylate stimulates low-density lipoprotein receptor-related protein 1-mediated ERK phosphorylation in insulin-producing cells.

• Fred RG, Boddeti SK, Lundberg M, Welsh N.
• Clinical science (London, England : 1979).Clin Sci (Lond).2015 Jan 1;128(1):17-28. doi: 10.1042/CS20130560.
• Low-density lipoprotein receptor-related protein 1 (LRP1) is an endocytic and multi-functional type I cell surface membrane protein, which is known to be phosphorylated by the activated platelet-derived growth factor receptor (PDGFR). The tyrosine kinase inhibitor imatinib, which inhibits PDGFR and
• PMID 24865476

• New angle of view on the role of rho/rho kinase pathway in human diseases.

• Luo W1, Liu CT1, Yang QH2, Yu Q3, Wang T4.
• Iranian journal of allergy, asthma, and immunology.Iran J Allergy Asthma Immunol.2014 Dec;13(6):378-95.
• Rho-kinase is an effector molecule of RhoA, a monomeric GTP-binding protein, and causes Ca2+ sensitization through inactivation of myosin phosphatase. The major physiological functions of Rho/Rho-kinase cascade include contraction, proliferation and migration in cells.There are some excellent review
• PMID 25148796

• Signaling components of the 1α,25(OH)2D3-dependent Pdia3 receptor complex are required for Wnt5a calcium-dependent signaling.

• Doroudi M1, Olivares-Navarrete R2, Hyzy SL2, Boyan BD3, Schwartz Z4.
• Biochimica et biophysica acta.Biochim Biophys Acta.2014 Nov;1843(11):2365-75. doi: 10.1016/j.bbamcr.2014.06.006. Epub 2014 Jun 16.
• Wnt5a and 1α,25(OH)2D3 are important regulators of endochondral ossification. In osteoblasts and growth plate chondrocytes, 1α,25(OH)2D3 initiates rapid effects via its membrane-associated receptor protein disulfide isomerase A3 (Pdia3) in caveolae, activating phospholipase A2 (PLA2)-activating pr
• PMID 24946135

Japanese Journal

• The EML4-ALK oncogene: targeting an essential growth driver in human cancer

• Proceedings of the Japan Academy, Series B 91(5), 193-201, 2015
• … A small chromosomal inversion thus leads to fusion of the amino-terminal portion of the microtubule-associated protein EML4 to the intracellular kinase domain of ALK, a receptor-type protein tyrosine kinase. … Constitutive dimerization of EML4-ALK mediated by a dimerization motif of EML4 results in kinase activation. …
• NAID 130005067231

• Oleic Acid Stimulates Glucose Uptake Into Adipocytes by Enhancing Insulin Receptor Signaling

• , , ,
• Journal of Pharmacological Sciences, 2014
• … In the cell-free assay of protein tyrosine phosphatase 1B (PTP1B), cis-unsaturated FFAs such as linoleic, linolenic, and oleic acid significantly suppressed PTP1B activity in a concentration (1 – 100 μM)-dependent manner, with the highest potential for oleic acid. … Oleic acid (1 μM) stimulated insulin (0.1 nM)-induced phosphorylation of the insulin receptor at Tyr1185 and increased insulin (0.1 nM)-induced phosphorylation of Akt at Thr308 and Ser473 in differentiated 3T3-L1-GLUT4myc adipocytes. …
• NAID 130004933175

• Oleic Acid Stimulates Glucose Uptake Into Adipocytes by Enhancing Insulin Receptor Signaling

• , , ,
• Journal of Pharmacological Sciences 126(4), 337-343, 2014
• … In the cell-free assay of protein tyrosine phosphatase 1B (PTP1B), cis-unsaturated FFAs such as linoleic, linolenic, and oleic acid significantly suppressed PTP1B activity in a concentration (1 – 100 μM)-dependent manner, with the highest potential for oleic acid. … Oleic acid (1 μM) stimulated insulin (0.1 nM)-induced phosphorylation of the insulin receptor at Tyr1185 and increased insulin (0.1 nM)-induced phosphorylation of Akt at Thr308 and Ser473 in differentiated 3T3-L1-GLUT4myc adipocytes. …
• NAID 130004704283

Related Links

• Receptor tyrosine kinase - Wikipedia, the free encyclopedia

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 nonreceptor tyrosine kinases which do not possess ...

• Tyrosine kinase - Wikipedia, the free encyclopedia

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 ...

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