tyrosine kinase receptor

WordNet

1. 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
2. an enzyme that catalyzes the conversion of a proenzyme to an active enzyme
3. an amino acid found in most proteins; a precursor of several hormones
4. the basic unit of money in Papua New Guinea

PrepTutorEJDIC

1. =sense organ / 受信装置

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/01/12 15:23:40」(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
Pfam	PF07714
OPM superfamily	207
OPM protein	2k1k
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Receptor tyrosine kinases (RTK)s 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 nonreceptor tyrosine kinases which do not possess transmembrane domains.

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 25-38 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 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.

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

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 慢性骨髄性白血病に対するチロシンキナーゼ阻害剤の臨床使用 clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia
• 2. 血管新生阻害剤の概要 overview of angiogenesis inhibitors
• 3. 進行消化管間質腫瘍に対するチロシンキナーゼ阻害剤療法 tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors
• 4. 成人における抗癌剤の投与 dosing of anticancer agents in adults
• 5. 慢性骨髄性白血病の治療の概要 overview of the treatment of chronic myeloid leukemia

English Journal

• DNA methyltransferase 3, a target of microRNA-29c, contributes to neuronal proliferation by regulating the expression of brain-derived neurotrophic factor.

• Yang G1, Song Y2, Zhou X3, Deng Y1, Liu T1, Weng G1, Yu D3, Pan S1.
• Molecular medicine reports.Mol Med Rep.2015 Jul;12(1):1435-42. doi: 10.3892/mmr.2015.3531. Epub 2015 Mar 23.
• Alzheimer's disease (AD), the most common form of dementia in the aged population, presents an increasing clinical challenge in terms of diagnosis and treatment. Neurodegeneration is one of the hallmarks of AD, which consequently induces cognitive impairment. Brain‑derived neurotrophic factor (BDN
• PMID 25815896

• Overexpression of Tyro3 receptor tyrosine kinase leads to the acquisition of taxol resistance in ovarian cancer cells.

• Lee C1.
• Molecular medicine reports.Mol Med Rep.2015 Jul;12(1):1485-92. doi: 10.3892/mmr.2015.3542. Epub 2015 Mar 24.
• The majority of patients with ovarian cancer are diagnosed at the advanced stages (III/IV) and their 5‑year‑survival rate is relatively low. One of the major causes of the poor prognosis of ovarian cancer is the development of resistance to first‑line chemotherapy, including platinum and taxol
• PMID 25815442

• Effects of glucose-dependent insulinotropic polypeptide receptor knockout and a high-fat diet on cognitive function and hippocampal gene expression in mice.

• Lennox RR1, Moffett C1, Porter DW1, Irwin N1, Gault VA1, Flatt PR1.
• Molecular medicine reports.Mol Med Rep.2015 Jul;12(1):1544-8. doi: 10.3892/mmr.2015.3447. Epub 2015 Mar 6.
• It has been previously demonstrated that compromise of glucose‑dependent insulinotropic polypeptide receptor (GIPR) action and chronic consumption of a high‑fat diet can independently impair memory and learning ability, however, the underlying pathology remain to be elucidated. The present study
• PMID 25760229

Japanese Journal

• Crucial roles of RSK in cell motility by catalysing serine phosphorylation of EphA2

• Zhou Yue,Yamada Naoki,Tanaka Tomohiro,Hori Takashi,Yokoyama Satoru,Hayakawa Yoshihiro,Yano Seiji,Fukuoka Junya,Koizumi Keiichi,Saiki Ikuo,Sakurai Hiroaki
• Nature Communications 6, 7679, 2015-07-09
• … Crosstalk between inflammatory signalling pathways and receptor tyrosine kinases has been revealed as an indicator of cancer malignant progression. … In the present study, we focus on EphA2 receptor tyrosine kinase, which is overexpressed in many human cancers. …
• NAID 120005625367

• B細胞腫瘍に対する新規BTK阻害剤ONO-4059の臨床開発 (特集 リンパ系腫瘍に対するさらなる新薬開発と国内外の診療)

• 棟方 理
• 血液内科 = Hematology 71(1), 47-52, 2015-07
• NAID 40020549604

• A protein tyrosine kinase receptor, c-RET signaling pathway contributes to the enteric neurogenesis induced by a 5-HT₄ receptor agonist at an anastomosis after transection of the gut in rodents

• Goto Kei,Kawahara Isao,Kuniyasu Hiroki [他]
• The journal of physiological sciences 65(4), 377-383, 2015-07
• NAID 40020509938

Related Links

• Tyrosine kinaseとは - goo Wikipedia (ウィキペディア)

... 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 [] ...

• Receptor - Tyrosine Kinase

Find information on Receptor Tyrosine Kinases. There are approximately 60 receptor tyrosine kinases. Critical roles in cell growth, cell differentiation, cellular metabolism, cell adhesion, cell motility and cell death. Receptor tyrosine ...

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★リンクテーブル★

リンク元	「receptor protein-tyrosine kinase」「チロシンキナーゼレセプター」
関連記事	「kinase」

「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

「チロシンキナーゼレセプター」

　　[★]

英

tyrosine kinase receptor

関

チロシンキナーゼ受容体

「kinase」

　　[★] キナーゼ カイネース リン酸化酵素 phosphoenzyme phosphotransferase