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Das Prinzip der Signalübertragung von Hormonen mittels Rezeptoren und sekundärer Botenstoffe wurde 1960 erstmals postuliert, die Übertragung durch G-Proteine
wurde in den 70er bis 80er Jahren des 20. Jahrhunderts erarbeitet. Für diese Arbeiten wurden 1971 Earl W. Sutherland Jr. „für seine Entdeckungen über die
Wirkungsmechanismen von Hormonen“ und 1994 Alfred G. Gilman und Martin Rodbell „für die Entdeckung der Zellkommunikation und im speziellen der
Entdeckung der G-Proteine“ mit dem Nobelpreis für Medizin geehrt.
G-Protein-gekoppelte Rezeptoren gehören nach wie vor zu den am intensivsten untersuchten Zielen für die Entwicklung neuer Medikamente in der
Arzneimittelindustrie. Dabei rücken insbesondere neue, innerhalb der letzten 20 Jahre entdeckte Rezeptoren, wie beispielsweise Cannabinoid-Rezeptoren, CGRP-
Rezeptoren, Chemokin-Rezeptoren, Endothelin-Rezeptoren, Leptin-Rezeptoren, Neurokinin-Rezeptoren und Neuropeptid-Y-Rezeptoren, in das Interesse der
Forschung.
Receptor tyrosine kinase
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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
Gene Ontology
AmiGO / EGO
[show]Search
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.
[1]
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.
[2]
[edit] Receptor tyrosine kinase classes
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Approximately 20 different RTK classes have been identified.
[3]
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)
[edit] 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 absence of
hormone; moreover, ligand binding to the extracellular domain induces formation of receptor dimers.
[4]
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.
[5]
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.
[5]
.
[edit] 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.
[edit] Signal transduction