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A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. 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 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases, although additional types exist. Protein kinases are also found in bacteria and plants. 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.
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events. Most commonly, protein phosphorylation is catalyzed by protein kinases, ultimately resulting in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding in a receptor give rise to a biochemical cascade, which is a chain of biochemical events known as a signaling pathway.
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; 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.
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.
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. The receptors are generally activated by dimerization and substrate presentation. 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.
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The transforming growth factor beta (TGFB) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, cell migration, apoptosis, cellular homeostasis and other cellular functions. The TGFB signaling pathways are conserved. In spite of the wide range of cellular processes that the TGFβ signaling pathway regulates, the process is relatively simple. TGFβ superfamily ligands bind to a type II receptor, which recruits and phosphorylates a type I receptor. The type I receptor then phosphorylates receptor-regulated SMADs (R-SMADs) which can now bind the coSMAD SMAD4. R-SMAD/coSMAD complexes accumulate in the nucleus where they act as transcription factors and participate in the regulation of target gene expression.
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A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is 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.
Dalotuzumab is an anti-IGF1 receptor (IGF1R) humanized monoclonal antibody designed for the potential treatment of various cancers. Common adverse effects include hyperglycemia, nausea, vomiting, and fatigue. Dalotuzumab was developed by Merck and Co., Inc.
Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threonine or tyrosine residues within protein kinases, normally to regulate the catalytic activity. Autophosphorylation may occur when a kinases' own active site catalyzes the phosphorylation reaction, or when another kinase of the same type provides the active site that carries out the chemistry. The latter often occurs when kinase molecules dimerize. In general, the phosphate groups introduced are gamma phosphates from nucleoside triphosphates, most commonly ATP.
Tyrosine phosphorylation is the addition of a phosphate (PO43−) group to the amino acid tyrosine on a protein. It is one of the main types of protein phosphorylation. This transfer is made possible through enzymes called tyrosine kinases. Tyrosine phosphorylation is a key step in signal transduction and the regulation of enzymatic activity.
References
- ↑ Growth+Factor+Receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- ↑ A. V. Hoffbrand; P. A. H. Moss; J. E. Pettit (2006). Essential haematology. Wiley-Blackwell. pp. 6–. ISBN 978-1-4051-3649-5 . Retrieved 28 November 2010.
- ↑ McInnes, Campbell; Sykes, Brian D. (1997). "Growth factor receptors: Structure, mechanism, and drug discovery". Peptide Science. 43 (5): 339–366. doi:10.1002/(SICI)1097-0282(1997)43:5<339::AID-BIP2>3.0.CO;2-W. ISSN 1097-0282. PMID 9566117.
- ↑ Goodman, Steven R., ed. (2008-01-01), "Chapter 7 - Intercellular Signaling", Medical Cell Biology (Third Edition), Academic Press, pp. 227–248, doi:10.1016/B978-0-12-370458-0.50012-8, ISBN 978-0-12-370458-0 , retrieved 2020-04-29
- ↑ Kouvidi, Katerina; Nikitovic, Dragana; Berdiaki, Aikaterini; Tzanakakis, George N. (2014-01-01), Simpson, Melanie A.; Heldin, Paraskevi (eds.), "Chapter Twelve - Hyaluronan/RHAMM Interactions in Mesenchymal Tumor Pathogenesis: Role of Growth Factors", Advances in Cancer Research, Hyaluronan Signaling and Turnover, 123, Academic Press: 319–349, doi:10.1016/B978-0-12-800092-2.00012-5, PMID 25081535 , retrieved 2020-04-29
- 1 2 Trenker, Raphael; Jura, Natalia (2020-04-01). "Receptor tyrosine kinase activation: From the ligand perspective". Current Opinion in Cell Biology. 63: 174–185. doi: 10.1016/j.ceb.2020.01.016 . ISSN 0955-0674. PMC 7813211 . PMID 32114309.
- 1 2 Sasaki, Takamitsu; Hiroki, Kuniyasu; Yamashita, Yuichi (2013). "The Role of Epidermal Growth Factor Receptor in Cancer Metastasis and Microenvironment". BioMed Research International. 2013: 546318. doi: 10.1155/2013/546318 . ISSN 2314-6133. PMC 3748428 . PMID 23986907.
- 1 2 Bennasroune, Amar; Gardin, Anne; Aunis, Dominique; Crémel, Gérard; Hubert, Pierre (2004-04-01). "Tyrosine kinase receptors as attractive targets of cancer therapy". Critical Reviews in Oncology/Hematology. 50 (1): 23–38. doi:10.1016/j.critrevonc.2003.08.004. ISSN 1040-8428. PMID 15094157.