Tyrosine kinase receptors

This group of receptors mediates a signal from a series of androgenic substances including insulin, an epidermal factor of body height (EGF), a platelet factor of body height (platelet-derived growth factor — PDGF) - These receptors are created by one polypeptide chain which penetrates cytoplasmatic membrane, forming three domains: extracellular, trans membrane and intracellular which contains the site providing enzymatic activity. Some of these receptors, for example insulin, exist in the form of dimer from two receptors interfaced with each other by non-covalent bonds. Others, such as EGF receptor, exist in a membrane in a single form and form dimeasures in response to accession of ligand to each subunits. Anyway linkng of a factor of body height with a receptor leads to allosteric activation of tirozinkinaz activity in the cytoplasmatic domain of a receptor.

The first step in this activation includes cross phosphorylation of the multiple remains of tirozin of two receptor subunits in the intratsellyulyarny domain. This works as a signal to binding of other intracellular proteins which tirozin remains fosforilirutsya by a receptor and thus are activated. Specificity of the cellular answer is determined by combinations of proteins, specific to this cage, which join receptors of factors of growth. Please pay attention to Honluten.

Recently a large amount of the proteins joining the activated receptors of factors of growth has been identified. Having various structure, these proteins turn on two conservative domains known as SH2 and SH3 (Sre homology region). For the first time they have been revealed in the protooncogene called Sre-protein, from here and the name; SH2-domains distinguish fosfotirozina on receptors of factors of growth, functions of SNZ-domains aren't clear yet.

The characteristic of the proteins containing SH2-and SNZ-domains is a subject of many researches today. The role of some of them is shown. For example, one of mechanisms which factors of growth regulate the cellular growth and a differentiation is activation of the cascade proteincinase, known as mitogenaktiviruyem proteinkinaza (mitogen activated protein kinas — MAP kinase pathway). Activation of this way is initiated by phosphorylation of tirozin of protein of Grb2 containing SH2-and SNZ-domains. The SH3 domain on Grb2 attaches other protein known as mSOS, and in common the Grb2/mSOS complex activates Ras, monomeric G-protein. Ras has the structure similar to a α-subunits of G-proteins which interacts with 7-transmembrane (interfaced to G-proteins) receptors and is activated and inactivated by similar mechanisms. From here interaction of Ras with Grb2/mSOS accelerates exchange of GDF for GTF for Ras, stimulating his activation.

Cycle of activation inactivation G-protein

The following step in this cascade includes, apparently, Ras activation serine / threoninekinases, known as Raf which then activates phosphorylation other kinase, MEK (known as MAR-kinaznaya a kinase) which in turn fosforilirut a MAR-kinase which is capable to pass through a nuclear membrane, and in a kernel she fosforilirut various factors of a transcription. The arising changes of a transcription of a gene initiate processes of proliferation or differentiation.

Other proteins interacting with receptors of factors of body height are capable to regulate intracellular secondary messengers. For example, members of family of phospholipase which regulate the level of intracellular IP3 and diacylglycerol as well as the PLC-P family considered above contain SH2-and SH3-domains and can be activated by tirozincinaz receptors. So far from receptors of factors of body height only insulin are used as pharmacological targets at patients with diabetes. However a role of these receptors in cellular body height, uncontrollable carrying out signals through them at inflammatory and neoplastic diseases define great interest to development of the agents blocking their activity. For example, mutant Ras-proteins were found more than in 30% of tumors of the person therefore now as drugs of treatment of tumors the substances capable to inhibit mutant proteins of Ras and others in MAHER-kinase of a way are developed.