Platelet-derived growth factor receptor (PDGF-R) is a cell surface receptor tyrosine kinase members platelet-derived growth factor (PDGF) family. Included cancer.There-B subunit and PDGF-A, cell proliferation, cell differentiation, cell growth, development, and is an important factor which regulates many diseases, PDGF-R, which is encoded by different genes, α and in the form of one β2. Depending on the growth factor, two, and bind hetero or homo-PDGF-R.
(PDGF-AA, AB-,-BB, CC-,-DD) PDGF-A,-B, C-, and-D PDGF family consisting of, or forming a homo-or heterodimers. Four PDGFs is inert in the form of monomer them. Order – fake in PDGFs associated with the PDGF receptor and the protein tyrosine kinase receptor. Receptor isoforms of these two dimerization, ie connection leads to a possible combination of the three of the receptor, the dimer PDGF, – and tail-to-tail – fake tail. The intracellular domain consisting of immunoglobulin-like domains of the five extracellular domains of the receptor are part of a tyrosine kinase. Ligand-binding site of the receptor is an immunoglobulin-like domain of the first three. PDGF-CC has reacted specifically with PDGFR – not the fake tail, – tail-to-tail, and therefore, it is similar to PDGF-AB. Binds to, in a lower degree PDGFR significantly high affinity PDGFR-tail-to-tail, therefore, PDGF-DD is regarded as PDGFR-tail-to-tail-specific. PDGF, as were able PDGF-AA only be connected to a combination of three of the receptor with high affinity binding PDGFR, only the PDGF-BB. Dimerization is a prerequisite for the activation of the kinase. Activation of the kinase, appears as a tyrosine phosphorylation of the receptor molecule that occurs between dimer molecules (phosphate transfer). By related to activation and dimerization of the kinase, leading to enzyme activity for the complete tyrosine residues of other receptor molecules, receptor, “unlock” the kinase, an important residue of tyrosine kinase substrates for kinases and other molecules, undergoes a conformational change that allows the basal activity to phosphorylate the group. Expression of the receptor, and for each of the PDGFs has four independent, system flexibility and high PDGF / PDGFR, is under control. Cell types and very different value, PDGF isoforms expressed PDGFRs. By adjusting the external stimuli and various other inflammation, differentiation and embryogenesis, the expression of cell receptors, instead of some PDGFs, you can connect others. Furthermore, some cells showed PDGFR isoforms 1 and simultaneously express both isoforms or separately other cells.
Has the purpose of two main phosphorylation sites in growth factor receptor tyrosine: for monitoring the status of the activity of kinases, to create a binding site for the signaling molecules downstream substrate for kinases in many cases. Tyrosine kinase domain tail PDGF receptor is phosphorylated at tyrosine -857 second part mutant receptor kinase activity carrying phenylalanine is being reduced in this position. Therefore Tear -857, role in the regulation of positive kinase activity is assigned. Juxtamembrane region, kinase inputs, and tyrosine phosphorylation sites in the binding of signaling molecules have been identified in the C-terminal tail of the tail PDGF receptor. The total number of C-terminal three amino acid residues and the adjacent phosphorylated tyrosine residues to form a binding site specific for the signaling molecule. When you connect these sites, a common storage area of the mark (SH) 2 domain and phosphotyrosine binding domain and / or (PTB) is included homology Src. The specificity of these interactions by phosphorylating different mutant receptors carrying a phenylalanine residue at one or more locations may lack the ability to bind to its target signaling molecules generally Because it is, it seems to be very high. It is the adapter molecule several distinct enzymatic activities and signaling molecules, or is equipped with, but it has been found in complex with subunits having a catalytic activity cases not at all. Or tyrosine phosphorylation, generates a signal which can be unique for each type of signaling molecule.Examination of inducing the RTK signaling cascades various reaction with an activated receptor catalytic activity was created more downstream of latitude (PLC latitude) route – and phospholipase PI-3 kinase as an important mediator Las / mitogen-activated protein kinase to be adjustable by other mechanisms (MAPK), of PDGFR signaling.
Class IA phospholipid kinase, PI-3 kinase is activated by a majority of RTK. As with the SH2 domain-containing proteins other to form a complex with a portion PY PI-3 kinase activation receptor. The main function of the activation of PI3K is the generation of PIP3, which functions as a second messenger to activate after tyrosine kinase Btk Noto ITK, serine / threonine kinase, and Akt of PDK1 (PKB). Proliferation cell survival, proliferation and – the main biological function of activated Akt may be classified into three categories. The Akt activity, many cancers to be involved in breast cancer are known in particular. Appointed by the RTK activation by the binding of SH2 domain of tyrosine phosphorylated receptor site of them immediately PLCγ. (4,5) P2 to form diacylglycerol and two second messenger in the (1,4,5) P3 to its substrate PtdIns after hydrolysis activation, the PLCγ. In (1,4,5) P3 + to stimulate the release of Ca 2 from intracellular stores. Of Ca 2 + binding to calmodulin to activate the protein kinase family calmodulindependent then. In addition, diacylglycerol, and activated members 2 + PKC family Ca. Proliferation of such second stag which is generated by (4,5) P2 PtdIns stimulates the hydrolysis various cellular processes angiogenesis, as cell motility.
To form a complex with Sos of SH3 domain of Grb2 of the adapter protein Grb2. Thereby, of Grb2 of Grb2/Sos complex (or) is recruited to the membrane of the SH2 domain of Grb2 binds to activated PDGFR SHP2 is to enable the interaction with the exchange of GDP for GTP in Las and RAS, the relevant have. Interaction between PDGFR of Grb2 Whereas carried out by reaction with proteins SHP2, the SHC, Grb2 is activated via adapter proteins to form complexes with many receptors by PTB consumers I bind to EGFR. Activated Ras i.e. rough, it interacts with several proteins once . Is activated, the stimulation of Raf (MEK or MAPKK) MAPK kinase by phosphorylation of Ser residues in the activation loop. MAPKK is phosphorylated Y residues and (ERK1 / 2) T in the activation loop MAPK leading to its activation. When you move to the nucleus and a variety of substrates, cytoplasmic, and is active MAPK phosphorylates transcription factors. To modulate a variety of biological functions through the phosphorylation of specific target molecule present in the nuclear membrane and cytoplasm are found, thus the proliferation of such cells, members of the MAPK family, differentiation, etc. It contributes in the regulation of various cellular processes
It is a ligand-induced tyrosine phosphorylation associated with the 64 KD protein (PDGFR) PLC-γ1, RasGAP, PI3K and platelet-derived growth factor (PDGF) receptor β subunits. To determine the relative role of each of these fusion proteins in PDGFR signaling may PDGFR mutants to bind to only one of the binding proteins and their receptors Our “back added” mutants was constructed so that it is possible to connect to each of the compositions. PLC-γ1, F5 PDGFR will not be able to fail in order to activate the Ras and PI3K, to induce DNA synthesis. Restore the mitogenic response and Ras activation of PI3K-related permit and PLC-γ1 or F5 PDGFR. Surprisingly, it is recovered almost completely the binding of the 64 KD protein is Ras activity unsaved the ability of the receptor to trigger DNA synthesis. Thus, activation of Ras is not sufficient to cause the PI3K independent downstream mediators and PLC-γ1 and PDGF-dependent DNA synthesis of mitogenic signal of PDGF.
In the malignant tissue to grow rapidly, tumor blood vessels are exposed to growth factors and cytokines many. Role of the signaling pathway and various factors in the regulation of tumor angiogenesis has been well-studied relatively, but a little, in order to promote the transition and tumor angiogenesis, cooperation and their effects these factors and little is known about the complex interactions between. Recent studies of our vascular endothelial cells dormant, usually, and PDGF receptor expression in the transcriptional activation endothelial cells stimulate fibroblast growth factor in (FGF) -2 platelet-derived growth factor (PDGF)-BB stimulation silence that for obtaining hypersensitivity after is shown. Interestingly, also the PDGF-BB, and transmits a feedback signal positive FGF-2 signal transduction system by increasing the expression of the receptor in vascular wall cells. I leads to the formation of the primitive vascular system and disorder incoherent interaction of these in the tumor environment to promote tumor growth and metastasis in mice. These findings are examples of complex interactions between the tumor angiogenesis factor. Therefore, the development of anti-angiogenic therapeutic agents for the treatment of cancer should be directed to block the loop interactive and angiogenic multiple signaling pathways.