Importancia de los receptores híbridos receptor de insulina/receptor del factor de crecimiento similar a la insulina tipo I (InsR/IGF-1R) en las redes de señalización del sistema IGF

Abstract

Cells are information processing devices, which integrate millions of extracellular and intracellular signals to produce an optimal cellular response within of an organism. Many diseases, for example cancer, can be understood as pathological alterations in the signalling networks. Therefore, the study of the signal processing mechanisms constitutes one of the most complex and at the same time more significant in biological research questions. The signaling events include intricate signaling networks, which enclose "feedback loops, cross-signaling with other networks and the integration of the internal state of the cell, all of these, regulated spatially and temporally. The signalling system of the IGFs is a complex regulatory network that has functions throughout the body, at the cellular and sub-cellular levels. The IGF system isrelated to the development of the organism and maintenance of cell function normal. In addition, it has been linked in various pathological conditions to a role particularly important in cancer. The structural similarities between the receptor of IGF and the insulin receptor, allow the formation of hybrid receptors, where an IGF-1R αβ string is connected to an InsR-A or InsR-B string. When co-express IGF and insulin receptors in the same cell, these receptors hybrids can be formed randomly and represent the most abundant receptor form. However, very little is known about its importance in transduction of signals and the biological effects they may be modulating; this paper addresses the problem of studying the signalling of the IGF system from a that reflects the biological environment in which it is found; making use of both of classic analysis techniques, as well as avant-garde techniques, we sought to understand the mechanisms underlying the signal processing that triggers an effect biological. The trophoblast cells are part of the placenta and are responsible for invading the maternal endometrium during the blastocyst implantation process, furthermore, they evade the effectors of the maternal immune response, being of vital importance for the fetoplacental development. The invasion of the trophoblast into the extracellular matrix of the uterus is an example of a highly controlled invasion. This process shares many characteristics with metastatic tumors, however it is spatially regulated and temporarily. From the HTR8 trophoblast line, two lines were obtained Stably silenced cell phones in the IGF-1R and IGF-2R/M6P receptors with which proliferation, migration, invasion, MMP-9 expression and cAMP, a parallel proteomic study of the proteins activated by IGF-2 in normal and silenced models in order to obtain a comprehensive view of biological phenomena induced in the cell after IGF stimulation. The results showed that IGF ligands are important mediators of the malignant phenomena shared between trophoblast cells and cells cancers, such as proliferation, migration and invasion. These effects are mediated by the InsR/IGF-1R hybrid receptors and involve dozens of proteins that were identified by mass spectrometry. Proteins were studied activated by IGF-2 and built from them networks of interaction protein-protein related to the main effects mediated by this ligand in trophoblastic cells. Using two-dimensional electrophoresis and the cell model silenced for the IGF-1R receptor, its role was evaluated by analyzing the induced changes for their depletion in the protein activation maps. Finally, the silenced cell line was used stably in the IGF-2/M6P to study its role in IGF-mediated bilogical effects and in the signalling networks. The presence of the type 2 receptor was found to be key in the migration, invasion and expression of Mmp-9. Additionally, evidence was obtained that this receptor can activate G-protein-coupled receptors, probably with intermediation of the S1P. This work is the first study to address the problem of system signalling IGF from a vision that frames proteins within complex networks of signaling. Using phosphoprotein analysis techniques in conjunction with biological activity tests, there is strong evidence of the close relationship between the three receptors of the IGF system in the regulation of biological effects mediated by ligands IGF-1 and IGF-2. It also shows the central role of the IGF-2/M6P receptor in the signal transduction of the IGF system and how its absence generates noticeable changes in the phosphoprotein which are reflected in the most important biological agents in cancer, migration and invasion. These results extend the knowledge of the signaling mediated by the IGFs, highlight the importance of IGF-2/M6P receptor as a key mediator in the transduction phenomena of signals; they represent the first large-scale study of signalling networks activated by the IGFs and their relationship with biological phenomena important to the development of cancer.