Abstract
In adult tissue the quiescent state of a single cell is maintained by the steady state conditions of its own microenvironment for what concern both cell-cell as well as cell-ECM interaction and soluble factors concentration. Physiological or pathological conditions can alter this quiescent state through an imbalance of both soluble and insoluble factors that can trigger a cellular phenotypic response. The kind of cellular response depends by many factors but one of the most important is the concentration of soluble cytokines sensed by the target cell. In addition, due to the intrinsic plasticity of many cellular types, every single cell is able, in response to the same stimulus, to rapidly switch phenotype supporting minimal changes of microenviromental cytokines concentration. Wound healing is a typical condition in which epithelial, endothelial as well as mesenchymal cells are firstly subjected to activation of their motility in order to repopulate the damaged region and then they show a strong proliferative response in order to successfully complete the wound repair process. This schema constitute the leitmotif of many other physiological or pathological conditions such as development vasculogenesis/angiogenesis as well as cancer outgrowth and metastasis.Our review focuses on the molecular mechanisms that control the starting and, eventually, the switching of cellular phenotypic outcome in response to changes in the symmetry of the extracellular environment.
Highlights
Receptor tyrosine kinase (RTKs) is a very important class of transmembrane proteins whose function is to sense and transduce extracellular environmental changes
Ligand binding mediated activation of RTKs consists in the receptor dimerization and activation of its intrinsic tyrosine kinase activity that leads to transphosphorylation on specific tyrosine residues that act as docking sites for intracellular signaling proteins [2]
The recruitment of these proteins leads to the activation of many signaling pathways, including ERK1/2, phosphatidylinositol 3-phosphate kinase (PI-3K), phospholipase C-g (PLC-g), the Src family of tyrosine kinases, the SHP-2 tyrosine phosphatase and the signal transducers and activators of transcription (STATS) whose function is to transduce the activation signals to the nucleus eliciting the corresponding transcriptional response
Summary
Receptor tyrosine kinase (RTKs) is a very important class of transmembrane proteins whose function is to sense and transduce extracellular environmental changes. In a very important work Jékely et al [8], demonstrate that, in drosophila model, RTKs elicit polarized signaling within a cell being localized in the leading edge of the migrating cell They showed that receptor endocytosis is required for this kind of signaling restriction and that Cbl and Spring are the two signaling proteins that mediate this event. The relocation of the receptor from plasmacellular or subplasmacellular to “cytosolic” site changes the intracellular signaling proteins recruited by the receptor itself and, this event leads to the activation of pro-mitogenic signaling modules (MAPK, PI-3K etc) [3,19], in the the recycle rate of PDGF-R to the cell surface is reduced and the receptor is addressed to late endosome/lysosomal compartment for degradation, consistently with the fact that the cell is committed irreversibly to mitosis and RTK has ended its function for the remaining cell cycle completion time
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