Inhibition by Rapamycin
The mechanism underlying the cell specificity of rapamycin-induced mTORC2 inhibition is unknown, which is particularly significant given that many of the negative metabolic side effects of rapamycin reported in mouse studies and human clinical trials have recently been attributed to mTORC2 inhibition. The expression levels of several FK506-binding proteins (FKBPs), especially FKBP12 and FKBP51, are identified as important factors for rapamycin-mediated inhibition of mTORC2. In support of this, reducing FKBP12 totally changes a cell line that is sensitive to mTORC2 inhibition to an insensitive cell line, while increasing FKBP12 expression can augment mTORC2 inhibition.
Further FKBP12 decrease in cell lines with already low FKBP12 levels totally prevents rapamycin-induced mTORC1 inhibition, demonstrating that relative FKBP12 levels are important for both mTORC1 and mTORC2 inhibition, although at different levels. FKBP51 deficiency, on the other hand, makes cells more susceptible to mTORC2 inhibition. Our findings show that the expression of FKBP12 and FKBP51 is the rate-limiting factor that defines a cell line’s or tissue’s rapamycin responsiveness. These discoveries have implications for treating particular diseases such as neurodegeneration and cancer, as well as general anti-aging efforts. 06-binding proteins (FKBPs), namely FKBP12 and FKBP51, as important determinants of rapamycin-mediated mTORC2 inhibition
mTOR Signaling Pathway
Cell signaling (cell communication in British English) is the capacity of a cell to receive, process, and transmit messages with its surroundings and with itself. Cell signaling is a basic characteristic of all prokaryotic and eukaryotic cellular life. Cell signaling can take place across short or long distances, and is thus classed as autocrine, juxtacrine, paracrine, and endocrine. Signaling molecules can be produced via a variety of biosynthetic pathways and released by passive or active transporters, as well as cell injury.
Receptors are important in cell signaling because they can sense chemical signals as well as physical inputs. Receptors are proteins that are found on the cell surface or within the cell’s interior, such as the cytoplasm, organelles, and nucleus. Additional enzymatic activity such as proteolytic cleavage, phosphorylation, methylation, and ubiquitinylation may occur as a result of these signaling pathways. Each cell is designed to respond to certain extracellular signal molecules, which serve as the foundation for development, tissue repair, immunology, and homeostasis.