Mammalian target of rapamycin in inflammatory skin conditions

The conserved serine/threonine kinase mammalian target of rapamycin (mTOR) is a major regulator of survival growth, proliferation and motility in response to mitogens, energy as well as nutrient levels, exerting its effects through two distinct signaling complexes, known as mTOR complex (mTORC) 1 and mTORC2. In particular, the rapamycin-sensitive mTORC1 promotes cell growth and proliferation whereas mTORC2, rapamycin-non sensitive, is involved in the regulation of cell polarity and in the functional phosphorylation of cytoskeleton actin fibres. Therefore, mTOR functions as a central node in a complex network of signaling pathways that are involved both in normal physiological, as well as pathogenic events. mTOR signaling occurs in concert with upstream phosphoinositide-3-OH kinase (PI3K)/Akt and tuberous sclerosis complex (TSC) and several downstream effectors. Because of its central role in many different cellular activities, mTOR dysregulation can be involved in a great number of either inflammatory or neoplastic conditions through the coordinated phosphorylation of proteins that directly regulate cell-cycle progression and metabolism, as well as transcription factors that regulate the expression of genes involved in the oncogenic processes. The importance of mTOR signaling in oncology is now widely accepted, and agents that selectively target mTOR have been developed as anticancer drugs. Moreover, mTOR functions are also reported to be altered in metabolic disorders, such as obesity and type 2 diabetes as well as in autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease and lupus erythematosus. Recently, mTOR pathway was shown to play a role in regulating the immune response, not only in myeloid cells, but also in keratinocytes, potentially contributing to cytokines production in skin inflammation. Indeed, mTOR involvement in some of the most common inflammatory dermatoses has now been demonstrated.