mTOR signaling, function, novel inhibitors, and therapeutic targets

Abstract

Mammalian target of rapamycin (mTOR) is an evolutionally conserved serine/threonine kinase that integrates signals from multiple pathways, including nutrients (e.g., amino acids and glucose), growth factors (e.g., insulin and insulinlike growth factor 1), hormones (e.g., leptin), and stresses (e.g., starvation, hypoxia, and DNA damage) to regulate a wide variety of eukaryotic cellular functions, such as translation, transcription, protein turnover, cell growth, differentiation, cell survival, metabolism, energy balance, and stress response. Dysregulation of the mTOR pathway is closely associated with cancers and other human diseases. Thus, mTOR is of considerable interest in view of its potential as a therapeutic drug target. However, only limited success has been achieved in clinical applications of mTOR inhibitors because of the inherent complexity in the regulation and function of mTOR. Emerging new developments in this area, such as novel readouts (potential biomarkers) for mTOR activity, dynamic assembly and translocation of the mTOR complex, cross-regulation between mTOR complex 1 and mTOR complex 2 via inter- and intracomplex loops, new mTOR regulators, and new inhibitors, are providing insights that may help overcome these challenges. The introduction of innovative imaging strategies is also expected to give rise to breakthroughs in understanding mTOR network complexity and mTOR inhibitor action by visualizing the regulation and function of mTOR.