Abstract
Almost three decades after its seminal discovery, our understanding of the remarkable TOR pathway continues to expand. As a TOR complex, TORC2 lies at the nexus of many signaling pathways and directs a diverse array of fundamental processes such as cell survival, proliferation, and metabolism by integrating environmental and intracellular cues. The dysregulation of TORC2 activity disrupts cellular homeostasis and leads to many pathophysiological conditions. With continued efforts at mapping the signaling landscape, the pace of discovery in TORC2 regulation has been accelerated in recent years. Consequently, emerging evidence has expanded the repertoire of upstream regulators and has revealed unexpected diversity in the modes of TORC2 regulation. Multiple environmental cues and plasma membrane proteins that fine-tune TORC2 activity are unfolding. Furthermore, TORC2 signaling is intricately intertwined with other major signaling pathways. Therefore, feedback and crosstalk regulation also extensively modulate TORC2. In this context, we provide a comprehensive overview of revolutionary concepts regarding emerging regulators of TORC2 and discuss evidence of feedback and crosstalk regulation that shed new light on TORC2 biology.
Highlights
In eukaryotes, the evolutionarily conserved Ser/Thr kinase target of rapamycin (TOR) functions as a central integrator when growth factors, nutrients, and cellular energy status favor anabolism
Exciting progress has been made over the last few years in elucidating the complex network of TORC2 signaling and its broad implications in human physiology and pathology
Basic investigations into the genetics, cellular biology, biochemistry, and structural biology of TORC2 have yielded a sophisticated view of how the activity of this multi-protein kinase is regulated
Summary
The evolutionarily conserved Ser/Thr kinase target of rapamycin (TOR) functions as a central integrator when growth factors, nutrients, and cellular energy status favor anabolism. TORC2 activity might initiate a downstream signaling axis in a cell/tissue-dependent manner (discussed below), the rigorous approach to document TORC2 activity requires measurement of the phosphorylation status of all these AGC kinases as well as their substrates. Signals generated at the plasma membrane, such as receptor tyrosine kinase (RTK), oncogenic Ras, cell adhesion receptors, membrane tension, as well as bacteria-derived pathogens, effectively modulate TORC2 activity through distinct mechanisms (Figure 1).
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