Hálová et al. identify a new mechanism by which yeast and mammalian cells regulate the activity of TOR protein kinases.
In response to environmental stimuli, TOR kinases regulate a range of cellular processes, from growth and proliferation to differentiation and cytoskeletal organization. The kinases assemble into two distinct complexes, TORC1 and TORC2, whose activities are tightly regulated by multiple signaling pathways. Hálová et al. wondered whether any of these pathways might regulate TOR by controlling the kinase’s phosphorylation.
The researchers initially focused on fission yeast Tor1. This kinase, which assembles into the TORC2 complex, was phosphorylated on a conserved residue, threonine 1972, in the enzyme’s ATP-binding domain. A nonphosphorylatable version of Tor1 showed increased kinase activity, and yeast expressing this mutant showed increased resistance to oxidative and osmotic stress. Compared with wild-type cells, however, yeast expressing nonphosphorylatable Tor1 were less able to arrest and differentiate in response to nitrogen starvation, a process that requires Tor1 activity to be suppressed.
Hálová et al. found that the kinase Gad8 inhibited Tor1 by phosphorylating threonine 1972 under low nitrogen conditions. How the inhibition of Tor1 promotes arrest and differentiation is unclear; Gad8 itself is a target of Tor1, but other, yet-to-be identified substrates may be more significant.
In mammalian cells, the Gad8 homologue AKT also phosphorylated and inhibited mTOR. As in fission yeast, this phosphorylation was remarkably stable, which could help environmentally induced changes in TOR activity to persist. Senior author Janni Petersen now wants to investigate whether protein turnover, rather than phosphatase activity, is required for cells to reactivate Tor1 signaling when conditions change once more.
Text by Ben Short