Fission yeast Tor1 functions as part of TORC1 to control mitotic entry through the stress MAPK pathway following nutrient stress

Abstract

TOR signalling coordinates growth and division to control cell size. Inhibition of Schizosaccharomyces pombe Tor1, in response to a reduction in the quality of the nitrogen source (nutrient stress), promotes mitotic onset through activation of the mitogen-activated protein kinase (MAPK) Sty1 (also known as Spc1). Here we show that `nutrient starvation' (complete withdrawal of nitrogen or leucine) blocks mitotic commitment by altering Sty1 signalling and that different degrees of Sty1 activation determine these differences in mitotic commitment decisions. Mammals contain one TOR kinase, whereas yeasts contain two. In each case, they comprise two distinct complexes: TORC1 and TORC2. We find that nutrient-stress-induced control of mitotic onset, through Tor1, is regulated through changes in TORC1 signalling. In minimal medium, Tor1 interacts with the TORC1 component Mip1 (raptor), and overexpression of tor1+ generates growth defects reminiscent of TORC1 mutants. Strains lacking the TORC2-specific components Sin1 and Ste20 (rictor) still advance mitotic onset in response to nutrient stress. By contrast, Mip1 and the downstream effector Gad8 (a S6K kinase homologue), like Tor1, are essential for nutrient stress to advance mitotic onset. We conclude that S. pombe Tor1 and Tor2 can both act in TORC1. However, it is the inhibition of Tor1 as part of TORC1 that promotes mitosis following nutrient stress.

TOR Complex 2 Controls Gene Silencing, Telomere Length Maintenance, and Survival under DNA-Damaging Conditions

“…Thus, the effect of Tor1 on mitotic entry may rely on its level of activity. Indeed, while we were revising the manuscript, it was reported that Tor1 can act as part of TORC1 in regulating entrance into mitosis (13). It is the inhibition of a Tor1-Mip1 (TORC1) complex that induces entrance into mitosis under poor nitrogen conditions (13).…”

“…Indeed, while we were revising the manuscript, it was reported that Tor1 can act as part of TORC1 in regulating entrance into mitosis (13). It is the inhibition of a Tor1-Mip1 (TORC1) complex that induces entrance into mitosis under poor nitrogen conditions (13). Thus, whether Tor1 acts as an inducer or inhibitor of mitosis may also rely on its partner proteins.…”

The Centrosome and Its Duplication Cycle

“…It is unclear whether Fin1 is also another mode of feedback control, or whether it coordinates division with specific external cues. In contrast, direct control of Polo Plo1 's SPB affinity clearly does couple division timing to environmental cues (Petersen and Hagan 2005;Petersen and Nurse 2007;Hartmuth and Petersen 2009;Halova and Petersen 2011). Phosphorylation of the conserved serine 402 between the kinase and Polo-box domains enhances SPB recruitment of Polo Plo1 in response to signaling flux through the Sty1 MAP kinase stress-response pathway (equivalent to p38 of higher eukaryotes) (Petersen and Hagan 2005;Halova and Petersen 2011).…”

“…Phosphorylation of the conserved serine 402 between the kinase and Polo-box domains enhances SPB recruitment of Polo Plo1 in response to signaling flux through the Sty1 MAP kinase stress-response pathway (equivalent to p38 of higher eukaryotes) (Petersen and Hagan 2005;Halova and Petersen 2011). Heat, pressure, and nutritional signaling from the TOR network compromise the function of the protein phosphatase Pyp2 (equivalent to human DUSP65) toward the MAP kinase Sty1 (George et al 2007;Petersen and Nurse 2007;Hartmuth and Petersen 2009;Halova and Petersen 2011). This reduction in Pyp2 function enhances MAP kinase signaling to boost serine 402 phosphorylation, thereby driving Polo Plo1 onto the SPB (Petersen and Nurse 2007) to couple division to at least three external cues: nutrition, heat, and pressure stresses.…”

Control of Sty1 MAPK activity through stabilisation of the Pyp2 MAPK phosphatase

“…In contrast, in fission yeast Schizosaccharomyces pombe one main MAPK, Sty1 (also known as Spc1 or Phh1), is activated in response to a variety of extracellular stimuli (Millar et al, 1995;Shiozaki and Russell, 1995a;Degols et al, 1996;Shiozaki and Russell, 1996). Strong Sty1 activation transiently blocks cell division to prevent segregation of damaged organelles or chromosomes (Degols et al, 1996;Hartmuth and Petersen, 2009). To allow for cells to adapt following stress and for cell division to resume, Sty1 is negatively regulated by deactivating phosphatases (Millar et al, 1995;Shiozaki and Russell, 1995a;Shiozaki and Russell, 1995b).…”