scholarly journals Fission yeast TOR complex 1 phosphorylates Psk1 through evolutionarily conserved interaction mediated by the TOS motif

2021 ◽  
Author(s):  
Yuichi Morozumi ◽  
Ai Hishinuma ◽  
Suguru Furusawa ◽  
Fajar Sofyantoro ◽  
Hisashi Tatebe ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Fission Yeast ◽  
Substrate Recognition ◽  
Evolutionary Conservation ◽  
Cellular Growth ◽  
Environmental Cues ◽  
Tor Signaling ◽  
S6 Kinase ◽  
Regulatory Subunits ◽  
Evolutionarily Conserved

TOR complex 1 (TORC1) is a multi-subunit protein kinase complex that controls cellular growth in response to environmental cues. The regulatory subunits of mammalian TORC1 (mTORC1) include RAPTOR, which recruits mTORC1 substrates, such as S6K1 and 4EBP1, by interacting with their TOR signaling (TOS) motif. Despite the evolutionary conservation of TORC1, no TOS motif has been described in lower eukaryotes. Here, we show that the fission yeast S6 kinase Psk1 contains a TOS motif that interacts with Mip1, a RAPTOR ortholog. The TOS motif in Psk1 resembles those in mammals, including the conserved Phe and Asp residues essential for the Mip1 interaction and TORC1-dependent phosphorylation of Psk1. The binding of the TOS motif to Mip1 is dependent on Mip1 Tyr-533, whose equivalent in RAPTOR is known to interact with the TOS motif in their co-crystals. Furthermore, we utilized the mip1-Y533A mutation to screen the known TORC1 substrates in fission yeast and successfully identified Atg13 as a novel TOS motif-containing substrate. These results strongly suggest that the TOS motif represents an evolutionarily conserved mechanism of the substrate recognition by TORC1.

scholarly journals Structural Insights into TOR Signaling

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 885
Author(s):  
Lucas Tafur ◽  
Jennifer Kefauver ◽  
Robbie Loewith
Keyword(s):  
Electron Microscopy ◽  
Protein Kinase ◽  
Molecular Biology ◽  
Cellular Responses ◽  
Therapeutic Strategies ◽  
Cellular Growth ◽  
Tor Signaling ◽  
Cellular Homeostasis ◽  
Cryo Electron Microscopy ◽  
Structural Insights

The Target of Rapamycin (TOR) is a highly conserved serine/threonine protein kinase that performs essential roles in the control of cellular growth and metabolism. TOR acts in two distinct multiprotein complexes, TORC1 and TORC2 (mTORC1 and mTORC2 in humans), which maintain different aspects of cellular homeostasis and orchestrate the cellular responses to diverse environmental challenges. Interest in understanding TOR signaling is further motivated by observations that link aberrant TOR signaling to a variety of diseases, ranging from epilepsy to cancer. In the last few years, driven in large part by recent advances in cryo-electron microscopy, there has been an explosion of available structures of (m)TORC1 and its regulators, as well as several (m)TORC2 structures, derived from both yeast and mammals. In this review, we highlight and summarize the main findings from these reports and discuss both the fascinating and unexpected molecular biology revealed and how this knowledge will potentially contribute to new therapeutic strategies to manipulate signaling through these clinically relevant pathways.

scholarly journals Genotype and Trait Specific Responses to Rapamycin Intake in Drosophila melanogaster

Insects ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 474
Author(s):  
Palle Duun Rohde ◽  
Asbjørn Bøcker ◽  
Caroline Amalie Bastholm Jensen ◽  
Anne Louise Bergstrøm ◽  
Morten Ib Juul Madsen ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Heat Stress ◽  
Side Effects ◽  
Protein Kinase ◽  
Stress Tolerance ◽  
Treated Group ◽  
Model System ◽  
Treatment Efficiency ◽  
Evolutionarily Conserved ◽  
Heat Stress Tolerance

Rapamycin is a powerful inhibitor of the TOR (Target of Rapamycin) pathway, which is an evolutionarily conserved protein kinase, that plays a central role in plants and animals. Rapamycin is used globally as an immunosuppressant and as an anti-aging medicine. Despite widespread use, treatment efficiency varies considerably across patients, and little is known about potential side effects. Here we seek to investigate the effects of rapamycin by using Drosophila melanogaster as model system. Six isogenic D. melanogaster lines were assessed for their fecundity, male longevity and male heat stress tolerance with or without rapamycin treatment. The results showed increased longevity and heat stress tolerance for male flies treated with rapamycin. Conversely, the fecundity of rapamycin-exposed individuals was lower than for flies from the non-treated group, suggesting unwanted side effects of the drug in D. melanogaster. We found strong evidence for genotype-by-treatment interactions suggesting that a ‘one size fits all’ approach when it comes to treatment with rapamycin is not recommendable. The beneficial responses to rapamycin exposure for stress tolerance and longevity are in agreement with previous findings, however, the unexpected effects on reproduction are worrying and need further investigation and question common believes that rapamycin constitutes a harmless drug.

Role of PRAS40 in Akt and mTOR signaling in health and disease

2012 ◽  
Vol 302 (12) ◽  
pp. E1453-E1460 ◽  
Author(s):  
Claudia Wiza ◽  
Emmani B. M. Nascimento ◽  
D. Margriet Ouwens
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Cellular Growth ◽  
S6 Kinase ◽  
Binding Partners ◽  
Health And Disease ◽  
Mtor Complex 1 ◽  
Mtor Activity

The proline-rich Akt substrate of 40 kDa (PRAS40) acts at the intersection of the Akt- and mammalian target of rapamycin (mTOR)-mediated signaling pathways. The protein kinase mTOR is the catalytic subunit of two distinct signaling complexes, mTOR complex 1 (mTORC1) and mTORC2, that link energy and nutrients to the regulation of cellular growth and energy metabolism. Activation of mTOR in response to nutrients and growth factors results in the phosphorylation of numerous substrates, including the phosphorylations of S6 kinase by mTORC1 and Akt by mTORC2. Alterations in Akt and mTOR activity have been linked to the progression of multiple diseases such as cancer and type 2 diabetes. Although PRAS40 was first reported as substrate for Akt, investigations toward mTOR-binding partners subsequently identified PRAS40 as both component and substrate of mTORC1. Phosphorylation of PRAS40 by Akt and by mTORC1 itself results in dissociation of PRAS40 from mTORC1 and may relieve an inhibitory constraint on mTORC1 activity. Adding to the complexity is that gene silencing studies indicate that PRAS40 is also necessary for the activity of the mTORC1 complex. This review summarizes the regulation and potential function(s) of PRAS40 in the complex Akt- and mTOR-signaling network in health and disease.

Sign in / Sign up

Export Citation Format

Share Document