The N-terminus of S6K1 and the C-terminus of 4EBP1 contain a consensus sequence of approximately five amino acid residues called the TOR signaling (TOS) motif that binds to RAPTOR. RAPTOR physically interacts with an AGC-family kinase known as ribosomal protein S6 kinase 1 (S6K1, also known as RPS6KB1), as well as eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4EBP1, also known as EIF4EBP1), two of the best-characterized mTORC1 substrates ( Hara et al., 2002 Nojima et al., 2003). mTORC1 has been proposed to recruit its substrates through the mTORC1-specific subunit RAPTOR. Accumulating evidence indicates that deregulated activation of mTORC1 is associated with a variety of human diseases, including cancers, diabetes and neurodegenerative disorders ( Laplante and Sabatini, 2012 Saxton and Sabatini, 2017 Zoncu et al., 2011).Īs the mTOR kinase serves as a catalytic subunit in both mTORC1 and mTORC2, the distinct substrate specificities of the two complexes are likely to be determined by the regulatory subunits unique to each complex. Mammalian TORC1 (mTORC1), whose regulatory subunits include RAPTOR (also known as RPTOR) ( Hara et al., 2002 Kim et al., 2002) and mLST8 ( Kim et al., 2003), promotes protein synthesis and other anabolic processes, while suppressing cellular catabolic processes such as autophagy. TOR forms two distinct multi-subunit complexes termed TOR complex 1 (TORC1) and TOR complex 2 (TORC2), each of which phosphorylates specific sets of cellular substrates in response to diverse stimuli, such as nutrients and growth factors ( Laplante and Sabatini, 2012 Saxton and Sabatini, 2017 Zoncu et al., 2011). The target of rapamycin (TOR) kinase, a member of the phosphoinositide 3-kinase-related kinase (PIKK) family, is highly conserved among diverse eukaryotes as a master regulator of cell growth and metabolism ( Soulard et al., 2009 Wullschleger et al., 2006). These results strongly suggest that the TOS motif represents an evolutionarily conserved mechanism of the substrate recognition by TORC1. 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. 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. The TOS motif in Psk1 resembles those in mammals, including the conserved phenylalanine and aspartic acid residues essential for the Mip1 interaction and TORC1-dependent phosphorylation of Psk1. In the present study, we show that the fission yeast S6 kinase Psk1 contains a TOS motif that interacts with Mip1, a RAPTOR ortholog. Despite the evolutionary conservation of TORC1, no TOS motif has been described in lower eukaryotes. The regulatory subunits of mammalian TORC1 (mTORC1) include RAPTOR (also known as RPTOR), which recruits mTORC1 substrates, such as S6K1 (also known as RPS6KB1) and 4EBP1 (EIF4EBP1), by interacting with their TOR signaling (TOS) motif. Sveiczer A, Tyson JJ, Novak B (2004) Modelling the fission yeast cell cycle.TOR complex 1 (TORC1) is a multi-subunit protein kinase complex that controls cellular growth in response to environmental cues. Sveiczer A, Novak B, Mitchison JM (1996) The size control of fission yeast revisited. Nishitani H, Nurse P (1995) p65 cdc18 plays a major role controlling the initiation of DNA replication in fission yeast. Mitchison JM, Nurse P (1985) Growth in cell length in the fission yeast Schizosaccharomyces pombe. Mitchison JM (1990) The fission yeast, Schizosaccharomyces pombe. In: Nasim A, Young P, Johnson BF (eds) Molecular biology of the fission yeast. Mitchison JM (1989) Cell cycle growth and periodicities. Oxford University Press, Oxford, pp 63–105 In: Hutchison C, Glover DM (eds) Cell cycle control. MacNeill SA, Fantes PA (1995) Controlling entry into mitosis in fission yeast. MacNeill SA (2002) Genome sequencing: and then there were six. Hayles J, Fisher D, Woolard A, Nurse P (1994) Temporal order of S-phase and mitosis in fission yeast is determined by the state of the p34 cdc2/mitotic B cyclin complex.
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