Cells of all living organisms contain complex signal transduction networks to ensure that a wide range of physiological properties are properly adapted to the environmental conditions. The fundamental concepts and individual building blocks of these signalling networks are generally well-conserved from yeast to man; yet, the central role that growth factors and hormones play in the regulation of signalling cascades in higher eukaryotes is executed by nutrients in yeast. Several nutrient-controlled pathways, which regulate cell growth and proliferation, metabolism and stress resistance, have been defined in yeast. These pathways are integrated into a signalling network, which ensures that yeast cells enter a quiescent, resting phase (G 0 ) to survive periods of nutrient scarceness and that they rapidly resume growth and cell proliferation when nutrient conditions become favourable again. A series of well-conserved nutrient-sensory protein kinases perform key roles in this signalling network: i.e. Snf1, PKA, Tor1 and Tor2, Sch9 and Pho85-Pho80. In this review, we provide a comprehensive overview on the current understanding of the signalling processes mediated via these kinases with a particular focus on how these individual pathways converge to signalling networks that ultimately ensure the dynamic translation of extracellular nutrient signals into appropriate physiological responses.

Sphingolipids play crucial roles in the determination of growth and survival of eukaryotic cells. The budding yeast protein kinase Sch9 is not only an effector, but also a regulator of sphingolipid metabolism. This new function provides a crucial link between nutrient and sphingolipid signaling.

When starved of P(i), yeast cells activate the PHO signalling pathway, wherein the Pho4 transcription factor mediates expression of genes involved in P(i) acquisition, such as PHO84, encoding the high-affinity H(+)/P(i) symporter. In contrast, transcription of PHO87 and PHO90, encoding the low-affinity H(+)/P(i) transport system, is independent of phosphate status. In the present work, we reveal that, upon P(i) starvation, these low-affinity P(i) transporters are endocytosed and targeted to the vacuole. For Pho87, this process strictly depends on SPL2, another Pho4-dependent gene that encodes a protein known to interact with the N-terminal SPX domain of the transporter. In contrast, the vacuolar targeting of Pho90 upon Pi starvation is independent of both Pho4 and Spl2, although it still requires its SPX domain. Furthermore, both Pho87 and Pho90 are also targeted to the vacuole upon carbon-source starvation or upon treatment with rapamycin, which mimics nitrogen starvation, but although these responses are independent of PHO pathway signalling, they again require the N-terminal SPX domain of the transporters. These observations suggest that other SPX-interacting proteins must be involved. In addition, we show that Pho90 is the most important P(i) transporter under high P(i) conditions in the absence of a high-affinity P(i)-transport system. Taken together, our results illustrate that Pho87 and Pho90 represent non-redundant P(i) transporters, which are tuned by the integration of multiple nutrient signalling mechanisms in order to adjust P(i)-transport capacity to the general nutritional status of the environment.

The protein kinase Sch9 is proposed to be a downstream effector of TORC1 that is required for activation of ribosome biogenesis and repression of entry into G(0). However, Sch9 apparently functions antagonistically to TORC1, when considering the induction of several stress defence genes that are normally repressed by TORC1. To further investigate the relationship between Sch9 and TORC1, we compared the rapamycin-induced transcriptional responses in an sch9Delta mutant and the isogenic wild type. The data indicate that Sch9 is necessary for proper integration of the rapamycin-induced stress signal, i.e. in sch9Delta cells, typical effects of rapamycin-like repression of ribosomal protein genes and induction of stress response genes are diminished or abolished. Moreover, they reveal for the first time a direct link between Sch9 and nitrogen metabolism. A sch9Delta mutant has an increased basal activation of targets of the general amino acid control pathway and of the nitrogen discrimination pathway, including the ammonium permease MEP2 and the amino acid permease GAP1. The mutant also shows enhanced expression of the transcription factor Gcn4 required for amino acid biosynthesis. Our data favour a model in which (1) the role of Sch9 in the general stress response switches depending on TORC1 activity and (2) Sch9 and TORC1 have independent and additive effects on genes induced upon nitrogen and amino acid starvation.

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