Nutrient signals driving cell growth

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Regulation of cell growth in response to nutrients is crucial for the survival of all organisms. In yeast, cell growth and division require two signaling pathways, TORC1 and PKA. Activation of these pathways crucially depends on intracellular metabolic signals, but the mechanisms remain elusive. Recent studies have identified potential activators of TORC1 and have highlighted a crucial role for the endomembrane system. Moreover, calcium was recognized as an important second messenger for TORC1 activation in response to amino acid levels. On the contrary, genetic analysis indicates that PKA activation depends on an intracellular glucose metabolite. Together with novel quantitative approaches, these findings provide important groundwork in our understanding of the molecular mechanisms for nutrient sensing in yeast and humans.

Introduction

Cell growth and division must be intimately linked and regulated in response to the environment and nutrient availability. Thus, cells need to constantly monitor the availability of nutrients and adjust cell growth and proliferation accordingly. In addition, these nutritional signals have to be integrated with hormonal signals derived from growth factors [1], which are secreted by specialized cell types in response to nutritional cues and serve to coordinate cell growth at the organismal level [2].

Indeed, much of our understanding of the regulation of cell growth stems from genetic analysis of growth factor signaling in animal systems [2], which identified conserved signaling pathways including the kinases TOR (target of rapamycin) and AMPK (AMP-activated kinase) [1]. However, much less is known about how nutrients are sensed, how nutrient-derived signals regulate cell growth and how these nutritional signals are integrated with growth factor pathways in higher eukaryotes.

As the important kinases and signaling pathways implicated in growth control are well conserved in budding yeast [3, 4], this simple eukaryote offers a powerful opportunity to study mechanisms of nutrient sensing. It is likely that the elucidation of the fundamental mechanisms governing growth control in model systems will significantly contribute to our understanding of complex metabolic diseases in humans.

Section snippets

Nutrient-regulated pathways in S. cerevisiae

Limitation of nutrients evokes a complex change in the physiology of yeast cells, which allows them to either reprogramme their metabolism such that they can cope with the change in nutrient supply or activate a survival programme to outlive sustained periods of starvation [3, 5]. This survival programme, which can also be termed ‘starvation response’, is centred on profound changes in cellular metabolism and reduction of energy consuming processes, such as protein synthesis. It includes the

Regulation of TORC1 by GTPases

TOR is a highly conserved protein kinase found in two functionally distinct protein complexes, TORC1 and TORC2 [12]. While TORC1 drives cell growth through its effects on protein synthesis and cellular metabolism, TORC2 functions mainly in the organization of the actin cytoskeleton. Similarly, rapamycin treatment results in inactivation of TORC1, but not TORC2 [12]. The mechanisms regulating TORC2 are still poorly understood, but do not appear to be directly connected to nutrient levels [4] and

Regulation of TORC1 by the endomembrane system

In budding yeast, TOR is encoded by two partially redundant genes, TOR1 and TOR2, and both genes contribute to TORC1 function. By contrast, only Tor2p is part of TORC2 [12]. Thus, cells deleted for TOR1 are viable, but have impaired TORC1 activity, which allows for easy genetic screenings for positive regulators of TORC1. A comprehensive synthetic lethal screening has identified a large set of putative regulators of TORC1, including the EGO complex [24•]. Many candidate genes emanating from the

Metabolic input into TORC1

Although multiple pathways contribute to TORC1 activation in yeast and mammals, it remains a matter of debate that which specific amino acids regulate TORC1. Unlike yeast, mammalian cells cannot synthesize all amino acids de novo, and thus, these amino acids may become limiting upon starvation. Indeed, numerous studies have highlighted a specific role for the essential amino acid leucine, and other branched chain amino acids, in the activation of cell growth in mammalian cells. For example,

Upstream regulators of PKA

The other essential pathway driving cell growth in yeast, the PKA pathway, assumes an important role in glucose signaling. In this organism, PKA is essential for viability and regulates multiple processes including progression through G1 [10, 36], and partly acts through regulation of two transcription factors, Msn2p and Msn4p, via regulation of their localization and activity [37, 38, 39]. In addition, PKA has multiple targets in metabolism and is a crucial regulator of ribosome biogenesis [36

Metabolic input into Ras/PKA

Consistent with a role of glucose metabolism in the activation of Ras/PKA, mutants in a gene encoding for pyruvate kinase, CDC19, the RasGEF, CDC25, and adenylate cyclase, CDC35, (Figure 3) have been isolated in the original screen for cell cycle mutants and have been placed into the same phenotypic category. These mutants are characterized by a defect in both cell growth and proliferation and arrest as small cells in early G1 [53, 54]. Thus, Cdc19p might activate the Ras/PKA pathway to promote

Conservation of glucose mediated activation of Ras/PKA

While the regulation of TORC1 seems to underlie the same principles in yeast and mammalian cells, the direct application of data on yeast PKA regulation to higher model organisms is complicated by two facts. First, in most animal cells, PKA is mainly activated through adenylate cyclases functioning downstream of hormonally regulated GPCRs [60], which however have not been linked to small G-proteins of the Ras family. Rather, Ras G-proteins function upstream of mitogen-activated protein kinases

Complementary approaches to nutrient signaling

To understand the activation of TORC1 and PKA by metabolic signals, we have so far only considered genetic and cell-biological approaches focusing on the understanding of the underlying signaling pathways. Ultimately, however, it will be necessary to determine changes in metabolism and signal transduction during starvation and nutrient replete conditions at the same time scale. Modern analytic methods allow the determination of >100 metabolites simultaneously [68] and provide invaluable

Conclusions

In the past years, we have witnessed a tremendous increase in our knowledge of the control of cell growth in response to nutrients. Yet, mechanisms of nutrient sensing are only beginning to emerge. In yeast and mammalian cells, similar principles seem to operate that drive cell growth and proliferation in response to nutrients. With the establishment of robust tools for metabolic analysis, it should now be possible to combine genetic analysis of signaling pathways with a quantitative

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors would like to thank Dirk Müller, Christoph Schüller, Matthias Heinemann and members of the Peter lab for the critical reading of the manuscript and helpful discussions. We are grateful to Steven Zheng for communicating unpublished data and apologize to many colleagues whose work could not be cited owing to space limitations. Work in the Peter Lab is supported by the Competence Center for Systems Physiology and Metabolic Disease (CC-SPMD), the EU projects QUASI and UNICELLSYS, the

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