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Curr Opin Microbiol. Author manuscript; available in PMC Dec 1, 2012.
Published in final edited form as:
PMCID: PMC3230781
Pleiotropic Signaling Pathways Orchestrate Yeast Development
Joshua A. Granek,a Ömür Kayıkçı,a and Paul M. Magwenecorresponding authora
aDepartment of Biology and IGSP Center for Systems Biology, Duke University, Box 90338, Durham, NC 27708, USA
corresponding authorCorresponding author.
Developmental phenotypes in Saccharomyces cerevisiae and related yeasts include responses such as filamentous growth, sporulation, and the formation of biofilms and complex colonies. These developmental phenotypes are regulated by evolutionarily conserved, nutrient-responsive signaling networks. The signaling mechanisms that control development in yeast are highly pleiotropic – all of the known pathways contribute to the regulation of multiple developmental outcomes. This degree of pleiotropy implies that perturbations of these signaling pathways, whether genetic, biochemical or environmentally induced, can manifest in multiple (and sometimes unexpected) ways. We summarize the current state of knowledge of developmental pleiotropy in yeast and discuss its implications for understanding functional relationships.
Keywords: pleiotropy, gene networks, tradeoffs, developmental switches
In response to stress, the baker’s yeast Saccharomyces cerevisiae and related fungi undergo a variety of developmental switches. These developmental switches include transitions to filamentous growth [1], changes in interactions between cells that lead to biofilms [2] and architecturally complex colonies [3, 4], or the induction of meiosis and sporulation [5]. These responses are induced by signals that act through a variety of signaling pathways, all of which regulate multiple developmental phenotypes. In this review, we emphasize the pleiotropic nature of developmental pathways in yeast. We consider the implications of pleiotropy for understanding functional relationships among developmental responses and discuss the ecological, industrial, and clinical implications of developmental pleiotropy.
Filamentous growth
Filamentous growth refers to both diploid pseudohyphal growth and haploid invasive growth, both of which are induced by nutrient limitation. Pseudohyphal growth is primarily induced by nitrogen starvation [6], although several reports demonstrate a secondary role for carbon type and quality in its regulation (Figure 1B) [7, 8, 9]. The pseudohyphal response is characterized by a switch from bipolar to unipolar budding, incomplete mother-daughter cell separation, and cell elongation. These characteristics result in branching chains of cells that give the margins of pseudohyphal colonies a characteristic “fuzzy” appearance (Figure 1A). Haploid invasive growth [10] is primarily triggered by glucose limitation [11] and involves a switch from axial to bipolar budding. Substrate invasion is common to both responses. Filamentous growth is of medical interest because these phenotypes contribute to virulence in both S. cerevisiae [12] and related fungal pathogens such as Candida albicans.
Figure 1
Figure 1
Developmental pathways in Saccharomyces cerevisiae. Yeast cells detect and transduce information on nutrients and pH through the combined action of the cAMP-PKA, SNF1/AMPK, TOR, Kss1-MAPK, and Rim101 pathways. The networks on the left (A,C,E) depict the (more ...)
Complex colony morphology and biofilms
Complex colony morphology is another form of mitotic growth that is characterized by intricate, organized, and strain-specific patterns of colony growth and architecture (Figure 1D) [13, 4]. The switch from smooth, simple colonies to the formation of complex colonies is reliably induced by a combination of limited fermentable carbon with rich nitrogen (Figure 1C) [4].
There is mounting evidence that complex colonies are a form of biofilm [3]. Biofilms are emergent microbial communities that provide benefits to their constituents, including cooperative metabolism, and protection from biotic and abiotic stresses [14, 15]. Microbial biofilms are a concern for human health and human infrastructure because of their tendency to form on solid surfaces and their resistance to conventional antimicrobial treatments [16, 17].
Severe limitation of both nitrogen and fermentable carbon sources can induce diploid cells to sporulate (Figure 1E) [18]. In addition to nutrient availability, sporulation is also sensitive to pH [19]. During sporulation, cells exit vegetative growth and undergo meiosis. Spores, the haploid products of meiosis, are encased in thick cell walls and are packaged into a structure called an ascus (Figure 1F) [20]. Spores are highly resistant to a variety of environmental insults, including temperature extremes, desiccation, and the absence of nutrients.
Genetic and biochemical studies have identified five major signaling pathways [21] that are involved in nutrient-induced developmental responses in yeast: 1) the cAMP-PKA pathway; 2) the TOR pathway; 3) the SNF1/AMPK pathway; 4) the Rim101 pathway; and 5) the Kss1-MAPK pathway. As we discuss below, all of these pathways have known or predicted pleiotropic effects on at least two (and in some cases all three) developmental phenotypes.
The cAMP-PKA pathway
The cAMP-PKA signaling pathway is a prime regulator of metabolism, cell differentiation, and development in animals, fungi, and amoebae. The basic structure and signaling logic of the pathway is highly conserved [22]. In S. cerevisiae, cAMP-PKA activity is correlated with the availability and quality of carbon sources [23, 24]. When glucose is ample, cAMP-PKA signaling promotes cell cycle progression, ribosome biogenesis, and mass accumulation. Simultaneously, cAMP-PKA signaling downregulates stress responses, such as autophagy [25].
cAMP-PKA signaling is required for pseudohyphal growth [26, 27] and complex colony morphology [28, 4], and therefore is positively pleiotropic with respect to these phenotypes. Conversely, increased cAMP-PKA pathway activity inhibits sporulation [5, 29, 30], and thus is antagonistically pleiotropic for sporulation relative to the aforementioned responses.
TOR signaling
TOR (Target of Rapamycin) signaling regulates temporal and spatial aspects of cell growth, primarily in response to nitrogen availability, although carbon likely plays a role [31, 32]. The regulation of growth related activities by TOR runs parallel to cAMP-PKA signaling, and the interactions of these pathways govern cellular growth and proliferation [33, 34, 35]. TOR signaling involves two functionally distinct, yet structurally overlapping complexes: TOR Complex 1 (TORC1) and TOR Complex 2 (TORC2) [31]. The rapamycin-sensitive TORC1 facilitates mass accumulation by upregulating protein synthesis through ribosome biogenesis, translation initiation, and elongation [36, 37]. TORC1 antagonizes stress-induced processes, such as Nitrogen Catabolite Repression (NCR), the mitochondrial retrograde response (RTG) pathway, and autophagy [38, 25, 39]. The rapamycin-insensitive TORC2 contributes to the regulation of cell polarity through actin polymerization [40].
Both treatment with rapamycin and loss-of-function mutations in TOR pathway genes result in decreased pseudohyphal growth [41]. In contrast, cells treated with rapamycin show increased sporulation efficiency [42], possibly via induced changes in the stability and localization of the transcriptional activator Ime1, a key regulator of meiosis and sporulation [43]. Thus, the TOR pathway exhibits antagonistic pleiotropy with respect to pseudohyphal growth and sporulation. A direct role for TOR signaling in S. cerevisiae colony morphology has not been demonstrated, although we predict that this pathway contributes positively to the complex colony response based on the phenotype’s sensitivity to elevated nitrogen levels [4]. Thus, like the cAMP-PKA pathway, the TOR pathway exhibits both positive and antagonistic pleiotropy on developmental traits.
SNF1/AMPK pathway
In eukaryotes, Snf1/AMPK signaling is a central mediator of carbon metabolism through its effects on gene expression and metabolic enzyme activities [44, 45]. Snf1/AMPK functions as a metabolic switch that represses anabolic reactions and promotes catabolism. Under poor conditions, Snf1/AMPK helps maintain energy balance and cell growth by negatively regulating costly processes such as protein and phospholipid biosynthesis [44]. In parallel, it generates cellular energy by triggering the uptake and metabolism of alternative carbon sources, fatty-acid breakdown, and organelle recycling through autophagy [9].
SNF1 signaling is required for both sporulation [46, 47] and filamentous growth on non-glucose carbon sources [9]. Recent work in our lab (unpublished studies) also implicates SNF1 signaling in the regulation of colony morphology. Thus the effects of the SNF1 pathway on all three phenotypes appear to be largely positively pleiotropic.
Rim101 pathway
Alkaline conditions, which can interfere with nutrient acquisition and homeostasis, induce the activation of the Rim101/PacC pathway [48]. Lamb et al. [49] showed that Rim101 signaling is required for both sporulation and haploid invasive growth. Piccirillo et al. [50] recently reported that structured patterns of differentiation within colonies are also driven by Rim101 signaling. Rim101 represses the transcription factor Nrg1, a negative regulator of glucose-repressed genes. Nrg1’s targets include FLO11 [51], a gene that encodes a key cell surface protein required for invasive and pseudohyphal growth [52]. Lamb and Mitchell [51] also identified Smp1 as a target of Rim101. Smp1 is a transcription factor of unknown function, and smp1 mutants suppress rim101 defects in invasive growth and sporulation and restore rough colony morphology. Thus, like the SNF1 pathway, Rim101 signaling is positively pleiotropic with respect to all three developmental responses in S. cerevisiae.
Kss1-MAPK pathway
MAPK (Mitogen Activated Protein Kinase) signaling mechanisms regulate cell survival and death under adverse conditions, including nutrient deprivation [53]. In S. cerevisiae, nutrient depletion activates the Kss1-MAPK pathway. The Ras2-Cdc42 complex activates Ste20 (MAPKKKK), which in turn triggers a phosphorylation cascade involving Ste11 (MAPKKK) and Ste7 (MAPKK), both of which are shared with the pheromoneresponsive Fus3-MAPK module [54]. Ste7, in turn, activates Kss1 (MAPK), whose kinase activity regulates a variety of transcription factors important for developmental responses [55].
The Kss1-MAPK pathway affects both pseudohyphal growth [55] and the formation of complex colonies and biofilms [56, 4], although it has no reported effects on sporulation. Cullen and colleagues [57] recently presented evidence that many of the signaling pathways described above contribute to the regulation of the Kss1-MAPK pathway.
Combinatorial patterns of pathway activity regulate yeast development
If almost every one of the key signaling pathways regulates multiple developmental phenotypes, often in the same direction, how then do yeast mount appropriate responses in the face of particular nutrient challenges? The answer almost surely lies in combinatorial pathway interactions. The joint effects of multiple signaling pathways and their relative activities are key features of the cellular decision making that leads to different developmental fates in yeast [58]. Recent studies have used both experimental and computational methods to understand the roles of different pathways in transducing the nutrient signals that control developmental outputs [59, 60, 61].
Correlations between developmental traits are the default expectation
Given the predominance of pleiotropy in key signaling networks, correlated phenotypic responses are the default expectation for genetic or chemical manipulations of pathway function. For example, mutations and drugs that decrease cAMP-PKA signaling activity are known to enhance sporulation while simultaneously repressing pseudohyphal growth (a negative correlation) [27]. Similarly, mutations that upregulate Rim101 signaling are expected to positively affect sporulation, haploid invasive growth, and the formation of complex colonies (positive correlations) [51]. Simultaneously assaying multiple phenotypes to probe the state of several signaling pathways has the potential to provide a very sensitive readout of pathway interactions. We suggest that violations of expected pleiotropic relationships (e.g. [62]) may be useful for identifying parts of networks where feedback, conditional interactions, and complex epistasis are particularly important.
Pleiotropic interactions and phenotypic variability
With the ubiquity of pleiotropic effects, one question of interest is how these pleiotropic interactions impact standing patterns of phenotypic variation among S. cerevisiae lineages. For example, our lab recently demonstrated a tradeoff between sporulation efficiency and pseudohyphal growth in S. cerevisiae [63]. The mechanistic basis of this tradeoff is likely attributable to naturally segregating variation that affects one or more of the pleiotropic pathways discussed above. Similarly, Sicard and colleagues have documented a life history tradeoff in S. cerevisiae related to resource utilization [64, 65]. We predict that variation in nutrient responsive signaling pathways may underlie this tradeoff as well.
Pleiotropy and aging
Antagonistic pleiotropy involving tradeoffs between reproduction and senescence is one of the predominant hypotheses explaining why organisms age [66]. Caloric restriction and general nutrient stress extend lifespan in both microbes and multicellular eukaryotes [67, 68]. Because yeast developmental responses involve nutrient limitation, an intriguing question is the extent to which lifespan (either chronological or replicative) is correlated with one or more of the developmental processes under consideration. Complex morphology is of particular interest because low dextrose media, the most reliable inducer of complex morphology, is calorie restricted and has been shown to extend lifespan in S. cerevisiae. Furthermore, key pathways like TOR and SNF1 are implicated in both lifespan and induction of colony morphology.
Industrial and clinical considerations
Signaling pathways that control fungal morphogenesis have been proposed to be good targets for antifungal drugs [1, 69]. For example, drugs that inhibit cAMP-PKA or TOR signaling should lead to decreased pseudohyphal and invasive growth. However, because of pleiotropic pathway effects, such drugs might also lead to greater stress resistance or induce sporulation, potentially allowing virulent cells to persist. This suggests that effective treatments might require a combination of therapies that target multiple pathways simultaneously in order to minimize “escape” due to pleiotropy. Similar considerations should be made in genetic engineering or artificial selection experiments for industrial applications. For example, selection for phenotypes such as velum formation, a biofilm-like response of interest in wine production [70, 71], is likely to also select for mutations that favor pseudohyphal and invasive growth thereby creating a greater risk for opportunistic pathogenicity.
Yeast, like most microbes, make developmental decisions in response to nutrient cues. Most investigations aimed at understanding the mechanisms that regulate developmental switches in S. cerevisiae have focused on single developmental outcomes, without considering the potential for parallel responses in other phenotypes. As we have outlined above, the gene networks that regulate development in yeast are highly pleiotropic, and thus correlated changes in developmental responses are likely to be common when such networks are perturbed by genetic or biochemical means. Future studies should employ multi-trait approaches and consider development switches not as a set of individual outcomes but rather as a spectrum of related responses. Such work will lead to new insights regarding the structure, function, and evolution of developmental signaling networks in yeast.
  • > 
    Nutrient stress induces developmental switches in Saccharomyces cerevisiae (baker's yeast) and related fungi.
  • > 
    The signaling pathways that control development are highly pleoiotropic.
  • > 
    Because of signaling pathway pleiotropy, developmental phenotypes can be strongly correlated.
  • > 
    Pleiotropy can be exploited in functional studies to discover or understand interactions within and between signaling pathways.
  • > 
    Understanding the causes and consequences of pleiotropy is important in ecological, clinical, and agricultural contexts.
We thank Jennifer Reininga and Debra Murray for helpful comments on this manuscript. This work was supported in part by the NIH(P50GM081883-01) and NSF (MCB-0614959).
1. Pan X, Harashima T, Heitman J. Signal transduction cascades regulating pseudohyphal differentiation of Saccharomyces cerevisiae. Curr Opin Microbiol. 2000;3:567–572. [PubMed]
2. Smukalla S, Caldara M, Pochet N, Beauvais A, Guadagnini S, Yan C, Vinces MD, Jansen A, Prevost MC, Latgé JP, et al. FLO1 is a variable green beard gene that drives biofilm-like cooperation in budding yeast. Cell. 2008;135:726–737. [PubMed] ** Demonstrates that Flo1, a flocculin, drives social behavior in yeast through flocculation, providing resistance to environmental stresses to participants in flocs.
3. Stovícek V, Váchová L, Kuthan M, Palková Z. General factors important for the formation of structured biofilm-like yeast colonies. Fungal Genet Biol. 2010;47:1012–1022. [PubMed]
4. Granek JA, Magwene PM. Environmental and genetic determinants of colony morphology in yeast. PLoS Genet. 2010;6 e1000823. [PMC free article] [PubMed]
5. Honigberg SM, Purnapatre K. Signal pathway integration in the switch from the mitotic cell cycle to meiosis in yeast. J Cell Sci. 2003;116:2137–2147. [PubMed]
6. Gimeno CJ, Ljungdahl PO, Styles CA, Fink GR. Unipolar cell divisions in the yeast S. cerevisiae lead to filamentous growth: regulation by starvation and RAS. Cell. 1992;68:1077–1090. [PubMed]
7. Kuchin S, Vyas VK, Carlson M. Snf1 protein kinase and the repressors Nrg1 and Nrg2 regulate FLO11, haploid invasive growth, and diploid pseudohyphal differentiation. Mol Cell Biol. 2002;22:3994–4000. [PMC free article] [PubMed]
8. Lambrechts MG, Bauer FF, Marmur J, Pretorius IS. Muc1, a mucin-like protein that is regulated by Mss10, is critical for pseudohyphal differentiation in yeast. Proc Natl Acad Sci USA. 1996;93:8419–8424. [PubMed]
9. Van de Velde S, Thevelein JM. Cyclic AMP-protein kinase A and Snf1 signaling mechanisms underlie the superior potency of sucrose for induction of filamentation in Saccharomyces cerevisiae. Eukaryot Cell. 2008;7:286–293. [PMC free article] [PubMed]
10. Roberts RL, Fink GR. Elements of a single MAP kinase cascade in Saccharomyces cerevisiae mediate two developmental programs in the same cell type: mating and invasive growth. Genes Dev. 1994;8:2974–2985. [PubMed]
11. Cullen PJ, Sprague GF. Glucose depletion causes haploid invasive growth in yeast. Proc Natl Acad Sci USA. 2000;97:13619–13624. [PubMed]
12. McCusker JH, Clemons KV, Stevens DA, Davis RW. Saccharomyces cerevisiae virulence phenotype as determined with CD-1 mice is associated with the ability to grow at 42 degrees C and form pseudohyphae. Infect Immun. 1994;62:5447–5455. [PMC free article] [PubMed]
13. Palková Z, Váchová L Life within a community: benefit to yeast long-term survival. FEMS Microbiol Rev. 2006;30:806–824. [PubMed] * Reviews the evidence that yeast are communal microbes, and discusses the multicellular behaviors exhibited by yeast living in communities.
14. Hall-Stoodley L, Costerton JW, Stoodley P. Bacterial biofilms: from the natural environment to infectious diseases. Nat Rev Microbiol. 2004;2:95–108. [PubMed]
15. Schink B. Energetics of syntrophic cooperation in methanogenic degradation. Microbiol Mol Biol Rev. 1997;61:262–280. [PMC free article] [PubMed]
16. Hall-Stoodley L, Stoodley P. Evolving concepts in biofilm infections. Cell Microbiol. 2009;11:1034–1043. [PubMed]
17. Coenye T, Nelis HJ. In vitro and in vivo model systems to study microbial biofilm formation. J Microbiol Meth. 2010;83:89–105. [PubMed]
18. Kassir Y, Adir N, Boger-Nadjar E, Raviv NG, Rubin-Bejerano I, Sagee S, Shenhar G. Transcriptional regulation of meiosis in budding yeast. Int Rev Cytol. 2003;224:111–171. [PubMed]
19. Ohkuni K, Hayashi M, Yamashita I. Bicarbonate-mediated social communication stimulates meiosis and sporulation of Saccharomyces cerevisiae. Yeast. 1998;14:623–631. [PubMed]
20. Neiman AM. Ascospore formation in the yeast Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 2005;69:565–584. [PMC free article] [PubMed]
21. Schneper L, Düvel K, Broach JR. Sense and sensibility: nutritional response and signal integration in yeast. Curr Opin Microbiol. 2004;7:624–630. [PubMed]
22. Thevelein JM, de Winde JH. Novel sensing mechanisms and targets for the cAMP-protein kinase A pathway in the yeast Saccharomyces cerevisiae. Mol Microbiol. 1999;33:904–918. [PubMed]
23. Thevelein JM, Gelad’e R, Holsbeeks I, Lagatie O, Popova Y, Rolland F, Stolz F, de Velde SV, Dijck PV, Vandormael P, et al. Nutrient sensing systems for rapid activation of the protein kinase A pathway in yeast. Biochem Soc Trans. 2005;33:253–256. [PubMed]
24. Zaman S, Lippman SI, Zhao X, Broach JR How Saccharomyces responds to nutrients. Annu Rev Genet. 2008;42:27–81. [PubMed] * A detailed and comprehensive review of how yeast cells sense, integrate, and respond to nutrient signals at the molecular level. This is an excellent reference for nutrient signaling pathways.
25. Stephan JS, Yeh YY, Ramachandran V, Deminoff SJ, Herman PK. The Tor and cAMP-dependent protein kinase signaling pathways coordinately control autophagy in Saccharomyces cerevisiae. Autophagy. 2010;6:294–295. [PubMed]
26. Pan X, Heitman J. Protein kinase A operates a molecular switch that governs yeast pseudohyphal differentiation. Mol Cell Biol. 2002;22:3981–3993. [PMC free article] [PubMed]
27. Pan X, Heitman J. Cyclic AMP-dependent protein kinase regulates pseudohyphal differentiation in Saccharomyces cerevisiae. Mol Cell Biol. 1999;19:4874–4887. [PMC free article] [PubMed]
28. Váchová L, Devaux F, Kucerová H, Ricicová M, Jacq C, Palková Z. Sok2p transcription factor is involved in adaptive program relevant for long term survival of Saccharomyces cerevisiae colonies. J Biol Chem. 2004;279:37973–37981. [PubMed]
29. Rubin-Bejerano I, Sagee S, Friedman O, Pnueli L, Kassir Y. The in vivo activity of Ime1, the key transcriptional activator of meiosis-specific genes in Saccharomyces cerevisiae, is inhibited by the cyclic AMP/protein kinase A signal pathway through the glycogen synthase kinase 3-beta homolog Rim11. Mol Cell Biol. 2004;24:6967–6979. [PMC free article] [PubMed]
30. McDonald CM, Wagner M, Dunham MJ, Shin ME, Ahmed NT, Winter E. The Ras/cAMP pathway and the CDK-like kinase Ime2 regulate the MAPK Smk1 and spore morphogenesis in Saccharomyces cerevisiae. Genetics. 2009;181:511–523. [PubMed]
31. Loewith R. A brief history of TOR. Biochem Soc Trans. 2011;39:437–442. [PubMed]
32. Kim J, Guan KL. Amino acid signaling in TOR activation. Annu Rev Biochem. 2011;80:1001–1032. [PubMed]
33. Zurita-Martinez SA, Cardenas ME. Tor and cyclic AMP-protein kinase A: two parallel pathways regulating expression of genes required for cell growth. Eukaryot Cell. 2005;4:63–71. [PMC free article] [PubMed]
34. Soulard A, Cremonesi A, Moes S, Schütz F, Jenö P, Hall MN. The rapamycin-sensitive phosphoproteome reveals that TOR controls protein kinase A toward some but not all substrates. Mol Biol Cell. 2010;21:3475–3486. [PMC free article] [PubMed]
35. Ramachandran V, Herman PK Antagonistic interactions between the cAMP-dependent protein kinase and Tor signaling pathways modulate cell growth in Saccharomyces cerevisiae. Genetics. 2011;187:441–454. [PubMed] * By using mutants, phosphorylation assays, and pathway inhibitors this study provides new insights into the coordination of cAMP-PKA and TOR signaling. The authors find evidence that decreased activity in one pathway is coupled to increased activity of the other.
36. Barbet NC, Schneider U, Helliwell SB, Stansfield I, Tuite MF, Hall MN. TOR controls translation initiation and early G1 progression in yeast. Mol Biol Cell. 1996;7:25–42. [PMC free article] [PubMed]
37. Thomas G, Hall MN. TOR signalling and control of cell growth. Curr Opin Cell Biol. 1997;9:782–787. [PubMed]
38. Georis I, Feller A, Tate JJ, Cooper TG, Dubois E. Nitrogen catabolite repression-sensitive transcription as a readout of Tor pathway regulation: the genetic background, reporter gene and GATA factor assayed determine the outcomes. Genetics. 2009;181:861–874. [PubMed]
39. Liu Z, Butow RA. Mitochondrial retrograde signaling. Annu Rev Genet. 2006;40:159–185. [PubMed]
40. Cybulski N, Hall MN. TOR complex 2: a signaling pathway of its own. Trends Biochem Sci. 2009;34:620–627. [PubMed]
41. Cutler NS, Pan X, Heitman J, Cardenas ME. The TOR signal transduction cascade controls cellular differentiation in response to nutrients. Mol Biol Cell. 2001;12:4103–4113. [PMC free article] [PubMed]
42. Zheng XF, Schreiber SL. Target of rapamycin proteins and their kinase activities are required for meiosis. Proc Natl Acad Sci USA. 1997;94:3070–3075. [PubMed]
43. Colomina N, Liu Y, Aldea M, Gari E TOR regulates the subcellular localization of Ime1, a transcriptional activator of meiotic development in budding yeast. Mol Cell Biol. 2003;23:7415–7424. [PubMed] * Showed that nutritional conditions regulate Ime1 localization via TOR signaling.
45. Zhang J, Vemuri G, Nielsen J. Systems biology of energy homeostasis in yeast. Curr Opin Microbiol. 2010;13:382–388. [PubMed]
46. Honigberg SM, Lee RH. Snf1 kinase connects nutritional pathways controlling meiosis in Saccharomyces cerevisiae. Mol Cell Biol. 1998;18:4548–4555. [PMC free article] [PubMed]
47. Purnapatre K, Piccirillo S, Schneider BL, Honigberg SM. The CLN3/SWI6/CLN2 pathway and SNF1 act sequentially to regulate meiotic initiation in Saccharomyces cerevisiae. Genes Cells. 2002;7:675–691. [PubMed]
48. Davis DA. How human pathogenic fungi sense and adapt to pH: the link to virulence. Curr Opin Microbiol. 2009;12:365–370. [PubMed]
49. Lamb TM, Xu W, Diamond A, Mitchell AP. Alkaline response genes of Saccharomyces cerevisiae and their relationship to the RIM101 pathway. J Biol Chem. 2001;276:1850–1856. [PubMed]
50. Piccirillo S, White MG, Murphy JC, Law DJ, Honigberg SM The Rim101p/PacC pathway and alkaline pH regulate pattern formation in yeast colonies. Genetics. 2010;184:707–716. [PubMed] ** Identified discrete bands of sporulated cells induced within colonies growing on sporulation media, and showed that this spatially organization is induced by a localized alkalization within the colony. The spatial patterning resembles that seen in metazoan development.
51. Lamb TM, Mitchell AP. The transcription factor Rim101p governs ion tolerance and cell differentiation by direct repression of the regulatory genes NRG1 and SMP1 in Saccharomyces cerevisiae. Mol Cell Biol. 2003;23:677–686. [PMC free article] [PubMed]
52. Lo WS, Dranginis AM. The cell surface flocculin Flo11 is required for pseudohyphae formation and invasion by Saccharomyces cerevisiae. Mol Biol Cell. 1998;9:161–171. [PMC free article] [PubMed]
53. Pimienta G, Pascual J. Canonical and alternative MAPK signaling. Cell Cycle. 2007;6:2628–2632. [PubMed]
54. Saito H. Regulation of cross-talk in yeast MAPK signaling pathways. Curr Opin Microbiol. 2010;13:677–683. [PubMed]
55. Chen RE, Thorner J. Function and regulation in MAPK signaling pathways: lessons learned from the yeast Saccharomyces cerevisiae. Biochim Biophys Acta. 2007;1773:1311–1340. [PMC free article] [PubMed]
56. Reynolds TB, Fink GR. Bakers’ yeast, a model for fungal biofilm formation. Science. 2001;291:878–881. [PubMed]
57. Chavel CA, Dionne HM, Birkaya B, Joshi J, Cullen PJ Multiple signals converge on a differentiation MAPK pathway. PLoS Genet. 2010;6 e1000883. [PMC free article] [PubMed] * By screening the yeast deletion collection for mutations that effect the secretion of a protein that affects Kss1-MAPK signaling, this study provides evidence of an unexpectedly high degree of signaling pathway integration.
58. Borneman AR, Leigh-Bell JA, Yu H, Bertone P, Gerstein M, Snyder M. Target hub proteins serve as master regulators of development in yeast. Genes Dev. 2006;20:435–448. [PubMed]
59. Chen RE, Thorner J Systematic epistasis analysis of the contributions of protein kinase A- and mitogen-activated protein kinase-dependent signaling to nutrient limitation-evoked responses in the yeast Saccharomyces cerevisiae. Genetics. 2010;185:855–870. [PubMed] ** Using combinations of mutations, the authors dissect the relative contributions of the Kss1-MAPK and cAMP-PKA pathways to filamentous growth. They find evidence of additivity of the two pathway in the case of haploid invasive growth and differential regulation of invasive, cell elongation, and unipolar budding in haploids and diploids.
60. Zaman S, Lippman SI, Schneper L, Slonim N, Broach JR Glucose regulates transcription in yeast through a network of signaling pathways. Mol Syst Biol. 2009;5:245. [PubMed] ** Using signaling mutants and overexpression in combination with gene expression microarrays, the authors tease apart the relative contributions of different nutrient responsive pathways to glucose-induced transcriptional changes. They find that cAMP-PKA and Sch9 (a TORC1 regulated kinase) play the primary roles, with Snf1 and Rgt pathways having a minor role.
61. Vinod PK, Sengupta N, Bhat PJ, Venkatesh KV. Integration of global signaling pathways, cAMP-PKA,MAPK and TOR in the regulation of FLO11. PLoS ONE. 2008;3 e1663. [PMC free article] [PubMed]
62. Strudwick N, Brown M, Parmar VM, Schröder M. Ime1 and Ime2 are required for pseudohyphal growth of Saccharomyces cerevisiae on nonfermentable carbon sources. Mol Cell Biol. 2010;30:5514–5530. [PMC free article] [PubMed]
63. Magwene PM, Ömür Kayıkçı, Granek JA, Reininga JM, Scholl Z, Murray D. Outcrossing, mitotic recombination, and life-history trade-offs shape genome evolution in Saccharomyces cerevisiae. Proc Natl Acad Sci USA. 2011;108:1987–1992. [PubMed]
64. Spor A, Wang S, Dillmann C, de Vienne D, Sicard D. "Ant" and "grasshopper" life-history strategies in Saccharomyces cerevisiae. PLoS One. 2008;3 e1579. [PMC free article] [PubMed]
65. Spor A, Nidelet T, Simon J, Bourgais A, de Vienne D, Sicard D. Niche-driven evolution of metabolic and life-history strategies in natural and domesticated populations of Saccharomyces cerevisiae. BMC Evol Biol. 2009;9:296. [PMC free article] [PubMed]
67. Fontana L, Partridge L, Longo VD. Extending healthy life span–from yeast to humans. Science. 2010;328:321–326. [PMC free article] [PubMed]
69. Borges-Walmsley MI, Walmsley AR. cAMP signalling in pathogenic fungi: control of dimorphic switching and pathogenicity. Trends Microbiol. 2000;8:133–141. [PubMed]
70. Fidalgo M, Barrales RR, Ibeas JI, Jimenez J. Adaptive evolution by mutations in the FLO11 gene. Proc Natl Acad Sci USA. 2006;103:11228–11233. [PubMed]
71. Govender P, Kroppenstedt S, Bauer FF. Novel wine-mediated FLO11 flocculation phenotype of commercial Saccharomyces cerevisiae wine yeast strains with modified FLO gene expression. FEMS Microbiol Lett. 2011;317:117–126. [PubMed]
72. Stephan JS, Yeh YY, Ramachandran V, Deminoff SJ, Herman PK The Tor and PKA signaling pathways independently target the Atg1/Atg13 protein kinase complex to control autophagy. Proc Natl Acad Sci USA. 2009;106:17049–17054. [PubMed] * This study established that the cAMP-PKA signaling regulates autophagy by targeting the Atg1/Atg13 protein complex and that this affect is independent of TOR. Because the regulation of autophagy effects filamentous growth, this work provides mechanistic insights that link pathway signaling to developmental outcomes.