cAMP Signaling in S. pombe
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cAMP Signaling in S. pombe

The fission yeast S. pombe (Schizosaccharomyces pombe) is homothallic and has a defined sexual cycle involving mating between haploid cells of opposite mating types. In S. pombe, two signaling pathways coordinately regulate mating; the pheromone-activated MAPK (Mitogen-Activated Protein Kinase) signaling and nutrient-regulated, G-protein-cAMP (Cyclic Adenosine 3,5-monophosphate)-PKA (cAMP-Dependent Protein Kinase) pathway (Ref.1). In S. cerevisiae (Saccharomyces cerevisiae), these two signaling pathways have evolved cell type specificity, so that one functions in response to pheromone during Mating and both function to detect nutrients in diploid cells for Filamentous Growth. In contrast, in S. pombe, these two pathways function coordinately in the same cell type to regulate Mating under adverse nutrient conditions and in response to pheromone (Ref.1 & 2).

In budding yeast, Glucose stimulates cAMP production but in S. pombe, either Glucose limitation or Nitrogen limitation results in a reduction in cAMP levels. cAMP levels decline rapidly in response to Glucose starvation, whereas cAMP levels decline more gradually in response to Nitrogen limitation, showing different levels of control for Carbon compared to Nitrogen source sensing. S. pombe expresses GIT3 (Glucose Insensitive Transcription Protein-3/Glucose Receptor Protein-GIT3), which is a homolog of the S. cerevisiae GPR1 (G-Protein Coupled Receptor-1). Interestingly, GIT3 lacks the Asparagine-rich third intracellular loop found in GPR1, indicating that this unusual region does not play an obligate role in signaling. GIT3 is required for Glucose-induced repression of the FBP1 (Fructose-1,6-Bisphosphatase)/FBPase (D-Fructose-1,6-Bisphosphate-1-Phosphohydrolase) gene. GIT3 receptor is coupled to the GIT8/GPA2 (Guanine Nucleotide-Binding Protein-Alpha2 Subunit). GIT8/GPA2 is most homologous to the nutrient-sensing GPA2 protein of S. cerevisiae that is required for Pseudohyphal Growth (Ref. 3). Interestingly, the single GIT5/GPB1 (Guanine Nucleotide-Binding Protein-Beta Subunit) is required for Cyr1/GIT2/AC (Adenylyl Cyclase) activation in S. pombe, in response to Glucose and repression of the FBP1 gene by Glucose. GIT5/GPB1 is coupled to the GIT8/GPA2 protein and not to the pheromone-activated GPA1 (Guanine Nucleotide-Binding Protein-Alpha1 Subunit) protein. GIT5/GPB1 is not required for basal cAMP production, whereas GIT8/GPA2 is, showing some GIT5/GPB1-independent action of GIT8/GPA2 on AC. Additional components represent the Cap1/Cap (Adenylyl Cyclase Associated Protein), the GIT11/GBG (Guanine Nucleotide-Binding Protein-Gamma Subunit), Hexokinase, all of which regulate Glucose signaling to AC (Ref.4 & 5).

AC may exist as a dimer in which different domains of the protein have unique functions. When Glucose levels are high, cAMP is produced, PKA is active and mating of S. pombe is repressed. PKA represses the transcription of both the Ste11 gene, a key regulator of many mating-specific genes and the FBP1 gene. PKA consists of both the regulatory Cgs1 (cAMP-Dependent Protein Kinase Regulatory Subunit) and the catalytic subunit, GIT6/PKA1 (cAMP-Dependent Protein Kinase Catalytic Subunit). When Glucose or Nitrogen levels fall, cAMP production is reduced, PKA is less active and Ste11 is induced. An important point is that because the role of PKA is to mediate repression of Ste11, thus cAMP has a negative effect on mating in S. pombe. GIT6/PKA1 feedback regulates AC activity. The decrease in cAMP level turns down the GIT6/PKA1 activity and therefore induces sexual reproduction by releasing the factors repressed by GIT6/PKA1 (Ref.4). One of such factors, Rst2 (Zinc Finger Protein-Rst2) transcription factor, turns on the transcription of Ste11 gene encoding the master transcription factor of sexual development. Ste11 activates transcription of itself, Mating-Specific genes, Ste6 (a regulator of projection tube elongation encoding Ras1GEF), an initiator of meiosis Mei2 (Meiosis Protein-Mei2), and other factors that are important for each step of sexual differentiation (Ref.6).

The cAMP signaling pathway is independent of the S. pombe Ras1 gene and works by activation of PKA. One very intriguing recent report is that the addition of Methionine stimulates mating of S. pombe on nutrient-rich medium, which normally represses mating. One possible model is that Methionine biosynthesis is stimulated and represses cAMP production in response to Nitrogen source limitation. cAMP levels decline in presence of Methionine. Methionine also restores Ste11 and FBP1 expression in cells exposed to high levels of exogenous cAMP, showing that the effects of Methionine may occur downstream or independently of cAMP production. Future efforts should include the molecular analysis of the GIT genes in order to elucidate the mechanism(s) of Glucose repression in S. pombe (Ref.7 & 8).