Novel sensing mechanisms and targets for the cAMP–protein kinase A pathway in the yeast Saccharomyces cerevisiae

Abstract

The cAMP–protein kinase A (PKA) pathway in the yeast Saccharomyces cerevisiae plays a major role in the control of metabolism, stress resistance and proliferation, in particular in connection with the available nutrient conditions. Extensive information has been obtained on the core section of the pathway, i.e. Cdc25, Ras, adenylate cyclase, PKA, and on components interacting directly with this core section, such as the Ira proteins, Cap/Srv2 and the two cAMP phosphodiesterases. Recent work has now started to reveal upstream regulatory components and downstream targets of the pathway. A G‐protein‐coupled receptor system (Gpr1–Gpa2) acts upstream of adenylate cyclase and is required for glucose activation of cAMP synthesis in concert with a glucose phosphorylation‐dependent mechanism. Although a genuine signalling role for the Ras proteins remains unclear, they appear to mediate at least part of the potent stimulation of cAMP synthesis by intracellular acidification. Recently, several new targets of the PKA pathway have been discovered. These include the Msn2 and Msn4 transcription factors mediating part of the induction of STRE‐controlled genes by a variety of stress conditions, the Rim15 protein kinase involved in stationary phase induction of a similar set of genes and the Pde1 low‐affinity cAMP phosphodiesterase, which specifically controls agonist‐induced cAMP signalling. A major issue that remains to be resolved is the precise connection between the cAMP–PKA pathway and other nutrient‐regulated components involved in the control of growth and of phenotypic characteristics correlated with growth, such as the Sch9 and Yak1 protein kinases. Cln3 appears to play a crucial role in the connection between the availability of certain nutrients and Cdc28 kinase activity, but it remains to be clarified which nutrient‐controlled pathways control Cln3 levels.

In Saccharomyces cerevisiae an unbalanced level of tyrosine phosphorylation down-regulates the Ras/PKA pathway

“…All phenotypes displayed by Stp1-expressing strains are consistent with a down-regulation of the Ras branch of the cAMP-pathway that plays a key role in stress resistance and nutrient sensing (reviewed in Thevelein & deWinde, 1999), although we cannot exclude that other, previously identified S. cerevisiae substrates for Stp1, including enzymes involved in carbon metabolism (Modesti et al, 2001) and the immunophillin Fpr3 Marchetta et al, 2004), may contribute to one or more of the phenotypes here reported. The evidence for a cross-talk between a tyrosine phosphorylation/dephosphorylation pathway(s) and the Ras/PKA pathway is many fold, since Stp1-expressing cells share a number of phenotypes with mutants with attenuated Ras/PKA pathway.…”

“…cAMP-activated PKA phosphorylates a number of proteins involved in metabolism, cell cycle progression, accumulation of glycogen and trehalose and heat-shock resistance. Reduced activity of this pathway leads to growth arrest at the beginning of G1 phase (the same stage at which the cells arrest following nutrient deprivation), causes enhanced levels of glycogen and trehalose and constitutive expression of heat-shock genes (reviewed in Rolland, Winderickx, & Thevelein, 2002;Thevelein & deWinde, 1999).…”

Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients

“…In yeast, glucose reduction (2-0.5%) increases protection against oxidative stress, whereas complete starvation by switching the population of cells to water, promotes protection to oxidative insults and heat shock and a major life span increase (Longo et al, 1997;Wei et al, 2008). Although the precise molecular mechanisms of increased protection by fasting have yet to be described in detail, in yeast they involve the reduced activity of the Ras/cAMP/PKA and the Tor/S6K nutrient signaling pathways and the activation of transcription factors downregulated by these pathways (Thevelein and de Winde, 1999;Wei et al, 2008). In fact, deletion of transcription factors Msn2/Msn4 and Gis1 reverses the protection caused by glucose restriction or starvation conditions, suggesting an important role for genes involved in metabolism, cellular protection and repair regulated by these factors in starvation-dependent stress resistance (Longo et al, 1997;Wei et al, 2008).…”

Response to acetaldehyde stress in the yeast Saccharomyces cerevisiae involves a strain‐dependent regulation of several ALD genes and is mediatedby the general stress response pathway

“…The S. cerevisiae Msn2p and Msn4p zinc finger proteins are responsive to the general stress response (Martínez-Pastor et al, 1996), and are repressed by the cAMP-dependent protein kinase A (PKA), which is regulated by the Ras/cAMP signalling pathway (Boy-Marcotte et al, 1998;Marchler et al, 1993). cAMP activates PKA by binding to the Bcy1p regulatory subunit, and dissociation of the Tpk1/2/3p catalytic subunits (Thevelein and de Winde, 1999). The S. cerevisiae heat shock factor (Hsf1p) activates the transcription of genes containing heat shock elements in their promoter, like those encoding heat shock proteins (Hsp).…”