Abstract
TOR and PKA signaling are the major growth-regulatory nutrient-sensing pathways in S. cerevisiae. A number of experimental findings demonstrated a close relationship between these pathways: Both are responsive to glucose availability. Both regulate ribosome production on the transcriptional level and repress autophagy and the cellular stress response. Sch9, a major downstream effector of TORC1 presumably shares its kinase consensus motif with PKA, and genetic rescue and synthetic defects between PKA and Sch9 have been known for a long time. Further, studies in the first decade of this century have suggested direct regulation of PKA by TORC1. Nonetheless, the contribution of a potential direct cross-talk vs. potential sharing of targets between the pathways has still not been completely resolved. What is more, other findings have in contrast highlighted an antagonistic relationship between the two pathways. In this review, I explore the association between TOR and PKA signaling, mainly by focusing on proteins that are commonly referred to as shared TOR and PKA targets. Most of these proteins are transcription factors which to a large part explain the major transcriptional responses elicited by TOR and PKA upon nutrient shifts. I examine the evidence that these proteins are indeed direct targets of both pathways and which aspects of their regulation are targeted by TOR and PKA. I further explore if they are phosphorylated on shared sites by PKA and Sch9 or when experimental findings point towards regulation via the PP2ASit4/PP2A branch downstream of TORC1. Finally, I critically review data suggesting direct cross-talk between the pathways and its potential mechanism.
Highlights
Protein kinase A (PKA) and TOR signaling are two highly conserved signaling pathways that respond to nutrient and stress signals and regulate various responses that govern cellular growth
I further explore if they are phosphorylated on shared sites by PKA and Sch9 or when experimental findings point towards regulation via the PP2ASit4 /PP2A
A second GFP-construct of the SV40 nuclear localization signals (NLS) and Msn2-NES localized to the cytoplasm in unstressed growth in glucose, but nuclear localization was triggered by glucose starvation, heat- or sorbate stress and rapamycin treatment
Summary
Protein kinase A (PKA) and TOR signaling are two highly conserved signaling pathways that respond to nutrient and stress signals and regulate various responses that govern cellular growth. S. cerevisiae expresses a PP2A-like phosphatase (referred to as PP2ASit4 ), consisting of catalytic subunit Sit and either Sap155, Sap185 or Sap190 [16,17]. Like other AGC kinases, it is basophilic and its limited number of known substrates suggest a preference for arginines and, to a lesser extent, lysines in the P-3 and P-2 positions [24,25]. It is phosphorylated by TORC1 on six serine and threonine residues near its C-terminus that reside within the so-called hydrophobic motif and turn motif [26]. Several mechanisms through which Sch regulates ribosome biogenesis are discussed below
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