Pkh1, -2, and -3 are the yeast orthologs of mammalian 3-phosphoinositide-dependent protein kinase-1 (PDK1). Although essential for viability, their functioning remains poorly understood. Sch9, the yeast protein kinase B and/or S6K ortholog, has been identified as one of their targets. We now have shown that in vitro interaction of Pkh1 and Sch9 depends on the hydrophobic PDK1-interacting fragment pocket in Pkh1 and requires the complementary hydrophobic motif in Sch9. We demonstrated that Pkh1 phosphorylates Sch9 both in vitro and in vivo on its PDK1 site and that this phosphorylation is essential for a wild type cell size. In vivo phosphorylation on this site disappeared during nitrogen deprivation and rapidly increased again upon nitrogen resupplementation. In addition, we have shown here for the first time that the PDK1 site in protein kinase A is phosphorylated by Pkh1 in vitro, that this phosphorylation is Pkh-dependent in vivo and occurs during or shortly after synthesis of the protein kinase A catalytic subunits. Mutagenesis of the PDK1 site in Tpk1 abolished binding of the regulatory subunit and cAMP dependence. As opposed to PDK1 site phosphorylation of Sch9, phosphorylation of the PDK1 site in Tpk1 was not regulated by nitrogen availability. These results bring new insight into the control and prevalence of PDK1 site phosphorylation in yeast by Pkh protein kinases.
"All rights reserved. catalytic Tpk1 subunit interferes with binding to the regulatory Bcy1 subunit and thus with cAMP-dependency (Voordeckers, et al., 2011, Haesendonckx, et al., 2012). This regulation establishes a link between sphingolipid signaling pathways and PKA. "
[Show abstract][Hide abstract] ABSTRACT: The yeast Saccharomyces cerevisiae has been a favorite organism for pioneering studies on nutrient-sensing and signaling mechanisms. Many specific nutrient responses have been elucidated in great detail. This has led to important new concepts and insight into nutrient-controlled cellular regulation. Major highlights include the central role of the Snf1 protein kinase in the glucose repression pathway, galactose induction, the discovery of a G-protein coupled receptor system and role of Ras in glucose-induced cAMP signaling, the role of the protein synthesis initiation machinery in general control of nitrogen metabolism, the cyclin-controlled protein kinase Pho85 in phosphate regulation, nitrogen catabolite repression and the nitrogen-sensing TOR pathway, and the discovery of transporter-like proteins acting as nutrient sensors. In addition, a number of cellular targets, like carbohydrate stores, stress tolerance and ribosomal gene expression, are controlled by the presence of multiple nutrients. The PKA signaling pathway plays a major role in this general nutrient response. It has led to the discovery of nutrient transceptors (transporter-receptors) as nutrient sensors. Major shortcomings in our knowledge are the relationship between rapid and steady-state nutrient signaling, the role of metabolic intermediates in intracellular nutrient sensing and the identity of the nutrient sensors controlling cellular growth. This article is protected by copyright. All rights reserved.
"TORC1 then signals to downstream effectors to regulate transcriptional and translational processes controlling cell growth and proliferation . The best-characterized TORC1 target in yeast is the AGC kinase family member Sch9, which is a functional ortholog to the Akt/PKB and ribosomal S6 kinases . Sch9 is phosphorylated on multiple serine and threonine residues by TORC1, resulting in Sch9 activation . "
[Show abstract][Hide abstract] ABSTRACT: The target of rapamycin complex 1 (TORC1) is an evolutionarily conserved signal transduction pathway activated by environmental nutrients that regulates gene transcription to control cell growth and proliferation. How TORC1 modulates chromatin structure to control gene expression, however, is largely unknown. Because TORC1 is a major transducer of environmental information, defining this process has critical implications for both understanding environmental effects on epigenetic processes and the role of aberrant TORC1 signaling in many diseases, including cancer, diabetes, and cardiovascular disease.
To elucidate the role of TORC1 signaling in chromatin regulation, we screened a budding yeast histone H3 and H4 mutant library using the selective TORC1 inhibitor rapamycin to identify histone residues functionally connected to TORC1. Intriguingly, we identified histone H3 lysine 37 (H3K37) as a residue that is essential during periods of limited TORC1 activity. An H3K37A mutation resulted in cell death by necrosis when TORC1 signaling was simultaneously impaired. The induction of necrosis was linked to alterations in high mobility group (HMG) protein binding to chromatin. Furthermore, the necrotic phenotype could be recapitulated in wild-type cells by deregulating the model HMG proteins, Hmo1 or Ixr1, thus implicating a direct role for HMG protein deregulation as a stimulus for inducing necrosis.
This study identifies histone H3 and H4 residues functionally required for TORC1-dependent cell growth and proliferation that are also candidate epigenetic pathways regulated by TORC1 signaling. It also demonstrates a novel role for H3K37 and TORC1 in regulating the binding of select HMG proteins to chromatin and that HMG protein deregulation can initiate a necrotic cell death response. Overall, the results from this study suggest a possible model by which chromatin anchors HMG proteins during periods of limited TORC1 signaling, such as that which occurs during conditions of nutrient stress, to suppress necrotic cell death.
"This is accompanied by a reduction of the REV1 DNA repair protein expression and of translesional synthesis. The phosphorylation of Sch9 is essential for a wild type cell size . The Sir2 deacetylase is a highly conserved gene, that modulates lifespan in yeast, worms, and flies and stress response in mammals. "
[Show abstract][Hide abstract] ABSTRACT: Body development requires the ability to control cell proliferation and metabolism, together with selective 'invasive' cell migration for organogenesis. These requirements are shared with cancer. Human height-associated loci have been recently identified by genome-wide SNP-association studies. Strikingly, most of the more than 100 genes found associated to height appear linked to neoplastic growth, and impose a higher risk for cancer. Height-associated genes drive the HH/PTCH and BMP/TGFβ pathways, with p53, c-Myc, ERα, HNF4A and SMADs as central network nodes. Genetic analysis of body-size-affecting diseases and evidence from genetically-modified animals support this model. The finding that cancer is deeply linked to normal, body-plan master genes may profoundly affect current paradigms on tumor development.
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