scholarly journals Chemical genetics of AGC-kinases reveals shared targets of Ypk1, Protein Kinase A and Sch9

2019 ◽  
Author(s):  
Michael Plank ◽  
Mariya Perepelkina ◽  
Markus Müller ◽  
Stefania Vaga ◽  
Xiaoming Zou ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Growth ◽  
Protein Kinase A ◽  
Chemical Genetics ◽  
Cellular Functions ◽  
Agc Kinases ◽  
Neutral Trehalase ◽  
Chemical Inhibition ◽  
Kinase A ◽  
Validation Experiments

ABSTRACTProtein phosphorylation cascades play a central role in the regulation of cell growth and protein kinases PKA, Sch9 and Ypk1 take centre stage in regulating this process in S. cerevisiae. To understand how these kinases co-ordinately regulate cellular functions we compared the phospho-proteome of exponentially growing cells without and with acute chemical inhibition of PKA, Sch9 and Ypk1. Sites hypo-phosphorylated upon PKA and Sch9 inhibition were preferentially located in RRxS/T-motifs suggesting that many are directly phosphorylated by these enzymes. Interestingly, when inhibiting Ypk1 we not only detected several hypo-phosphorylated sites in the previously reported RxRxxS/T-, but also in an RRxS/T-motif. Validation experiments revealed that neutral trehalase Nth1, a known PKA target, is additionally phosphorylated and activated downstream of Ypk1. Signalling through Ypk1 is therefore more closely related to PKA- and Sch9-signalling than previously appreciated and may perform functions previously only attributed to the latter kinases.

scholarly journals Chemical Genetics of AGC-kinases Reveals Shared Targets of Ypk1, Protein Kinase A and Sch9

2020 ◽  
Vol 19 (4) ◽  
pp. 655-671 ◽  
Author(s):  
Michael Plank ◽  
Mariya Perepelkina ◽  
Markus Müller ◽  
Stefania Vaga ◽  
Xiaoming Zou ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Growth ◽  
Protein Kinase A ◽  
Chemical Genetics ◽  
Cellular Functions ◽  
Agc Kinases ◽  
Neutral Trehalase ◽  
Chemical Inhibition ◽  
Kinase A ◽  
Validation Experiments

Protein phosphorylation cascades play a central role in the regulation of cell growth and protein kinases PKA, Sch9 and Ypk1 take center stage in regulating this process in S. cerevisiae. To understand how these kinases co-ordinately regulate cellular functions we compared the phospho-proteome of exponentially growing cells without and with acute chemical inhibition of PKA, Sch9 and Ypk1. Sites hypo-phosphorylated upon PKA and Sch9 inhibition were preferentially located in RRxS/T-motifs suggesting that many are directly phosphorylated by these enzymes. Interestingly, when inhibiting Ypk1 we not only detected several hypo-phosphorylated sites in the previously reported RxRxxS/T-, but also in an RRxS/T-motif. Validation experiments revealed that neutral trehalase Nth1, a known PKA target, is additionally phosphorylated and activated downstream of Ypk1. Signaling through Ypk1 is therefore more closely related to PKA- and Sch9-signaling than previously appreciated and may perform functions previously only attributed to the latter kinases.

scholarly journals The Rapamycin-sensitive Phosphoproteome Reveals That TOR Controls Protein Kinase A Toward Some But Not All Substrates

2010 ◽  
Vol 21 (19) ◽  
pp. 3475-3486 ◽  
Author(s):  
Alexandre Soulard ◽  
Alessio Cremonesi ◽  
Suzette Moes ◽  
Frédéric Schütz ◽  
Paul Jenö ◽  
...  
Keyword(s):  
Quantitative Analysis ◽  
Protein Kinase ◽  
Cell Growth ◽  
Protein Kinase A ◽  
Ribosome Biogenesis ◽  
Regulatory Subunit ◽  
Nutrient Metabolism ◽  
Cellular Processes ◽  
Targeted Analysis ◽  
Kinase A

Regulation of cell growth requires extensive coordination of several processes including transcription, ribosome biogenesis, translation, nutrient metabolism, and autophagy. In yeast, the protein kinases Target of Rapamycin (TOR) and protein kinase A (PKA) regulate these processes and are thereby the main activators of cell growth in response to nutrients. How TOR, PKA, and their corresponding signaling pathways are coordinated to control the same cellular processes is not understood. Quantitative analysis of the rapamycin-sensitive phosphoproteome combined with targeted analysis of PKA substrates suggests that TOR complex 1 (TORC1) activates PKA but only toward a subset of substrates. Furthermore, we show that TORC1 signaling impinges on BCY1, the negative regulatory subunit of PKA. Inhibition of TORC1 with rapamycin leads to BCY1 phosphorylation on several sites including T129. Phosphorylation of BCY1 T129 results in BCY1 activation and inhibition of PKA. TORC1 inhibits BCY1 T129 phosphorylation by phosphorylating and activating the S6K homolog SCH9 that in turn inhibits the MAP kinase MPK1. MPK1 phosphorylates BCY1 T129 directly. Thus, TORC1 activates PKA toward some substrates by preventing MPK1-mediated activation of BCY1.

scholarly journals A-kinase anchoring protein 8L interacts with mTORC1 and promotes cell growth

2020 ◽  
Vol 295 (23) ◽  
pp. 8096-8105 ◽  
Author(s):  
Chase H. Melick ◽  
Delong Meng ◽  
Jenna L. Jewell
Keyword(s):  
Protein Kinase ◽  
Cell Growth ◽  
Protein Kinase A ◽  
Terminal Region ◽  
Regulatory Subunit ◽  
Interacting Protein ◽  
Regulatory Subunits ◽  
Anchoring Protein ◽  
Regulate Cell Growth ◽  
Kinase A

mTOR complex 1 (mTORC1) senses nutrients to mediate anabolic processes within the cell. Exactly how mTORC1 promotes cell growth remains unclear. Here, we identified a novel mTORC1-interacting protein called protein kinase A anchoring protein 8L (AKAP8L). Using biochemical assays, we found that the N-terminal region of AKAP8L binds to mTORC1 in the cytoplasm. Importantly, loss of AKAP8L decreased mTORC1-mediated processes such as translation, cell growth, and cell proliferation. AKAPs anchor protein kinase A (PKA) through PKA regulatory subunits, and we show that AKAP8L can anchor PKA through regulatory subunit Iα. Reintroducing full-length AKAP8L into cells restored mTORC1-regulated processes, whereas reintroduction of AKAP8L missing the N-terminal region that confers the interaction with mTORC1 did not. Our results suggest a multifaceted role for AKAPs in the cell. We conclude that mTORC1 appears to regulate cell growth, perhaps in part through AKAP8L.

Inhibition of pancreatic cancer cell growth and induction of apoptosis with novel therapies directed against protein kinase A

Surgery ◽  
2003 ◽  
Vol 134 (2) ◽  
pp. 197-205 ◽  
Author(s):  
Buckminster Farrow ◽  
Piotr Rychahou ◽  
Carlos Murillo ◽  
Kathleen L. O'Connor ◽  
Takeshi Iwamura ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Protein Kinase ◽  
Cell Growth ◽  
Protein Kinase A ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Novel Therapies ◽  
Cancer Cell Growth ◽  
Induction Of Apoptosis ◽  
Kinase A

scholarly journals Tor and Cyclic AMP-Protein Kinase A: Two Parallel Pathways Regulating Expression of Genes Required for Cell Growth

2005 ◽  
Vol 4 (1) ◽  
pp. 63-71 ◽  
Author(s):  
Sara A. Zurita-Martinez ◽  
Maria E. Cardenas
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Cell Growth ◽  
Cyclic Amp ◽  
Protein Kinase A ◽  
Mammalian Cells ◽  
Regulatory Networks ◽  
Expression Of Genes ◽  
Transcriptional Pattern ◽  
Kinase A

ABSTRACT In the budding yeast Saccharomyces cerevisiae, the Tor and cyclic AMP-protein kinase A (cAMP-PKA) signaling cascades respond to nutrients and regulate coordinately the expression of genes required for cell growth, including ribosomal protein (RP) and stress-responsive (STRE) genes. The inhibition of Tor signaling by rapamycin results in repression of the RP genes and induction of the STRE genes. Mutations that hyperactivate PKA signaling confer resistance to rapamycin and suppress the repression of RP genes imposed by rapamycin. By contrast, partial inactivation of PKA confers rapamycin hypersensitivity but only modestly affects RP gene expression. Complete inactivation of PKA impairs RP gene expression and concomitantly enhances STRE gene expression; remarkably, this altered transcriptional pattern is still sensitive to rapamycin and thus subject to Tor control. These findings illustrate how the Tor and cAMP-PKA signaling pathways respond to nutrient signals to govern gene expression required for cell growth via two parallel routes, and they have broad implication for our understanding of analogous regulatory networks in normal and neoplastic mammalian cells.

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