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

Soulard, Alexandre; Cremonesi, Alessio; Moes, Suzette; Schütz, Frédéric; Jenö, Paul; Hall, Michael N.

doi:10.1091/mbc.e10-03-0182

Cited by 236 publications

(285 citation statements)

References 76 publications

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“…A similar situation occurs with Sch9, with rapamycin eliciting a much less convincing increase in the mobility of the full-length protein than observed with a smaller truncated fragment (43,47). This reasoning suggests that Gat1, like Gln3, is subject to phosphorylation/dephosphorylation, a suggestion consistent with the demonstration of phosphorylated Gat1 peptides detected by mass spectral analysis of the rapamycinsensitive phosphoproteome (64).…”

Section: Discussionsupporting

confidence: 62%

Constitutive and Nitrogen Catabolite Repression-sensitive Production of Gat1 Isoforms

Rai

Tate

Georis

et al. 2014

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 62%

Constitutive and Nitrogen Catabolite Repression-sensitive Production of Gat1 Isoforms

Rai

Tate

Georis

et al. 2014

Journal of Biological Chemistry

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“…2C and Fig. S5) (16,29). Our data underline functional connections between two critical signaling hubs, PKA and TOR.…”

Section: Filteau Et Alsupporting

confidence: 52%

“…To explore pathways by which methionine could signal to PKA, we tested several protein interactions using DHFR-PCA in vivo in the presence of methionine and/or rapamycin (Dataset S7). We found that Bcy1 interacts with Mck1, a downstream TOR kinase (16), and with Meh1, an EGO complex member, and that these interactions are modulated when methionine and rapamycin are present ( Fig. S6 and Dataset S7).…”

Section: Filteau Et Almentioning

confidence: 89%

“…However, the inbound and feedback signals this kinase integrates are not entirely known or well understood beyond the canonical Ras/cAMP and G protein-coupled receptor GPCR pathways (15), particularly in fungi. Direct mechanisms of PKA regulation include cAMP binding to the R subunits (8), phosphorylation (16), and subcellular localization of its subunits (17). In mammalian cells, there is extensive evidence for compartmentalization of cAMP signaling in which A kinase-anchoring proteins (AKAPs) play a major role by coupling PKA to a variety of other enzymes (9).…”

mentioning

confidence: 99%

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Systematic identification of signal integration by protein kinase A

Filteau

Diss

Torres-Quiroz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cellular processes and homeostasis control in eukaryotic cells is achieved by the action of regulatory proteins such as protein kinase A (PKA). Although the outbound signals from PKA directed to processes such as metabolism, growth, and aging have been well charted, what regulates this conserved regulator remains to be systematically identified to understand how it coordinates biological processes. Using a yeast PKA reporter assay, we identified genes that influence PKA activity by measuring proteinprotein interactions between the regulatory and the two catalytic subunits of the PKA complex in 3,726 yeast genetic-deletion backgrounds grown on two carbon sources. Overall, nearly 500 genes were found to be connected directly or indirectly to PKA regulation, including 80 core regulators, denoting a wide diversity of signals regulating PKA, within and beyond the described upstream linear pathways. PKA regulators span multiple processes, including the antagonistic autophagy and methionine biosynthesis pathways. Our results converge toward mechanisms of PKA posttranslational regulation by lysine acetylation, which is conserved between yeast and humans and that, we show, regulates protein complex formation in mammals and carbohydrate storage and aging in yeast. Taken together, these results show that the extent of PKA input matches with its output, because this kinase receives information from upstream and downstream processes, and highlight how biological processes are interconnected and coordinated by PKA.Ras/cAMP/PKA pathway | acetylation | methionine | autophagy | TOR

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“…29). In addition to Gip4, which does not appear to be the relevant target here, we note two Glc7 regulators (Shp1 and Reg1) among the TORC1 targets identified by screening the rapamycin-sensitive phosphoproteome by mass spectrometry (36,39). Shp1 is hyperphosphorylated at Ser106 and Ser108 following rapamycin treatment (36).…”

Section: Discussionmentioning

confidence: 90%

Temperature-sensitive ipl1-2/Aurora B mutation is suppressed by mutations in TOR complex 1 via the Glc7/PP1 phosphatase

Tatchell

Makrantoni

Stark

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Ipl1/Aurora B is the catalytic subunit of a complex that is required for chromosome segregation and nuclear division. Before anaphase, Ipl1 localizes to kinetochores, where it is required to establish proper kinetochore-microtubule associations and regulate the spindle assembly checkpoint. The protein phosphatase Glc7/ PP1 opposes Ipl1 for some of these activities. To more thoroughly characterize the Glc7 phosphatase that opposes Ipl1, we have identified mutations that suppress the thermosensitivity of an ipl1-2 mutant. In addition to mutations in genes previously associated with ipl1 suppression, we recovered a null mutant in TCO89, which encodes a subunit of the TOR complex 1 (TORC1), the conserved rapamycin-sensitive kinase activity that regulates cell growth in response to nutritional status. The temperature sensitivity of ipl1-2 can also be suppressed by null mutation of TOR1 or by administration of pharmacological TORC1 inhibitors, indicating that reduced TORC1 activity is responsible for the suppression. Suppression of the ipl1-2 growth defect is accompanied by increased fidelity of chromosome segregation and increased phosphorylation of the Ipl1 substrates histone H3 and Dam1. Nuclear Glc7 levels are reduced in a tco89 mutant, suggesting that TORC1 activity is required for the nuclear accumulation of Glc7. In addition, several mutant GLC7 alleles that suppress the temperature sensitivity of ipl1-2 exhibit negative synthetic genetic interactions with TORC1 mutants. Together, our results suggest that TORC1 positively regulates the Glc7 activity that opposes Ipl1 and provide a mechanism to tie nutritional status with mitotic regulation.

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

Cited by 236 publications

References 76 publications

Constitutive and Nitrogen Catabolite Repression-sensitive Production of Gat1 Isoforms

Constitutive and Nitrogen Catabolite Repression-sensitive Production of Gat1 Isoforms

Systematic identification of signal integration by protein kinase A

Temperature-sensitive ipl1-2/Aurora B mutation is suppressed by mutations in TOR complex 1 via the Glc7/PP1 phosphatase

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