Rapamycin Activates Tap42-associated Phosphatases by Abrogating Their Association with Tor Complex 1

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2006 Jul 29

PMID 16874307

Citations 64

Authors

Gonghong Yan

Xiaoyun Shen

Yu Jiang

Affiliations

Soon will be listed here.

Abstract

In Saccharomyces cerevisiae, the Tap42-phosphatase complexes are major targets of the Tor kinases in the rapamycin-sensitive signaling pathway. The immunosuppressive agent, rapamycin, induces a prompt activation of the Tap42-associated phosphatases, which is vitally important in Tor-mediated transcriptional regulation. However, the mechanism for the rapid phosphatase activation is poorly understood. In this study, we show that the Tap42-phosphatase complexes exist mainly on membrane structures through their association with Tor complex 1 (TORC1). Rapamycin abrogates this association and releases the Tap42-phosphatase complexes into the cytosol. Disassembly of the Tap42-phosphatase complexes occurs subsequently, following the release but at a much slower rate, presumably caused by Tap42 dephosphorylation. Release of the Tap42-phosphatase complexes from membrane structures also occurs when cells are deprived of nutrient. These findings suggest that the association of the Tap42-phosphatase complexes with TORC1 represents an important mechanism by which nutrient controls Tor signaling activity. In addition, our data support a model in which rapamycin acts not by inhibiting the kinase activity of Tor but by disrupting its interaction with downstream targets.

Citing Articles

The target of rapamycin signaling pathway regulates vegetative development, aflatoxin biosynthesis, and pathogenicity in .

Li G, Cao X, Tumukunde E, Zeng Q, Wang S Elife. 2024; 12.

PMID: 38990939 PMC: 11239180. DOI: 10.7554/eLife.89478.

TOR Complex 1: Orchestrating Nutrient Signaling and Cell Cycle Progression.

Foltman M, Sanchez-Diaz A Int J Mol Sci. 2023; 24(21).

PMID: 37958727 PMC: 10647266. DOI: 10.3390/ijms242115745.

The STRIPAK complex orchestrates cell wall integrity signalling to govern the fungal development and virulence of Fusarium graminearum.

Chen A, Liu N, Xu C, Wu S, Liu C, Qi H Mol Plant Pathol. 2023; 24(9):1139-1153.

PMID: 37278525 PMC: 10423325. DOI: 10.1111/mpp.13359.

TorC1 and nitrogen catabolite repression control of integrated GABA shunt and retrograde pathway gene expression.

Tate J, Rai R, Cooper T Yeast. 2023; 40(8):318-332.

PMID: 36960709 PMC: 10518031. DOI: 10.1002/yea.3849.

TORC1 Signaling in Fungi: From Yeasts to Filamentous Fungi.

Wang Y, Zheng X, Li G, Wang X Microorganisms. 2023; 11(1).

PMID: 36677510 PMC: 9864104. DOI: 10.3390/microorganisms11010218.

References

Wedaman K, Reinke A, Anderson S, Yates 3rd J, McCaffery J, Powers T . Tor kinases are in distinct membrane-associated protein complexes in Saccharomyces cerevisiae. Mol Biol Cell. 2003; 14(3):1204-20. PMC: 151591. DOI: 10.1091/mbc.e02-09-0609. View

Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo J, Bonenfant D . Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell. 2002; 10(3):457-68. DOI: 10.1016/s1097-2765(02)00636-6. View

Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K . The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem. 2003; 278(18):15461-4. DOI: 10.1074/jbc.C200665200. View

Duvel K, Santhanam A, Garrett S, Schneper L, Broach J . Multiple roles of Tap42 in mediating rapamycin-induced transcriptional changes in yeast. Mol Cell. 2003; 11(6):1467-78. DOI: 10.1016/s1097-2765(03)00228-4. View

Powers T, Dilova I, Chen C, Wedaman K . Yeast TOR signaling: a mechanism for metabolic regulation. Curr Top Microbiol Immunol. 2003; 279:39-51. DOI: 10.1007/978-3-642-18930-2_3. View

Wang H, Wang X, Jiang Y . Interaction with Tap42 is required for the essential function of Sit4 and type 2A phosphatases. Mol Biol Cell. 2003; 14(11):4342-51. PMC: 266755. DOI: 10.1091/mbc.e03-02-0072. View

Reinke A, Anderson S, McCaffery J, Yates 3rd J, Aronova S, Chu S . TOR complex 1 includes a novel component, Tco89p (YPL180w), and cooperates with Ssd1p to maintain cellular integrity in Saccharomyces cerevisiae. J Biol Chem. 2004; 279(15):14752-62. DOI: 10.1074/jbc.M313062200. View

Rubin G . The nucleotide sequence of Saccharomyces cerevisiae 5.8 S ribosomal ribonucleic acid. J Biol Chem. 1973; 248(11):3860-75. View

Thomas B, Rothstein R . Elevated recombination rates in transcriptionally active DNA. Cell. 1989; 56(4):619-30. DOI: 10.1016/0092-8674(89)90584-9. View

10.

Sneddon A, Cohen P, Stark M . Saccharomyces cerevisiae protein phosphatase 2A performs an essential cellular function and is encoded by two genes. EMBO J. 1990; 9(13):4339-46. PMC: 552220. DOI: 10.1002/j.1460-2075.1990.tb07883.x. View

11.

Rothstein R . Targeting, disruption, replacement, and allele rescue: integrative DNA transformation in yeast. Methods Enzymol. 1991; 194:281-301. DOI: 10.1016/0076-6879(91)94022-5. View

12.

Heitman J, Movva N, Hall M . Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science. 1991; 253(5022):905-9. DOI: 10.1126/science.1715094. View

13.

Kunz J, Henriquez R, Schneider U, Movva N, Hall M . Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell. 1993; 73(3):585-96. DOI: 10.1016/0092-8674(93)90144-f. View

14.

Zheng X, Florentino D, Chen J, Crabtree G, Schreiber S . TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell. 1995; 82(1):121-30. DOI: 10.1016/0092-8674(95)90058-6. View

15.

Di Como C, Arndt K . Nutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases. Genes Dev. 1996; 10(15):1904-16. DOI: 10.1101/gad.10.15.1904. View

16.

Barbet N, Schneider U, Helliwell S, Stansfield I, Tuite M, Hall M . TOR controls translation initiation and early G1 progression in yeast. Mol Biol Cell. 1996; 7(1):25-42. PMC: 278610. DOI: 10.1091/mbc.7.1.25. View

17.

Schmidt A, Kunz J, Hall M . TOR2 is required for organization of the actin cytoskeleton in yeast. Proc Natl Acad Sci U S A. 1996; 93(24):13780-5. PMC: 19424. DOI: 10.1073/pnas.93.24.13780. View

18.

Schmidt A, Beck T, Koller A, Kunz J, Hall M . The TOR nutrient signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease. EMBO J. 1998; 17(23):6924-31. PMC: 1171040. DOI: 10.1093/emboj/17.23.6924. View

19.

Jiang Y, Broach J . Tor proteins and protein phosphatase 2A reciprocally regulate Tap42 in controlling cell growth in yeast. EMBO J. 1999; 18(10):2782-92. PMC: 1171359. DOI: 10.1093/emboj/18.10.2782. View

20.

Beck T, Hall M . The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors. Nature. 1999; 402(6762):689-92. DOI: 10.1038/45287. View