Protein Phosphatase 2A Interacts with the 70-kDa S6 Kinase and is Activated by Inhibition of FKBP12-rapamycinassociated Protein

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1999 Apr 14

PMID 10200280

Citations 167

Authors

R T Peterson

B N Desai

J S Hardwick

S L Schreiber

Affiliations

Soon will be listed here.

Abstract

The FKBP12-rapamycin-associated protein (FRAP; also called RAFT1/mTOR) regulates translation initiation and entry into the cell cycle. Depriving cells of amino acids or treating them with the small molecule rapamycin inhibits FRAP and results in rapid dephosphorylation and inactivation of the translational regulators 4E-BP1(eukaryotic initiation factor 4E-binding protein 1) and p70(s6k) (the 70-kDa S6 kinase). Data published recently have led to the view that FRAP acts as a traditional mitogen-activated kinase, directly phosphorylating 4E-BP1 and p70(s6k) in response to mitogenic stimuli. We present evidence that FRAP controls 4E-BP1 and p70(s6k) phosphorylation indirectly by restraining a phosphatase. A calyculin A-sensitive phosphatase is required for the rapamycin- or amino acid deprivation-induced dephosphorylation of p70(s6k), and treatment of Jurkat I cells with rapamycin increases the activity of the protein phosphatase 2A (PP2A) toward 4E-BP1. PP2A is shown to associate with p70(s6k) but not with a mutated p70(s6k) that is resistant to rapamycin- and amino acid deprivation-mediated dephosphorylation. FRAP also is shown to phosphorylate PP2A in vitro, consistent with a model in which phosphorylation of PP2A by FRAP prevents the dephosphorylation of 4E-BP1 and p70(s6k), whereas amino acid deprivation or rapamycin treatment inhibits FRAP's ability to restrain the phosphatase.

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References

Liu J, Farmer Jr J, Lane W, Friedman J, Weissman I, Schreiber S . Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991; 66(4):807-15. DOI: 10.1016/0092-8674(91)90124-h. View

Weng Q, Andrabi K, Kozlowski M, Grove J, Avruch J . Multiple independent inputs are required for activation of the p70 S6 kinase. Mol Cell Biol. 1995; 15(5):2333-40. PMC: 230461. DOI: 10.1128/MCB.15.5.2333. View

Albers M, Brown E, Tanaka A, Williams R, Hall F, Schreiber S . An FKBP-rapamycin-sensitive, cyclin-dependent kinase activity that correlates with the FKBP-rapamycin-induced G1 arrest point in MG-63 cells. Ann N Y Acad Sci. 1993; 696:54-62. DOI: 10.1111/j.1749-6632.1993.tb17142.x. View

Haystead T, Haystead C, Hu C, Lin T, Lawrence Jr J . Phosphorylation of PHAS-I by mitogen-activated protein (MAP) kinase. Identification of a site phosphorylated by MAP kinase in vitro and in response to insulin in rat adipocytes. J Biol Chem. 1994; 269(37):23185-91. View

Brown E, Beal P, Keith C, Chen J, Shin T, Schreiber S . Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature. 1995; 377(6548):441-6. DOI: 10.1038/377441a0. View

Cheatham L, Monfar M, Chou M, Blenis J . Structural and functional analysis of pp70S6k. Proc Natl Acad Sci U S A. 1995; 92(25):11696-700. PMC: 40469. DOI: 10.1073/pnas.92.25.11696. View

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

Brown E, Schreiber S . A signaling pathway to translational control. Cell. 1996; 86(4):517-20. DOI: 10.1016/s0092-8674(00)80125-7. View

Dennis P, Pullen N, Kozma S, Thomas G . The principal rapamycin-sensitive p70(s6k) phosphorylation sites, T-229 and T-389, are differentially regulated by rapamycin-insensitive kinase kinases. Mol Cell Biol. 1996; 16(11):6242-51. PMC: 231627. DOI: 10.1128/MCB.16.11.6242. View

10.

Brunn G, Williams J, Sabers C, Wiederrecht G, Lawrence Jr J, Abraham R . Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBO J. 1996; 15(19):5256-67. PMC: 452270. View

11.

Begum N, Ragolia L . cAMP counter-regulates insulin-mediated protein phosphatase-2A inactivation in rat skeletal muscle cells. J Biol Chem. 1996; 271(49):31166-71. DOI: 10.1074/jbc.271.49.31166. View

12.

Brunn G, Hudson C, Sekulic A, Williams J, Hosoi H, Houghton P . Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science. 1997; 277(5322):99-101. DOI: 10.1126/science.277.5322.99. View

13.

Cohen P . Novel protein serine/threonine phosphatases: variety is the spice of life. Trends Biochem Sci. 1997; 22(7):245-51. DOI: 10.1016/s0968-0004(97)01060-8. View

14.

Murata K, Wu J, Brautigan D . B cell receptor-associated protein alpha4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. Proc Natl Acad Sci U S A. 1997; 94(20):10624-9. PMC: 23426. DOI: 10.1073/pnas.94.20.10624. View

15.

Brunn G, Fadden P, Haystead T, Lawrence Jr J . The mammalian target of rapamycin phosphorylates sites having a (Ser/Thr)-Pro motif and is activated by antibodies to a region near its COOH terminus. J Biol Chem. 1998; 272(51):32547-50. DOI: 10.1074/jbc.272.51.32547. View

16.

Thomas G, Hall M . TOR signalling and control of cell growth. Curr Opin Cell Biol. 1998; 9(6):782-7. DOI: 10.1016/s0955-0674(97)80078-6. View

17.

Pullen N, Dennis P, Andjelkovic M, Dufner A, Kozma S, Hemmings B . Phosphorylation and activation of p70s6k by PDK1. Science. 1998; 279(5351):707-10. DOI: 10.1126/science.279.5351.707. View

18.

Burnett P, Barrow R, Cohen N, Snyder S, Sabatini D . RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci U S A. 1998; 95(4):1432-7. PMC: 19032. DOI: 10.1073/pnas.95.4.1432. View

19.

WESTPHAL R, Anderson K, Means A, Wadzinski B . A signaling complex of Ca2+-calmodulin-dependent protein kinase IV and protein phosphatase 2A. Science. 1998; 280(5367):1258-61. DOI: 10.1126/science.280.5367.1258. View

20.

Hara K, Yonezawa K, Weng Q, Kozlowski M, Belham C, Avruch J . Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem. 1998; 273(23):14484-94. DOI: 10.1074/jbc.273.23.14484. View