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PMID: 9204908 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin.

Science (New York, N.Y.) ·Vol. 277 ·No. 5322 ·1997-07-04 ·Pages 99-101

Brunn GJ, Hudson CC, Sekulić A, Williams JM, Hosoi H, Houghton PJ, Lawrence JC, Abraham RT

Abstract

The immunosuppressant rapamycin interferes with G1-phase progression in lymphoid and other cell types by inhibiting the function of the mammalian target of rapamycin (mTOR). mTOR was determined to be a terminal kinase in a signaling pathway that couples mitogenic stimulation to the phosphorylation of the eukaryotic initiation factor (eIF)-4E-binding protein, PHAS-I. The rapamycin-sensitive protein kinase activity of mTOR was required for phosphorylation of PHAS-I in insulin-stimulated human embryonic kidney cells. mTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E. These studies define a role for mTOR in translational control and offer further insights into the mechanism whereby rapamycin inhibits G1-phase progression in mammalian cells.

MeSH Terms

Adaptor Proteins, Signal Transducing Androstadienes/pharmacology Animals Carrier Proteins/pharmacology Cell Cycle Proteins Cell Line DNA-Binding Proteins/pharmacology Eukaryotic Initiation Factor-4E G1 Phase Heat-Shock Proteins/pharmacology Humans Insulin/pharmacology Intracellular Signaling Peptides and Proteins Peptide Initiation Factors/metabolism Phosphoproteins/genetics,metabolism Phosphorylation Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors,metabolism Polyenes/pharmacology Protein Kinases Rats Recombinant Proteins/metabolism Repressor Proteins/genetics,metabolism Signal Transduction Sirolimus TOR Serine-Threonine Kinases Tacrolimus Binding Proteins Transfection Tumor Cells, Cultured Wortmannin

Chemicals

Adaptor Proteins, Signal Transducing Androstadienes Carrier Proteins Cell Cycle Proteins DNA-Binding Proteins EIF4EBP1 protein, human Eif4ebp1 protein, rat Eukaryotic Initiation Factor-4E Heat-Shock Proteins Insulin Intracellular Signaling Peptides and Proteins Peptide Initiation Factors Phosphoproteins Polyenes Recombinant Proteins Repressor Proteins Protein Kinases Phosphotransferases (Alcohol Group Acceptor) MTOR protein, human mTOR protein, rat TOR Serine-Threonine Kinases Tacrolimus Binding Proteins Sirolimus Wortmannin

Authors & Affiliations

8 authors, click to expand affiliations / ORCID

Brunn G J

Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

Hudson C C

Sekulić A

Williams J M

Hosoi H

Houghton P J

Lawrence J C

Abraham R T

Article Info

Journal

Science (New York, N.Y.)

Abbr.

Science

ISSN

0036-8075

DOI

10.1126/science.277.5322.99

Published

1997-07-04

Pages

99-101

Language

English

Region

United States

NLM ID

0404511

Subset

Grants

NIAMS NIH HHS · AR41189 · United States

NIDDK NIH HHS · DK28312 · United States

NIDDK NIH HHS · DK50628 · United States

External Links

PubMed source DOI: 10.1126/science.277.5322.99 View journal details

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Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin.

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