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J. Biol. Chem., Vol. 278, Issue 48, 47459-47465, November 28, 2003

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Ser-64 and Ser-111 in PHAS-I Are Dispensable for Insulin-stimulated Dissociation from eIF4E^*

Gail Ferguson, Isabelle Mothe-Satney, and John C. Lawrence, Jr.¶

From the Departments of Pharmacology and Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22908

Insulin stimulates phosphorylation of multiple sites in the eIF4E-binding protein, PHAS-I, leading to dissociation of the PHAS-I·eIF4E complex and to an increase in cap-dependent translation. The Ser-64 and Ser-111 sites have been proposed to have key roles in controlling the association of PHAS-I and eIF4E. To determine whether the effects of insulin require these sites, we assessed the control of PHAS-I proteins having Ala-64 or Ala-111 mutations. The results indicate that phosphorylation of neither site is required for insulin to promote release of PHAS-I from eIF4E. Also, the mutation of Ser-111, which has been proposed to serve as a necessary priming site for the phosphorylation of other sites in PHAS-I, did not affect the phosphorylation of Thr-36/45, Ser-64, or Thr-69. Insulin promoted the release of eIF4E from PHAS-II, a PHAS isoform that lacks the Ser-111 site, but it was without effect on the amount of eIF4E bound to the third isoform, PHAS-III. The results demonstrate that contrary to widely accepted models, Ser-64 and Ser-111 are not required for the control of PHAS-I binding to eIF4E in cells, implicating phosphorylation of the Thr sites in dissociation of the PHAS-I·eIF4E complex. The findings also indicate that PHAS-II, but not PHAS-III, contributes to the control of protein synthesis by insulin.

Received for publication, July 22, 2003 , and in revised form, September 22, 2003.

^* This work was supported by National Institutes of Health Grants DK52753 and DK28312. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Pharmacology, P. O. Box 800735, University of Virginia Health System, 1300 Jefferson Park Ave., Charlottesville, VA 22908. Tel.: 434-924-1584; Fax: 434-982-3575; E-mail: jcl3p{at}virginia.edu.

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