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J. Biol. Chem., Vol. 279, Issue 47, 48904-48914, November 19, 2004

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The Inhibitor-1 C Terminus Facilitates Hormonal Regulation of Cellular Protein Phosphatase-1

FUNCTIONAL IMPLICATIONS FOR INHIBITOR-1 ISOFORMS^*

Douglas C. Weiser, Suzanne Sikes, Shi Li, and Shirish Shenolikar

From the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710

Inhibitor-1 (I-1) is a selective inhibitor of protein phosphatase-1 (PP1) and regulates several PP1-dependent signaling pathways, including cardiac contractility and regulation of learning and memory. The human I-1 gene has been spliced to generate two alternative mRNAs, termed I-1 and I-1, encoding polypeptides that differ from I-1 in their C-terminal sequences. Reverse transcription-PCR established that I-1 and I-1 mRNAs are expressed in a developmental and tissue-specific manner. Functional analysis of I-1 in a Saccharomyces cerevisiae strain dependent on human I-1 for viability established that a novel domain encompassing amino acids 77–110 is necessary for PP1 inhibition in yeast. Expression of human I-1 in S. cerevisiae with a partial loss-of-function eukaryotic initiation factor-2 (eIF2) kinase (Gcn2p) mutation permitted growth during amino acid starvation, consistent with the inhibition of Glc7p/PP1, the yeast eIF2 phosphatase. In contrast, human I-1, which lacks amino acids 83–134, and I-1 with C-terminal deletions were significantly less effective in promoting yeast growth under starvation conditions. These data suggest that C-terminal sequences of I-1 enhance regulation of the eukaryotic eIF2 phosphatase. In vitro studies established that C-terminal sequences, deleted in both I-1 and I-1, enhance PP1 binding and inhibition. Expression of full-length and C-terminally truncated I-1 in HEK293T cells established the importance of the I-1 C terminus in transducing cAMP signals that promote eIF2 phosphorylation. This study demonstrates that multiple domains in I-1 target cellular PP1 complexes and establishes I-1 as a cellular regulator of eIF2 phosphorylation.

Received for publication, April 21, 2004 , and in revised form, August 31, 2004.

^* This work was supported in part by National Institutes of Health Grant RO1-DK52054 (to S. S.). 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.

Supported by Predoctoral Fellowship DAMD17-02-1-0378 from the United States Department of Defense Breast Cancer Program.

To whom correspondence should be addressed: Dept. of Pharmacology and Cancer Biology, Duke University Medical Center, LSRC C315, Research Dr., Durham, NC 27710. Tel.: 919-681-6178/9; Fax: 919-681-9567; E-mail: sheno001{at}mc.duke.edu.

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