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M404416200v1
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Papers In Press, published online ahead of print September 2, 2004
J. Biol. Chem, 10.1074/jbc.M404416200
Submitted on April 21, 2004
Revised on August 31, 2004
Accepted on September 2, 2004

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

Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710

Corresponding Author: sheno001{at}mc.duke.edu

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 is spliced to generate two alternate mRNAs, termed I-1alpha and I-1beta encoding polypeptides that differed from I-1 in their C-terminal sequences. RT-PCR established that I-1alpha and I-1beta mRNA are expressed in a developmental and tissue-specific manner. Functional analysis of I-1 in a S. cerevisiae strain dependent on human I-1 for viability, established that a novel domain encompassing amino acids 77 to 110, was necessary for PP1 inhibition in yeast. Expression of human I-1 in S. cerevisiae with a partial-loss-of-function eIF2alpha kinase (Gcn2p) mutation permitted growth during amino acid starvation, consistent with the inhibition of Glc7p/PP1, the yeast eIF2alpha phosphatase. In contrast, human I-1alpha which lacks amino acids 83-134 and I-1 with C-terminal deletions were significantly less effective at promoting yeast growth under starvation conditions. These data suggest that C-terminal sequences of I-1 enhance regulation of the eukaryotic eIF2alpha phosphatase. In vitro studies established that C-terminal sequences, deleted in both I-1alpha and I-1beta enhance PP1 binding and inhibition. Expression of full-length and C-terminal truncated I-1 in HEK 293T cells established the importance of the I-1 C-terminus in transducing cAMP signals that promote eIF2alpha phosphorylation. These studies demonstrated that multiple domains in I-1 target cellular PP1 complexes, and establish I-1 as a cellular regulator of eIF2alpha phosphorylation.


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