Sites on FIP-3 (NEMO/IKKgamma) Essential for Its Phosphorylation and NF-kappaB Modulating Activity

Authors: Tarassishin L.1, 2; Horwitz M.S.1, 2, 3

Source: Biochemical and Biophysical Research Communications, Volume 285, Number 2, July 2001 , pp. 555-560(6)

Publisher: Academic Press

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Abstract:

FIP-3 (NEMO/IKKgamma) is an essential modulator of the activity of NF-kappaB by mechanisms that include alterations in the phosphorylation, ubiquination, and degradation of IkappaBalpha. The multiple protein-protein interactions of FIP-3 (NEMO/IKKgamma) in a high molecular weight IKK complex indicated that this protein may be a link between some of the receptor-proximal upstream signal transduction molecules such as RIP and the downstream effects on IkappaBalpha. Although FIP-3 (NEMO/IKKgamma) has no intrinsic kinase activity, it has been shown to increase the kinase activity of IKKbeta. In this manuscript, the results of serine to alanine mutations at five sites on FIP-3 (NEMO/IKKgamma) are described, and functional assays demonstrated that two of these mutants affect both the phosphorylation and kinase activity of IKKbeta. Protein kinase Calpha appeared to be the kinase that was required for the posttranslational modification of FIP-3 (NEMO/IKKgamma). One of the serine targets of the protein kinase Calpha enzyme at amino acid 141 was within a leucine zipper-like sequence of FIP-3 (NEMO/IKKgamma), which might affect its interactions with other proteins on the signal transduction pathway. The second serine, which augmented the inhibition, was at amino acid 85 within the FIP-3 (NEMO/IKKgamma) interaction site with IKKbeta. When both serines were mutated simultaneously, the effect on IKKbeta and IkappaBalpha phosphorylation was more profoundly affected. Copyright 2001 Academic Press.

Keywords: FIP-3 (NEMO/IKKgamma); IKK; NF-kappaB; PKC; phosphorylation

Language: English

Document Type: Research article

Affiliations: 1: Department of Microbiology 2: Department of Microbiology, Department of Immunology 3: Department of Microbiology, Department of Immunology, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, 10461

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