WIP1 Phosphatase is a Negative Regulator of NF-kappaB Signalling

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2009 Apr 21

PMID 19377466

Citations 83

Authors

Joanne Chew

Subhra Biswas

Sathyavageeswaran Shreeram

Mahathir Humaidi

Ee Tsin Wong

Manprit Kaur Dhillion

Hsiangling Teo

Amit Hazra

Cheok Chit Fang

Eduardo Lopez-Collazo

Dmitry V Bulavin

Vinay Tergaonkar

Affiliations

Soon will be listed here.

Abstract

Post-translational modifications of NF-kappaB through phosphorylations enhance its transactivation potential. Much is known about the kinases that phosphorylate NF-kappaB, but little is known about the phosphatases that dephosphorylate it. By using a genome-scale siRNA screen, we identified the WIP1 phosphatase as a negative regulator of NF-kappaB signalling. WIP1-mediated regulation of NF-kappaB occurs in both a p38-dependent and independent manner. Overexpression of WIP1 resulted in decreased NF-kappaB activation in a dose-dependent manner, whereas WIP1 knockdown resulted in increased NF-kappaB function. We show that WIP1 is a direct phosphatase of Ser 536 of the p65 subunit of NF-kappaB. Phosphorylation of Ser 536 is known to be essential for the transactivation function of p65, as it is required for recruitment of the transcriptional co-activator p300. WIP1-mediated regulation of p65 regulated binding of NF-kappaB to p300 and hence chromatin remodelling. Consistent with our results, mice lacking WIP1 showed enhanced inflammation. These results provide the first genetic proof that a phosphatase directly regulates NF-kappaB signalling in vivo.

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