WD Repeat Protein WDR48 in Complex with Deubiquitinase USP12 Suppresses Akt-dependent Cell Survival Signaling by Stabilizing PH Domain Leucine-rich Repeat Protein Phosphatase 1 (PHLPP1)

Narmadha Reddy, G. and Subba Reddy, Maddika (2013) WD Repeat Protein WDR48 in Complex with Deubiquitinase USP12 Suppresses Akt-dependent Cell Survival Signaling by Stabilizing PH Domain Leucine-rich Repeat Protein Phosphatase 1 (PHLPP1). Journal of Biological Chemistry, 288 (48). pp. 34545-34554. ISSN 0021-9258

Preview

Text
JBC 288 p34545.pdf
Download (3952Kb) | Preview

Official URL: http://dx.doi.org/10.1074/jbc.M113.503383

Abstract

PHLPP1 (PH domain leucine-rich repeat protein phosphatase 1) is a protein-serine/threonine phosphatase and a negative regulator of the PI3-kinase/Akt pathway. Although its function as a suppressor of tumor cell growth has been established, the mechanism of its regulation is not completely understood. In this study, by utilizing the tandem affinity purification approach we have identified WDR48 and USP12 as novel PHLPP1-associated proteins. The WDR48·USP12 complex deubiquitinates PHLPP1 and thereby enhances its protein stability. Similar to PHLPP1 function, WDR48 and USP12 negatively regulate Akt activation and thus promote cellular apoptosis. Functionally, we show that WDR48 and USP12 suppress proliferation of tumor cells. Importantly, we found a WDR48 somatic mutation (L580F) that is defective in stabilizing PHLPP1 in colorectal cancers, supporting a WDR48 role in tumor suppression. Together, our results reveal WDR48 and USP12 as novel PHLPP1 regulators and potential suppressors of tumor cell survival.

Item Type:	Article
Additional Information:	[Open Access from the Publisher]
Depositing User:	Users 2 not found.
Date Deposited:	02 Nov 2015 06:07
Last Modified:	12 Sep 2016 04:27
URI:	http://cdfd.sciencecentral.in/id/eprint/608

Actions (login required)

View Item