The Valosin-containing Protein (VCP) Is a Target of Akt Signaling Required for Cell Survival
Open Access
- 1 May 2006
- journal article
- Published by Elsevier BV
- Vol. 281 (20), 14307-14313
- https://doi.org/10.1074/jbc.m510003200
Abstract
The serine/threonine kinase Akt is a key mediator of cell survival and growth, but its precise mechanism of action, and more specifically, the nature of its signaling partners largely remain to be elucidated. We show, using a proteomics-based approach, that the valosin-containing protein (VCP), a member of the AAA (ATPases associated with a variety of cellular activities) family, is a target of Akt signaling. SDS-PAGE of Akt co-immunoprecipitated proteins obtained from MCF-7 breast cancer cells revealed the increase of a 97-kDa band under Akt activation. Mass spectrometry analysis allowed the identification of VCP, and we have shown a serine/threonine phosphorylation on an Akt consensus site upon activation by growth factors. Site-directed mutagenesis identified Ser-351, Ser-745, and Ser-747 as Akt phosphorylation sites on VCP. Confocal microscopy indicated a co-localization between Akt and VCP upon Akt stimulation. Interestingly, small interfering RNA against VCP induced an inhibition of the growth factor-induced activation of NF-kappaB and a potent pro-apoptotic effect. Together, these data identify VCP as an essential target of Akt signaling.Keywords
This publication has 27 references indexed in Scilit:
- The antiapoptotic effect of fibroblast growth factor-2 is mediated through nuclear factor-κB activation induced via interaction between Akt and IκB kinase-β in breast cancer cellsOncogene, 2005
- RNA interference of valosin-containing protein (VCP/p97) reveals multiple cellular roles linked to ubiquitin/proteasome-dependent proteolysisJournal of Cell Science, 2004
- The IKK NF-κB system: a treasure trove for drug developmentNature Reviews Drug Discovery, 2004
- Targeting the PI3K-Akt pathway in human cancerCancer Cell, 2003
- Tumor Necrosis Factor Receptor-associated Death Domain Protein Is Involved in the Neurotrophin Receptor-mediated Antiapoptotic Activity of Nerve Growth Factor in Breast Cancer CellsJournal of Biological Chemistry, 2003
- AAA proteinsCurrent Opinion in Structural Biology, 2002
- AAA+ proteins and substrate recognition, it all depends on their partner in crimeFEBS Letters, 2002
- Sphingosine generation, cytochrome c release, and activation of caspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cellsCell Death & Differentiation, 2001
- Peptide and Protein Library Screening Defines Optimal Substrate Motifs for AKT/PKBPublished by Elsevier BV ,2000
- Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase‐1 and p70 S6 kinaseFEBS Letters, 1996