Rac1 leads to phosphorylation-dependent increase in stability of the p66shc adaptor protein: role in Rac1-induced oxidative stress

Firdous A Khanday; Tohru Yamamori; Ilwola Mattagajasingh; Zhe Zhang; Artem Bugayenko; Asma Naqvi; Lakshmi Santhanam; Nusrat Nabi; Kenji Kasuno; Billy W Day; Kaikobad Irani

doi:10.1091/mbc.E05-06-0570

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Rac1 leads to phosphorylation-dependent increase in stability of the p66shc adaptor protein: role in Rac1-induced oxidative stress

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Rac1 leads to phosphorylation-dependent increase in stability of the p66shc adaptor protein: role in Rac1-induced oxidative stress

Firdous A Khanday, Tohru Yamamori, Ilwola Mattagajasingh, Zhe Zhang, Artem Bugayenko, Asma Naqvi, Lakshmi Santhanam, Nusrat Nabi, Kenji Kasuno, Billy W Day, …

Molecular biology of the cell, Vol.17(1), pp.122-129

01/2006

DOI: 10.1091/mbc.E05-06-0570

PMCID: PMC1345652

PMID: 16251354

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Abstract

The rac1 GTPase and the p66shc adaptor protein regulate intracellular levels of reactive oxygen species (ROS). We examined the relationship between rac1 and p66shc. Expression of constitutively active rac1 (rac1V12) increased phosphorylation, reduced ubiquitination, and increased stability of p66shc protein. Rac1V12-induced phosphorylation and up-regulation of p66shc was suppressed by inhibiting p38MAPK and was dependent on serine 54 and threonine 386 in p66shc. Phosphorylation of recombinant p66shc by p38MAPK in vitro was also partly dependent on serine 54 and threonine 386. Reconstitution of p66shc in p66shc-null fibroblasts increased intracellular ROS generated by rac1V12, which was significantly dependent on the integrity of residues 54 and 386. Overexpression of p66shc increased rac1V12-induced apoptosis, an effect that was also partly dependent on serine 54 and threonine 386. Finally, RNA interference-mediated down-regulation of endogenous p66shc suppressed rac1V12-induced cell death. These findings identify p66shc as a mediator of rac1-induced oxidative stress. In addition, they suggest that serine 54 and threonine 386 are novel phosphorylatable residues in p66shc that govern rac1-induced increase in its expression, through a decrease in its ubiquitination and degradation, and thereby mediate rac1-stimulated cellular oxidative stress and death.

Phosphorylation

Oxidative Stress

Apoptosis

Up-Regulation

Enzyme Stability

Cercopithecus aethiops

Rats

Serine - genetics

Threonine - metabolism

Serine - metabolism

Animals

Src Homology 2 Domain-Containing, Transforming Protein 1

Threonine - genetics

Adaptor Proteins, Signal Transducing - genetics

Mice

p38 Mitogen-Activated Protein Kinases - metabolism

Adaptor Proteins, Signal Transducing - metabolism

rac1 GTP-Binding Protein - metabolism

Shc Signaling Adaptor Proteins

rac1 GTP-Binding Protein - genetics

Details

Title: Subtitle: Rac1 leads to phosphorylation-dependent increase in stability of the p66shc adaptor protein: role in Rac1-induced oxidative stress
Creators: Firdous A Khanday - Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
Tohru Yamamori
Ilwola Mattagajasingh
Zhe Zhang
Artem Bugayenko
Asma Naqvi
Lakshmi Santhanam
Nusrat Nabi
Kenji Kasuno
Billy W Day
Kaikobad Irani
Resource Type: Journal article
Publication Details: Molecular biology of the cell, Vol.17(1), pp.122-129
DOI: 10.1091/mbc.E05-06-0570
PMID: 16251354
PMCID: PMC1345652
NLM abbreviation: Mol Biol Cell
ISSN: 1059-1524
eISSN: 1939-4586
Publisher: American Society for Cell Biology; United States
Grant note: R01 HL070929 / NHLBI NIH HHS P01 HL065608 / NHLBI NIH HHS R01 HL70929 / NHLBI NIH HHS P01 HL65608 / NHLBI NIH HHS
Language: English
Date published: 01/2006
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984047618502771

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