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Regulation of Akt-dependent cell survival by Syk and Rac

Jiang, Kun, Zhong, Bin, Ritchey, Connie, Gilvary, Danielle L., Hong-Geller, Elizabeth, Wei, Sheng, Djeu, Julie Y.·2003·Blood
DOI 10.1182/blood-2002-04-1251
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Abstract

Interleukin-2 (IL-2) prevents cell apoptosis and promotes survival, but the involved mechanisms have not been completely defined. Although phosphatidylinositide 3-kinase (PI 3-kinase) has been implicated in IL-2–mediated survival mechanisms, none of the 3 chains of the IL-2 receptor (IL-2R) expresses a binding site for PI 3-kinase. However, IL-2Rβ does express a Syk-binding motif. By using an IL-2–dependent natural killer (NK) cell line, followed by validation of the results in fresh human NK cells, we identified Syk as a critical effector essential for IL-2–mediated prosurvival signaling in NK cells. Down-regulation of Syk by piceatannol treatment impaired NK cellular viability and induced prominent apoptosis as effectively as suppression of PI 3-kinase function by LY294002. Expression of kinase-deficient Syk or pretreatment with piceatannol markedly suppressed IL-2–stimulated activation of PI 3-kinase and Akt, demonstrating that Syk is upstream of PI 3-kinase and Akt. However, constitutively active PI 3-kinase reversed this loss of Akt function caused by kinase-deficient Syk or piceatannol. Thus, Syk appears to regulate PI 3-kinase, which controls Akt activity during IL-2 stimulation. More important, we observed Rac1 activation by IL-2 and found that it mediated PI 3-kinase activation of Akt. This conclusion came from experiments in which dominant-negative Rac1 significantly decreased IL-2–induced Akt activation, whereas constitutively active Rac1 reelevated Akt activity not only in Syk-impaired but also in PI 3-kinase–impaired NK cells. These results constitute the first report of a Syk → PI3K → Rac1 → Akt signal cascade controlled by IL-2 that mediates NK cell survival.

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Cited by

Metadata

Authors
Jiang, K., Zhong, B., Ritchey, C., Gilvary, D. L., Hong-Geller, E., Wei, S., & Djeu, J. Y.
Affiliations
From the Immunology Program, H. Lee Moffitt Cancer Center, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa; and Los Alamos National Laboratories, NM.
Venue
Blood
Publisher
American Society of Hematology
Published
2003-01-01
Volume
101
Issue
1
Pages
236-244
ISSN
  • 1528-0020
  • 0006-4971
DOI
10.1182/blood-2002-04-1251
Cited by
54
References
0
Language
en

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