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Molecular and Cellular Biology, August 2000, p. 5469-5478, Vol. 20, No. 15
Department of Immunology, Imperial College,
London W12 0NN, United Kingdom1; Growth
Factors and Differentiation Laboratory, University of Bordeaux I, 33 405 Talence Cedex,2 and Laboratoire
d'Immunologie Cellulaire, CERVI, UMR 7627 CNRS, 75013 Paris,3 France; Department of
Medicine, Microbiology and Immunology, Howard Hughes Medical
Institute, University of California at San Francisco, San
Francisco, California 94143-07954; and
Laboratory for Physiological Chemistry, Utrecht University,
3584 CG Utrecht, The Netherlands5
Received 3 February 2000/Returned for modification 7 March
2000/Accepted 8 May 2000
The serine/threonine kinase Akt (also known as protein kinase B)
(Akt/PKB) is activated upon T-cell antigen receptor (TCR) engagement or
upon expression of an active form of phosphatidylinositide (PI)
3-kinase in T lymphocytes. Here we report that the small GTPase Rac1 is
implicated in this pathway, connecting the receptor with the lipid
kinase. We show that in Jurkat cells, activated forms of Rac1 or Cdc42,
but not Rho, stimulate an increase in Akt/PKB activity. TCR-induced
Akt/PKB activation is inhibited either by PI 3-kinase inhibitors
(LY294002 and wortmannin) or by overexpression of a dominant negative
mutant of Rac1 but not Cdc42. Accordingly, triggering of the TCR
rapidly stimulates a transient increase in GTP-Rac content in these
cells. Similar to TCR stimulation, L61Rac-induced Akt/PKB kinase
activity is also LY294002 and wortmannin sensitive. However, induction
of Akt/PKB activity by constitutive active PI 3-kinase is unaffected when dominant negative Rac1 is coexpressed, placing Rac1 upstream of PI
3-kinase in the signaling pathway. When analyzing the signaling hierarchy in the pathway leading to cytoskeleton rearrangements, we
found that Rac1 acts downstream of PI 3-kinase, a finding that is in
accordance with numerous studies in fibroblasts. Our results reveal a
previously unrecognized role of the GTPase Rac1, acting upstream of PI
3-kinase in linking the TCR to Akt/PKB. This is the first report of a
membrane receptor employing Rac1 as a downstream transducer for Akt/PKB activation.
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
The T-Cell Receptor Regulates Akt (Protein Kinase B) via a
Pathway Involving Rac1 and Phosphatidylinositide 3-Kinase
*
Corresponding author. Mailing address: Growth Factors
and Differentiation Laboratory, Batiment de Biologie Animale,
University of Bordeaux I, Avenue des facultés, 33 405 Talence
Cedex, France. Phone: (33) 5 56 84 89 25. Fax: (33) 5 56 84 87 05. E-mail: e.genot{at}croissance.u-bordeaux.fr.
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