The Journal of Experimental Medicine
Avanti Polar Lipids, Inc.
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Published online 19 February 2001.
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© The Rockefeller University Press, 0022-1007/2001/2/497/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 4, February 19, 2001 497-508

Original Article

Activation of the Cooh-Terminal Src Kinase (Csk) by Camp-Dependent Protein Kinase Inhibits Signaling through the T Cell Receptor

Torkel Vanga, Knut Martin Torgersena, Vibeke Sundvoldb, Manju Saxenac, Finn Olav Levya, Bjørn S. Skålhegga, Vidar Hanssona, Tomas Mustelinc,d, and Kjetil Taskéna

a Department of Medical Biochemistry, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway
b Institute of Immunology, University of Oslo, The National Hospital, N-0027 Oslo, Norway
c La Jolla Institute for Allergy and Immunology, San Diego, California 92121
d La Jolla Cancer Research Center, The Burnham Institute, La Jolla, California 92037
La Jolla Cancer Center, The Burnham Institute, 70901 North Torrey Pines Rd., La Jolla, CA 92037.858-713-6274858-713-6270

tmustelin{at}burnham-inst.org

In T cells, cAMP-dependent protein kinase (PKA) type I colocalizes with the T cell receptor–CD3 complex (TCR/CD3) and inhibits T cell function via a previously unknown proximal target. Here we examine the mechanism for this PKA-mediated immunomodulation. cAMP treatment of Jurkat and normal T cells reduces Lck-mediated tyrosine phosphorylation of the TCR/CD3 {zeta} chain after T cell activation, and decreases Lck activity. Phosphorylation of residue Y505 in Lck by COOH-terminal Src kinase (Csk), which negatively regulates Lck, is essential for the inhibitory effect of cAMP on {zeta} chain phosphorylation. PKA phosphorylates Csk at S364 in vitro and in vivo leading to a two- to fourfold increase in Csk activity that is necessary for cAMP-mediated inhibition of TCR-induced interleukin 2 secretion. Both PKA type I and Csk are targeted to lipid rafts where proximal T cell activation occurs, and phosphorylation of raft-associated Lck by Csk is increased in cells treated with forskolin. We propose a mechanism whereby PKA through activation of Csk intersects signaling by Src kinases and inhibits T cell activation.

Key Words: protein kinase A • Csk • T cell activation • tyrosine phosphorylation • immunomodulation

Abbreviations used in this paper: Cbp, Csk binding protein; Csk, COOH-terminal Src kinase; HA, hemagglutinin; IBMX, isobutyl-methylxanthine; LAT, linker for activation of T cell; PAG, phosphoprotein associated with glycosphingolipid-enriched membrane domains; PKA, protein kinase A or cAMP-dependent protein kinase; PKI, protein kinase inhibitor; SH2, Src homology 2.

Targeting of PKA type I, Csk, and Lck-Y505 for treatment of immunodeficiencies is described in pending patent applications, no. W098148809 and no. W099162315 with priority from April 20, 1997 and May 27, 1998, respectively.

K.M. Torgersen and V. Sundvold contributed equally to this work.

F.O. Levy's present address is Merck, Sharp, and Dohme Cardiovascular Research Center and Institute of Pharmacology, University of Oslo, Rikhospitalet University Hospital, N-0316 Oslo, Norway. B.S. Skålhegg's present address is Dept. of Nutrition Research, University of Oslo, N-0317 Oslo, Norway.

© 2001 The Rockefeller University Press


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