Release from tonic inhibition of T cell activation through transient displacement of C-terminal Src kinase (Csk) from lipid rafts.
In resting peripheral T cells, Csk is constitutively present in lipid rafts through an interaction with the Csk SH2-binding protein, PAG, also known as Cbp. Upon triggering of the T cell antigen receptor (TCR), PAG/Cbp is rapidly dephosphorylated leading to dissociation of Csk from lipid rafts. However, tyrosine phosphorylation of PAG/Cbp resumes after 3--5 min, at which time Csk reassociates with the rafts. Cells overexpressing a mutant Csk that lacks the catalytic domain, but displaces endogenous Csk from lipid rafts, have elevated basal levels of TCR-zeta-chain phosphorylation and spontaneous activation of an NFAT-AP1 reporter from the proximal interleukin-2 promoter as well as stronger and more sustained responses to TCR triggering than controls. We suggest that a transient release from Csk-mediated inhibition by displacement of Csk from lipid rafts is important for normal T cell activation.
Torgersen
K M
KM
Department of Medical Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Box 1112, Blindern, N-0317 Oslo, Norway.
Vang
T
T
Abrahamsen
H
H
Yaqub
S
S
Horejsí
V
V
Schraven
B
B
Rolstad
B
B
Mustelin
T
T
Taskén
K
K
D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000502:physiology*; D021962:Membrane Microdomains / Q000502:physiology*; D008954:Models, Biological; D016853:Muromonab-CD3 / Q000494:pharmacology; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014162:Transfection; D014638:Vanadates / Q000494:pharmacology; D018909:src Homology Domains; D019061:src-Family Kinases
D000952:Antigens, Polyomavirus Transforming; D016853:Muromonab-CD3; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; C076715:pervanadate; D019000:Phosphotyrosine; D014638:Vanadates; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human