Constitutively active Lck kinase in T cells drives antigen receptor signal transduction.
T cell antigen receptor (TCR) and coreceptor ligation is thought to initiate signal transduction by inducing activation of the kinase Lck. Here we showed that catalytically active Lck was present in unstimulated naive T cells and thymocytes and was readily detectable in these cells in lymphoid organs. In naive T cells up to approximately 40% of total Lck was constitutively activated, part of which was also phosphorylated on the C-terminal inhibitory site. Formation of activated Lck was independent of TCR and coreceptors but required Lck catalytic activity and its maintenance relied on monitoring by the HSP90-CDC37 chaperone complex to avoid degradation. The amount of activated Lck did not change after TCR and coreceptor engagement; however it determined the extent of TCR-zeta phosphorylation. Our findings suggest a dynamic regulation of Lck activity that can be promptly utilized to initiate T cell activation and have implications for signaling by other immune receptors.
Nika
Konstantina
K
T Cell Signaling Laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
Soldani
Cristiana
C
Salek
Mogjiborahman
M
Paster
Wolfgang
W
Gray
Adrian
A
Etzensperger
Ruth
R
Fugger
Lars
L
Polzella
Paolo
P
Cerundolo
Vincenzo
V
Dushek
Omer
O
Höfer
Thomas
T
Viola
Antonella
A
Acuto
Oreste
O
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation / Q000276:immunology; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology* / Q000378:metabolism; D018613:Microscopy, Confocal; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
D011948:Receptors, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)