Activation of the Lck tyrosine kinase targets cell surface T cell antigen receptors for lysosomal degradation.
The mechanism by which TCR expression is regulated was explored by expressing a constitutively active form of the tyrosine kinase Lck (Lck505F) in T cells. Expression of Lck505F down-regulated TCR levels, an effect that was even more pronounced in CD45- T cells, in which the activity of this tyrosine kinase is further enhanced. Cells expressing Lck505F synthesized all TCR subunits, but lysosomal degradation of assembled receptors was enhanced. TCRs were rapidly internalized and degraded after removal of a tyrosine kinase inhibitor that had permitted cell surface expression. Finally, TCR levels on thymocytes were increased by an Lck inhibitor, and activation- but not phorbol ester-induced internalization of TCRs on Jurkat cells was prevented by inhibition or loss of Lck. These studies identify a regulated nonreceptor tyrosine kinase-mediated pathway for targeting cell surface receptors for lysosomal degradation.
D'Oro
U
U
Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1152, USA.
Vacchio
M S
MS
Weissman
A M
AM
Ashwell
J D
JD
D000818:Animals; D000937:Antigen-Antibody Reactions; D017252:CD3 Complex / Q000502:physiology; D015536:Down-Regulation; D015180:Electrophoresis, Gel, Two-Dimensional; D004705:Endocytosis; D004789:Enzyme Activation; D005434:Flow Cytometry; D017493:Leukocyte Common Antigens / Q000032:analysis; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D009924:Organ Culture Techniques; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D013950:Thymus Gland / Q000196:embryology / Q000378:metabolism
D017252:CD3 Complex; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D017493:Leukocyte Common Antigens