Essential role of the T cell-specific adapter protein in the activation of LCK in peripheral T cells.
T cell-specific adapter protein (TSAd) is a SRC-homology-2 (SH2) domain-containing intracellular signaling molecule that is required for T cell antigen receptor (TCR)-induced cytokine synthesis in T cells. How TSAd functions in TCR signal transduction is not clear. Previous work has suggested a nuclear role for this adapter. However, other evidence suggests that TSAd also functions in the cytoplasm. Using T cells from TSAd-deficient mice, we now show that the major role of TSAd in the cytoplasm is in activation of the LCK protein tyrosine kinase at the outset of TCR signal transduction. Consequently, TSAd regulates several downstream signaling events, including intracellular calcium mobilization and activation of the Ras-extracellular signal-regulated kinase signaling pathway. TSAd regulates LCK activity directly through physical interaction with LCK SH3 and SH2 domains. These studies reveal TSAd as a positive regulator of proximal TCR signal transduction and provide important new information on the mechanism of TCR-induced LCK activation.
Marti
Francesc
F
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Garcia
Gonzalo G
GG
Lapinski
Philip E
PE
MacGregor
Jennifer N
JN
King
Philip D
PD
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D011948:Receptors, Antigen, T-Cell; C402726:Sh2d2a protein, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)