title: Lck regulates the threshold of activation in primary T cells, while both Lck and Fyn contribute to the magnitude of the extracellular signal-related kinase response.
abstract: The src family kinases p56lck (Lck) and p59fyn (Fyn) are the most proximal signaling molecules to be activated downstream of the T-cell receptor. Using an inducible transgenic model, we can regulate the expression of Lck in primary T cells and ask how the signaling cascade and differentiation potential are affected by the absence or the presence of reduced levels of Lck. We show that in naïve T cells, Lck controls the threshold of activation by preferentially regulating multiple signaling pathways that result in the mobilization of Ca2+ through activation of phospholipase C-gamma and protein kinase C as well as activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway. Fyn is also able to stimulate the ERK/MAPK pathway in primary T cells but has little influence on the mobilization of Ca2+. Only Lck efficiently stimulates production of diacylglycerol and therefore RasGRP1 recruitment to the plasma membrane and phosphorylation of Shc, suggesting that Fyn activates ERK via a different upstream signaling route. Finally, we show that signals through Lck are essential for the development of T-cell-effector potential, particularly for effective cytokine transcription.
authors.affiliation: Molecular Immunology, MRC National Institute for Medical Research, The Ridgeway, London NW71AA, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Lovatt
authors.forename: Andrew
authors.initials: A
authors.lastname: Filby
authors.forename: Valentino
authors.initials: V
authors.lastname: Parravicini
authors.forename: Guy
authors.initials: G
authors.lastname: Werlen
authors.forename: Ed
authors.initials: E
authors.lastname: Palmer
authors.forename: Rose
authors.initials: R
authors.lastname: Zamoyska
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D020013:Calcium Signaling; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D051076:Proto-Oncogene Proteins c-fyn / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D015854:Up-Regulation; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C110810:LAT protein, human; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; C494957:FYN protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn; D051746:ZAP-70 Protein-Tyrosine Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D051966:Phospholipase C gamma