Abstract
Ligation of the transmembrane protein T cell Ig and mucin domain (Tim)-1 can costimulate T cell activation. Agonistic Abs to Tim-1 are also capable of inducing T cell activation without additional stimuli. However, little is known about the biochemical mechanisms underlying T cell stimulation or costimulation through Tim-1. We show that a tyrosine in Tim-1 becomes phosphorylated in a lck-dependent manner, whereupon it can directly recruit p85 adaptor subunits of PI3K. This results in PI3K activation, which is required for Tim-1 function. We also provide genetic evidence that p85 expression is required for optimal Tim-1 function. Thus, we describe a pathway from Tim-1 tyrosine phosphorylation to the PI3K signaling pathway, which appears to be a major effector of Tim-1-mediated T cell activation.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigens, CD / metabolism
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Antigens, Differentiation, T-Lymphocyte / metabolism
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism*
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Hepatitis A Virus Cellular Receptor 1
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Humans
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Interleukin-2 / biosynthesis
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Jurkat Cells
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Lectins, C-Type
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Lymphocyte Activation / immunology*
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Membrane Glycoproteins / chemistry
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Knockout
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation
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Receptors, Virus / chemistry
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Receptors, Virus / metabolism*
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Signal Transduction / immunology*
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Transfection
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Tyrosine
Substances
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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CD69 antigen
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HAVCR1 protein, human
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Hepatitis A Virus Cellular Receptor 1
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Interleukin-2
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Lectins, C-Type
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Membrane Glycoproteins
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Receptors, Virus
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Tyrosine
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Phosphatidylinositol 3-Kinases