Abstract
The integrin LFA-1 (CD11a/CD18) plays a critical role in the interaction of T cells with antigen presenting cells (APCs) to promote lymphocyte differentiation and proliferation. This integrin can be present either in a closed or in an open active conformation and its activation upon T-cell receptor (TCR) stimulation is a critical step to allow interaction with APCs. In this study we demonstrate that the serine/threonine kinase Ndr2 is critically involved in the initiation of TCR-mediated LFA-1 activation (open conformation) in T cells. Ndr2 itself becomes activated upon TCR stimulation and phosphorylates the intracellular integrin binding partner Filamin A (FLNa) at serine 2152. This phosphorylation promotes the dissociation of FLNa from LFA-1, allowing for a subsequent association of Talin and Kindlin-3 which both stabilize the open conformation of LFA-1. Our data suggest that Ndr2 activation is a crucial step to initiate TCR-mediated LFA-1 activation in T cells.
Keywords:
Filamin A; Kindlin-3; LFA-1; Ndr2; T cells; TCR; Talin; inside-out signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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CD18 Antigens / immunology
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CD18 Antigens / metabolism
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Cells, Cultured
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Cytoskeletal Proteins / immunology
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Cytoskeletal Proteins / metabolism
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Filamins / genetics
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Filamins / immunology
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Filamins / metabolism*
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HEK293 Cells
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Healthy Volunteers
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Humans
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Jurkat Cells
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Lymphocyte Activation
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Lymphocyte Function-Associated Antigen-1 / immunology
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Lymphocyte Function-Associated Antigen-1 / metabolism*
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Membrane Proteins / immunology
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Mutation
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Neoplasm Proteins / immunology
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Neoplasm Proteins / metabolism
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Phosphorylation / immunology
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Primary Cell Culture
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / immunology
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Protein Serine-Threonine Kinases / metabolism*
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Proteins / genetics
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Proteins / metabolism*
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism*
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Serine / metabolism
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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Talin / immunology
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Talin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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CD18 Antigens
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Cytoskeletal Proteins
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FERMT3 protein, human
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FLNA protein, human
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Filamins
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FlnA protein, mouse
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Lymphocyte Function-Associated Antigen-1
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Membrane Proteins
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Ndr2 protein, mouse
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Neoplasm Proteins
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Proteins
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Receptors, Antigen, T-Cell
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Talin
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kindlin-3 protein, mouse
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Serine
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Protein Serine-Threonine Kinases
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STK38L protein, human