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Front Immunol. 2018 Dec 4;9:2852. doi: 10.3389/fimmu.2018.02852. eCollection 2018.

Filamin A Phosphorylation at Serine 2152 by the Serine/Threonine Kinase Ndr2 Controls TCR-Induced LFA-1 Activation in T Cells.

Author information

1
Institute of Molecular and Clinical Immunology, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-von-Guericke-University, Magdeburg, Germany.
2
Institute of Biology, Department of Genetics and Molecular Neurobiology, Otto-von-Guericke University, Magdeburg, Germany.
3
MD Anderson Cancer Center, University of Texas, Houston, TX, United States.
4
Department of Pharmacology, Yale School of Medicine, New Haven, CT, United States.
5
Protein Biochemistry Group, Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin, Germany.
6
Intravital Microscopy of Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig, Germany.
7
Department of Immune Control Helmholtz Center for Infection Research, Braunschweig, Germany.
8
Center for Behavioral Brain Sciences, Magdeburg, Germany.

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

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